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Immune checkpoint blockade (ICB) is standard-of-care for patients with metastatic melanoma. It may re-invigorate T cells recognizing tumors, and several tumor antigens have been identified as potential targets. However, little is known about the dynamics of tumor antigen-specific T cells in the circulation, which might provide valuable information on ICB responses in a minimally invasive manner. Here, we investigated individual signatures composed of up to 167 different melanoma-associated epitope (MAE)-specific CD8+ T cells in the blood of stage IV melanoma patients before and during anti-PD-1 treatment, using a peptide-loaded multimer-based high-throughput approach. Additionally, checkpoint receptor expression patterns on T cell subsets and frequencies of myeloid-derived suppressor cells and regulatory T cells were quantified by flow cytometry. Regression analysis using the MAE-specific CD8+ T cell populations was applied to identify those that correlated with overall survival (OS). The abundance of MAE-specific CD8+ T cell populations, as well as their dynamics under therapy, varied between patients. Those with a dominant increase of these T cell populations during PD-1 ICB had a longer OS and progression-free survival than those with decreasing or balanced signatures. Patients with a dominantly increased MAE-specific CD8+ T cell signature also exhibited an increase in TIM-3+ and LAG-3+ T cells. From these results, we created a model predicting improved/reduced OS by combining data on dynamics of the three most informative MAE-specific CD8+ T cell populations. Our results provide insights into the dynamics of circulating MAE-specific CD8+ T cell populations during ICB, and should contribute to a better understanding of biomarkers of response and anti-cancer mechanisms.

Objectives 1) To detect functionally active antibodies(abs) to the angiotensin II type-1-receptor (AT1R) by a novel luminometric assay. 2) To assess their prevalence in systemic sclerosis (SSc), other collagen disorders, as well as in further chronic inflammatory disorders including autoimmune, toxic and chronic viral diseases. 3) To compare these abs with anti-AT1R antibodies by ELISA as well as with antibodies to endothelin-type-A receptors (ETA1) and to topoisomerase I (topo-I) with respect to their specificity and clinical relevance. Methods Sera from 98 SSc-patients, 110 patients with other chronic inflammatory rheumatic disorders, 97 patients with autoimmune liver diseases, 57 patients with toxic or chronic viral liver diseases and 36 healthy controls were analyzed. A luminometric bioassay was established with Huh-7-cells constitutively expressing the AT1R. Patients’ sera were also tested by commercially available ELISA for anti-AT1R, -ETA1- and by an in-house ELISA for anti–topo-I-abs. Results Fifty-two percent of the SSc-patients had functionally active anti-AT1R-abs with stimulatory (34%) or inhibitory capacity (18%). They were present also in up to 59% of patients with other rheumatic diseases but only 22% of healthy individuals (sensitivity 52%, specificity 53%). The functionally active antibodies detected by the luminometric assay did not correlate with anti-AT1R-, -ETA1- or -topo-I-abs measured by ELISA, but there was a strong correlation between anti-topo-I-, AT1R-, and -ETA1-ab reactivity measured by ELISA. Sensitivities of 55%, 28% and 47% and specificities of 66%, 87%, and 99% were calculated for these anti-AT1R-, -ETA1-, and anti-topo-I-abs, respectively. Functionally active abs did not correlate with disease severity or any organ manifestation. In contrast, abs to topo-I, AT1R, and ETA1 were associated with digital ulcers, pulmonary- and esophageal manifestation. Conclusions Functionally active anti-AT1R-abs can be detected in SSc-patients but do not correlate with disease activity. They are not specific for this disease and occur also in other autoimmune disorders and even viral or toxic diseases. Also, the vascular antibodies detected by ELISA are not SSc-specific but correlated with disease manifestations. In contrast, anti-topo-I-abs were confirmed to be a highly specific biomarker for both, diagnosis and organ manifestations of SSc.

We describe the results of two vaccinations of a self-experimenting healthy volunteer with SARS-CoV-2-derived peptides performed in March and April 2020, respectively. The first set of peptides contained eight peptides predicted to bind to the individual's HLA molecules. The second set consisted of ten peptides predicted to bind promiscuously to several HLA-DR allotypes. The vaccine formulation contained the new TLR 1/2 agonist XS15 and was administered as an emulsion in Montanide as a single subcutaneous injection. Peripheral blood mononuclear cells isolated from blood drawn before and after vaccinations were assessed using Interferon-γ ELISpot assays and intracellular cytokine staining. We detected vaccine-induced CD4 T cell responses against six out of 11 peptides predicted to bind to HLA-DR after 19 days, following vaccination, for one peptide already at day 12. We used these results to support the design of a T-cell-inducing vaccine for application in high-risk patients, with weakened lymphocyte performance. Meanwhile, an according vaccine, incorporating T cell epitopes predominant in convalescents, is undergoing clinical trial testing.

Einleitung: Bei der progressiven systemischen Sklerodermie (pSS), einer Autoimmunerkrankung mit Fibrose und Sklerose des Hautbindegewebes und Beteiligung innerer Organe, kommen verschiedene Autoantikörper (Aak) vor, wie z.B. Aak gegen TopoisomeraseI, Zentromere, RNA polymerase oder Fibrillarin.[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Rheumatologiekongress 2020, 48. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 34. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh)

The pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 infection is a severe complication of coronavirus disease 2019. Since impaired coagulation and thrombosis/endotheliitis are suspected pathomechanisms, we treated 2 patients with defibrotide, a profibrinolytic, antithrombotic, antiinflammatory oligonucleotide. Symptoms resolved during treatment. Moreover, coagulation parameters indicating hypofibrinolysis and complement activation normalized. The pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 infection is a severe complication of coronavirus disease 2019. Since impaired coagulation and thrombosis/endotheliitis are suspected pathomechanisms, 2 patients received defibrotide, a profibrinolytic, antithrombotic, antiinflammatory oligonucleotide. Symptoms resolved and hypofibrinolysis/complement activation normalized during treatment.

The diversity of human leukocyte antigens (HLAs) enables the presentation of immense repertoires of peptides, including tumor-associated antigens (TAAs). As a surrogate for immunopeptidome diversity, the HLA evolutionary divergence (HED) between individual HLA alleles might directly define the ability to present TAAs, a prerequisite for graft-versus-leukemia effects. We therefore analyzed the impact of HED on survival within a cohort of 171 acute myeloid leukemia (AML) patients after matched donor allogeneic hematopoietic stem cell transplantation (HSCT). Low HED (&lt, 25th percentile) of HLA class I (HEDclass I) or HLA-DR antigens (HEDDR) was a strong determinant for adverse overall survival after allogeneic HSCT (OS), with a hazard ratio for death of 1.9 (95% CI 1.2&ndash, 3.2) and 2.1 (95% CI 1.3&ndash, 3.4), respectively. Defining a cutoff value for the combined HEDtotal (HEDclass I and HEDDR), the respective 5 year OS was 29.7% and 64.9% in patients with low and high HEDtotal (p &lt, 0.001), respectively. Furthermore, the risk of relapse was significantly higher in patients with low HEDtotal (hazard ratio (HR) 2.2, 95% CI 1.3&ndash, 3.6) and event-free survival (EFS) was significantly reduced (5 year EFS 25.7% versus 54.4%, p &lt, 0.001). We here introduce HED, a fundamental metric of immunopeptidome diversity, as a novel prognostic factor for AML patients undergoing allogeneic HSCT.

Background and Aims: In primary biliary cholangitis (PBC), antibodies to a peptide of the muscarinic acetylcholine receptor 3 (mAChR3) have been described. Since the mAChR3 is expressed on cholangiocytes and mAChR3-signaling is involved in the pathogenesis of chronic inflammatory biliary diseases, we wanted to investigate whether anti-mAChR3-antibodies influence the function of the receptor and the proliferative response of cholangiocytes.Methods: Immunoglobulins were isolated by ammonium sulfate precipitation using sera from patients with PBC (n = 63) and with other chronic liver disorders (n = 150). All immunoglobulins were analyzed by a luminometric assay using Chinese hamster ovary (CHO) cells overexpressing the mAChR3 and cholangiocytes (TFK-1-cells) expressing the receptor constitutively. Cell proliferation was measured by 3H-thymidine assay. PBC patients were also analyzed in the follow-up.Results: Antibodies inhibiting the mAChR3 were found in 49 and 79% of PBC patients using CHO-cells or TFK-1-cells, respectively, but only in up to 26% of controls (p < 0.01). Stimulatory antibodies were hardly detected. Antibody reactivity only marginally changed during the course of the disease, independently of the choice of treatment (ursodeoxycholic acid, immunosuppressive therapy, or no medication). There was no correlation with laboratory, clinical or histological parameters, but the antibodies were more frequently found in PBC patients with a benign course (96%) than in patients with active disease progressing to late stages within 10 years (57%; p < 0.01). Proliferation of cells was not influenced by immunoglobulins from PBC-patients.Conclusion: Sera from patients with PBC contain inhibitory antibodies to the mAChR3 on cholangiocytes (TFK-1 cells) without influencing TFK-1-cell proliferation. These antibodies were predominantly observed in patients with non-progressing PBC.

This nonrandomized controlled trial assesses safety and vision outcomes of gene therapy for patients with achromatopsia., Key Points Question What are the safety and vision outcomes associated with gene therapy for achromatopsia? Findings In this nonrandomized controlled trial of 9 patients with confirmed CNGA3-linked achromatopsia, gene therapy applying an adeno-associated viral vector encoding CNGA3, was not associated with substantial safety concerns and was associated with improvements of vision in patients. Meaning This study provides clinical proof of concept for viral vector–mediated gene supplementation therapy of inherited day blindness caused by pathogenic variants in the cone photoreceptor-specific gene CNGA3., Importance Achromatopsia linked to variations in the CNGA3 gene is associated with day blindness, poor visual acuity, photophobia, and involuntary eye movements owing to lack of cone photoreceptor function. No treatment is currently available. Objective To assess safety and vision outcomes of supplemental gene therapy with adeno-associated virus (AAV) encoding CNGA3 (AAV8.CNGA3) in patients with CNGA3-linked achromatopsia. Design, Setting, and Participants This open-label, exploratory nonrandomized controlled trial tested safety and vision outcomes of gene therapy vector AAV8.CNGA3 administered by subretinal injection at a single center. Nine patients (3 per dose group) with a clinical diagnosis of achromatopsia and confirmed biallelic disease-linked variants in CNGA3 were enrolled between November 5, 2015, and September 22, 2016. Data analysis was performed from June 6, 2017, to March 12, 2018. Intervention Patients received a single unilateral injection of 1.0 × 1010, 5.0 × 1010, or 1.0 × 1011 total vector genomes of AAV8.CNGA3 and were followed up for a period of 12 months (November 11, 2015, to October 10, 2017). Main Outcomes and Measures Safety as the primary end point was assessed by clinical examination of ocular inflammation. Systemic safety was assessed by vital signs, routine clinical chemistry testing, and full and differential blood cell counts. Secondary outcomes were change in visual function from baseline in terms of spatial and temporal resolution and chromatic, luminance, and contrast sensitivity throughout a period of 12 months after treatment. Results Nine patients (mean [SD] age, 39.6 [11.9] years; age range, 24-59 years; 8 [89%] male) were included in the study. Baseline visual acuity letter score (approximate Snellen equivalent) ranged from 34 (20/200) to 49 (20/100), whereas baseline contrast sensitivity log scores ranged from 0.1 to 0.9. All 9 patients underwent surgery and subretinal injection of AAV8.CNGA3 without complications. No substantial safety problems were observed during the 12-month follow-up period. Despite the congenital deprivation of cone photoreceptor–mediated vision in achromatopsia, all 9 treated eyes demonstrated some level of improvement in secondary end points regarding cone function, including mean change in visual acuity of 2.9 letters (95% CI, 1.65-4.13; P = .006, 2-sided t test paired samples). Contrast sensitivity improved by a mean of 0.33 log (95% CI, 0.14-0.51 log; P = .003, 2-sided t test paired samples). Conclusions and Relevance Subretinal gene therapy with AAV8.CNGA3 was not associated with substantial safety problems and was associated with cone photoreceptor activation in adult patients, as reflected by visual acuity and contrast sensitivity gains. Trial Registration ClinicalTrials.gov Identifier: NCT02610582

Supplemental Figure 1. Cytokine production by B cells of healthy volunteers with ibrutinib treatment (n = 4). B cells of healthy volunteers were stimulated with CpG for 24 h and treated with DMSO (Control) or ibrutinib (10 μM). With a Legendplex assay, cytokine levels of IL-6, TNF-⍺, IFN-γ and IL-10 were determined in the culture supernatant. Bars represent mean. Error bars indicate SEM. * p

Background: We previously showed that the bacterial lipopeptide Pam3Cys-Ser-Ser, meanwhile established as a toll-like receptor (TLR) 1/2 ligand, acts as a strong adjuvant for the induction of virus specific CD8+ T cells in mice, when covalently coupled to a synthetic peptide.Case presentation: We now designed a new water-soluble synthetic Pam3Cys-derivative, named XS15 and characterized it in vitro by a TLR2 NF-κB luciferase reporter assay. Further, the capacity of XS15 to activate immune cells and stimulate peptide-specific CD8+ T and NK cells by 6-sulfo LacNAc+ monocytes was assessed by flow cytometry as well as cytokine induction using immunoassays. The induction of a functional immune response after vaccination of a volunteer with viral peptides was assessed by ELISpot assay and flow cytometry in peripheral blood cells and infiltrating cells at the vaccination site, as well as by immunohistochemistry and imaging.XS15 induced strong ex vivo CD8+ and TH1 CD4+ responses in a human volunteer upon a single injection of XS15 mixed to uncoupled peptides in a water-in-oil emulsion (Montanide™ ISA51 VG). A granuloma formed locally at the injection site containing highly activated functional CD4+ and CD8+ effector memory T cells. The total number of vaccine peptide-specific functional T cells was experimentally assessed and estimated to be 3.0 × 105 in the granuloma and 20.5 × 106 in peripheral blood.Conclusion: Thus, in one volunteer we show a granuloma forming by peptides combined with an efficient adjuvant in a water-in-oil-emulsion, inducing antigen specific T cells detectable in circulation and at the vaccination site, after one single vaccination only. The ex vivo T cell responses in peripheral blood were detectable for more than one year and could be strongly boosted by a second vaccination. Hence, XS15 is a promising adjuvant candidate for peptide vaccination, in particular for tumor peptide vaccines in a personalized setting.

Background In a recent study we had evidence that sulphite oxidase (SO) may be a relevant autoantigen in primary sclerosing cholangitis (PSC). Aim of the present study was, therefore, to analyse humoral and cellular immune-reactivity towards SO in these patients in more detail. Methods Sera from 53 patients with PSC (30 untreated and 23 treated with ursodeoxycholic acid [UDCA] at time of analysis), from 422 patients with different hepatic and non-hepatic disorders, and from 50 healthy individuals were tested by ELISA for antibodies against full-length-SO (SO-fl) and its three major domains expressed in E.coli (SO-I, SO-II, SO-III). For epitope-mapping, 29 overlapping peptides were used. Peripheral blood mononuclear cells (PBMC) were obtained from 33 PSC-patients and analysed for SO-induced proliferation, production of cytokines, and expression of the activation marker cluster of differentiation (CD) 69. Results 43% of the 30 untreated and 26% of the 23 treated PSC-patients had IgG anti-SO-antibodies predominantly reacting with SO-fl, SO-I and SO-II. Antibody-reactivity decreased after UDCA-treatment. Prevalence and reactivity of anti-SO-antibodies were significantly higher in PSC than in patients with other hepatic and non-hepatic disorders. Epitope mapping revealed no distinct immuno-dominant regions within SO. Incubation of PBMC from PSC-patients (but not from controls) with SO-antigens revealed an activation of B-cells and a T-helper cell type-2 reaction pattern (production of interleukin [IL]-13, IL-10). Conclusions PSC-patients show humoral and cellular immune response towards SO. Antibodies may be predominantly directed against conformational epitopes. SO enhances in vitro especially T-helper cell type-2 immune-reactions, which may be pro-fibrotic. SO is a detoxifying enzyme present also in bacteria; further studies analysing its role in the aetiology and pathogenesis in PSC may, therefore, be important. Electronic supplementary material The online version of this article (10.1186/s12876-018-0787-x) contains supplementary material, which is available to authorized users.

Made available in DSpace on 2020-12-11T01:57:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-10-29 Griffith University Gowonda HPC Cluster Queensland Cyber Infrastructure Foundation Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research. Griffith Univ, Sch Informat & Commun Technol, Gold Coast, Qld 4222, Australia Griffith Univ, Inst Glyc, Gold Coast, Qld 4222, Australia Univ Colorado, Dept Med Med Oncol, Anschutz Med Campus, Denver, CO USA Tanta Univ, Fac Sci, Bot Dept, Tanta, Egypt Friedrich Schiller Univ, Jena Univ Hosp, Inst Human Genet, Jena, Germany Univ Med Ctr Schleswig Holstein, Dept Radiat Oncol, Campus Kiel, Kiel, Germany ARS, USDA, Plum Isl Anim Dis Ctr, Greenport, NY 11944 USA Univ Jyvaskyla, Dept Biol & Environm Sci, Jyvaskyla, Finland Graz Univ Technol, Inst Environm Biotechnol, Graz, Austria CSIC, CNB, Natl Biotechnol Ctr, Dept Macromol Struct, Madrid, Spain Univ Hong Kong, Fac Dent, Oral & Maxillofacial Radiol Appl Oral Sci & Commu, Hong Kong, Peoples R China Univ Kansas, Div Entomol, Biodivers Inst, Lawrence, KS 66045 USA SUNY Albany, RNA Inst, Albany, NY 12222 USA Robert Koch Inst, Dept Methods Dev & Res Infrastruct, Berlin, Germany Martin Luther Univ Halle Wittenberg, Dept Surg & Conservat Pediat & Adolescent Med, Halle, Germany Indiana Univ Purdue Univ, IU Sch Informat & Comp, Dept BioHlth Informat, Indianapolis, IN 46202 USA Univ Reading, Sch Pharm Stem Cell Biol & Regenerat Med, Reading, Berks, England Dali Univ, Sch Engn, Dali City, Yunnan, Peoples R China Univ Hosp Munich LMU, Dept Psychiat & Psychotherapy, Munich, Germany Univ Tsukuba, Fac Life & Environm Sci, Ibaraki, Japan UniLaSalle, Aghyle, Beauvais, France Henry Ford Hlth Syst, Dept Immunol, Detroit, MI USA Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Emergency, Hangzhou 310016, Zhejiang, Peoples R China Ist Nazl Tumori Fdn Pascale IRCCS, Anesthesia & Pain Med, Naples, Italy NIH, Dept Transfus Med, Bethesda, MD USA Univ Glasgow, Inst Infect Immun & Inflammat, Glasgow, Lanark, Scotland Polish Acad Sci, Inst Human Genet, Poznan, Poland Univ Padua, Dept Surg Oncol & Gastroenterol DISCOG, Padua, Italy Eindhoven Univ Technol, Biomed Engn, Eindhoven, Netherlands Univ Strasbourg, IBMC, Strasbourg, France Heidelberg Univ, Dept Gen Visceral & Transplantat Surg, Heidelberg, Germany Univ Notre Dame, Psychol, Notre Dame, IN 46556 USA Harvard Med Sch, Massachusetts Gen Hosp, Radiol & Pathol, Boston, MA 02115 USA Auburn Univ, Dept Biol Sci, Auburn, AL 36849 USA KK Womens & Childrens Hosp, KK Res Ctr, Singapore, Singapore Univ Alabama, Educ Psychol, Tuscaloosa, AL USA UCL, Wellcome EPSRC Ctr Intervent & Surg Sci, London, England Maastricht Univ, Dept Nutr & Movement Sci, Maastricht, Netherlands Univ Arkansas Med Sci, Dept Radiat Oncol, Little Rock, AR 72205 USA Univ Padua, Dept Land Environm Agr & Forestry, Padua, Italy Univ Gothenburg, Dept Biol & Environm Sci, Gothenburg, Sweden Univ Newcastle, Prior Res Ctr Reprod Sci, Callaghan, NSW, Australia Univ Cyprus, Med Sch, Nicosia, Cyprus Shandong Agr Univ, Coll Plant Protect, Agr Big Data Res Ctr, Tai An, Shandong, Peoples R China NIMH, Neuropsychol Lab, Bldg 9, Bethesda, MD 20892 USA Univ Wisconsin, Wisconsin Inst Discovery, Madison, WI USA Univ Oxford, Struct Genom Consortium, Oxford, England Weihenstephan Triesdorf Univ Appl Sci, TUM Campus Straubing Biotechnol & Sustainabil, Bioinformat, Straubing, Germany Univ Michigan, Cardiovasc Res, Ann Arbor, MI 48109 USA Bombay Coll Pharm, Pharmaceut Chem, Mumbai, Maharashtra, India Inst Invest Biol Clemente Estable, Dev Neurobiol, Montevideo, Uruguay Gem Hosp & Res Ctr, Surg Gastroenterol & HPB Surg, Coimbatore, Tamil Nadu, India Kafr El Sheikh Univ, Fac Sci, Dept Zool, Kafr Al Sheikh, Egypt Med Univ Innsbruck, Dept Internal Med 4, Innsbruck, Austria Australian Natl Univ, Div Biomed Sci & Biochem, Canberra, ACT, Australia Univ Cattolica Sacro Cuore, Appl Technol Neuropsychol Lab, Milan, Italy Shandong Inst Parasit Dis, Med Entomol, Jinan, Shandong, Peoples R China Kumamoto Univ, Sch Pharm, Kumamoto, Japan Nagoya City Univ, Grad Sch Pharmaceut Sci, Dept Biol Chem, Nagoya, Aichi, Japan Univ Karachi, ICCBS, PCMD, Jamil ur Rahman Ctr Genome Res, Karachi 75270, Pakistan Labormed Zentrum Dr Risch, Vaduz, Liechtenstein Univ Otago, Med, Dunedin, New Zealand KK Womens & Childrens Hosp, Maternal Fetal Med, Singapore, Singapore Albert Ludwigs Univ Freiburg, GERN Tissue Replacement Regenerat & Neogenesis, Dept Orthoped & Trauma Surg, Med Ctr,Fac Med, Freiburg, Germany Heinrich Heine Univ, Inst Biochem & Mol Biol, Dusseldorf, Germany Natl Univ Ireland Galway, Surg, Galway, Ireland Univ Western Australia, Inst Agr, Perth, WA, Australia Univ Oxford, Nuffield Dept Med, Oxford, England SingHlth Polyclin, Punggol Polyclin, Singapore, Singapore Med Univ Innsbruck, Bioctr, Div Biol Chem, Innsbruck, Austria La Trobe Univ, La Trobe Inst Mol Sci, Biochem & Genet, Melbourne, Vic, Australia Univ Bordeaux, INRA, Bordeaux, France Agr & Agri Food Canada, Lethbridge Res & Dev Ctr, Lethbridge, AB, Canada St George Hosp, Trauma & Orthopaed, London, England Max Planck Inst Dev Biol, Dept Prot Evolut, Tubingen, Germany Med Univ Lublin, Dept Gynaecol 2, Lublin, Poland ICIT, ICSI Analyt Natl Res & Dev, Ramnicu Valcea, VL, Romania Univ KwaZulu Natal, Occupat Therapy, Westville Campus, Durban, South Africa Inst Canc Res, Joint Dept Phys, London, England Karolinska Inst, Dept Mol Med & Surg, Solna, Sweden Wenzhou Med Univ, Affiliated Hosp 2, Orthopaed, Wenzhou, Zhejiang, Peoples R China Univ Republica, Fac Ciencias, Ctr Invest Nucl, Lab Virol Mol, Montevideo, Uruguay Univ Gothenburg, Dept Med Biochem & Cell Biol, Gothenburg, Sweden Charite Med Univ Berlin, Pediat Cardiol, Berlin, Germany Bambino Gesu Pediat Hosp, Dept Neurosci & Neurorehabil, Neurorehabil Unit, Rome, Italy Indiana Univ Sch Med Northwest, Microbiol & Immunol, Gary, IN USA Univ Regensburg, Dept Behav & Mol Neurobiol, Regensburg, Germany Univ Queensland, Diamantina Inst, Brisbane, Qld, Australia Translat Res Inst, Brisbane, Qld, Australia Univ Hong Kong, Sch Biomed Sci, Hong Kong, Peoples R China St Jude Childrens Res Hosp, Pharmaceut Sci Dept, 332 N Lauderdale St, Memphis, TN 38105 USA Univ Durham, Mus, Durham, England Univ Ioannina, Med Sch, Dept Hyg & Epidemiol, Ioannina, Greece Tech Univ Munich, Sch Life Sci Weihenstephan, Maximus von Imhof Forum 3, D-85354 Freising Weihenstephan, Germany Univ Hosp Essen, Inst Transfus Med, Essen, Germany Virginia Commonwealth Univ, Comp Sci, Richmond, VA USA Univ Queensland, Inst Social Sci Res, Brisbane, Qld, Australia Univ Lyon, Ctr Int Rech Infectiol, Lyon, France Griffith Univ, Sch Allied Hlth Sci, Gold Coast, Qld, Australia Univ Melbourne, Dept Biochem & Mol Biol, Parkville, Vic, Australia Indiana Univ Purdue Univ, Dept Biohlth Informat, Sch Informat & Comp, Indianapolis, IN 46202 USA Philipps Univ Marburg, Inst Lung Res, Marburg, Germany Indiana Univ, Dept Biol, Bloomington, IN USA Univ Florida, Oral Biol, Gainesville, FL USA Univ Colorado, Dept Biochem, Boulder, CO 80309 USA Kyoto Univ, Ctr Promot Interdisciplinary Educ & Res, Kyoto, Japan Friedrich Loeffler Inst, Inst Virus Diagnost, Greifswald, Germany Univ Oxford, Dept Zool, Oxford, England Tech Univ Munich, Dept Bioinformat, Munich, Germany Univ Adelaide, Sch Anim & Vet Sci, Adelaide, SA, Australia Stanford Univ, Canc Biol, Palo Alto, CA 94304 USA Covenant Univ, Dept Elect & Informat Engn, Ota, Nigeria Heinrich Heine Univ, Inst Stem Cell Res & Regenerat Med, Dusseldorf, Germany Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada Albert Einstein Coll Med, Psychiat, New York, NY USA Akdeniz Univ, Med Biol & Genet, Antalya, Turkey NIMH, NIH, Bethesda, MD 20892 USA Med Univ Hosp, Internal Med 1, Tubingen, Germany NET ESolut, Netelabs, Mclean, VA USA Univ Southern Denmark, Inst Publ Hlth, Odense, Denmark John Innes Ctr, Mol Microbiol, Norwich, Norfolk, England Univ Adelaide, Waite Res Precinct, Australian Res Council, Ctr Excellence Plant Energy Biol, Adelaide, SA, Australia Univ Cambridge, Cambridge Inst Publ Hlth, Cambridge, England Univ Munster, Inst Biochem, Munster, Germany Australian Natl Univ, Natl Ctr Epidemiol & Populat Hlth RSPH, Canberra, ACT, Australia Stanford Univ, Neurobiol & Bioengn, Palo Alto, CA 94304 USA Univ Birmingham, Geog Earth & Environm Sci, Birmingham, W Midlands, England Murdoch Univ, Sch Vet & Life Sci, Perth, WA, Australia George Mason Univ, Ctr Climate Change Commun, Fairfax, VA 22030 USA Univ Adelaide, Sch Agr Food & Wine, Adelaide, SA, Australia Southern Med Univ, Sch Pharmaceut Sci, Guangzhou, Guangdong, Peoples R China Stanford Univ, Pathol, Palo Alto, CA 94304 USA Univ Bologna, Dept Expt Diagnost & Specialty Med, Bologna, Italy Univ Padua, Dept Gen Psychol, Padua, Italy Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Dept Bioinformat & Syst Biol, Key Lab Mol Biophys,Minist Educ, Wuhan, Hubei, Peoples R China Huazhong Univ Sci & Technol, Collaborat Innovat Ctr Biomed Engn, Wuhan, Hubei, Peoples R China Queensland Univ Technol, Sch Biomed Sci, Brisbane, Qld, Australia French Natl Ctr Sci Res, CNRS, Inst Biol Physicochim, Paris, France Univ Warwick, Dept Sociol, Coventry, W Midlands, England European Mol Biol Lab, Struct & Computat Biol, Heidelberg, Germany Univ Cincinnati, Coll Med, Canc Biol, Cincinnati, OH USA Univ Waterloo, Biol, Waterloo, ON, Canada Sorbonne Univ, CNRS, Integrat Biol Marine Models LBI2M, SBR, Roscoff, France Univ Manitoba, Biochem & Med Genet, Winnipeg, MB, Canada Max Planck Inst Solid State Res, Ultrafast Solid State Spect, Stuttgart, Germany Imperial Coll London, Sch Publ Hlth, Dept Infect Dis Epidemiol, London, England Mansoura Univ, Fac Vet Med, Biochem, Mansoura, Egypt Univ Virginia, Mol Physiol & Biol Phys, Charlottesville, VA USA China Univ Geosci, State Key Lab Biogeol & Environm Geol, Wuhan, Hubei, Peoples R China Clin Neurol & Psychiat Children & Youth, Child Psychiat, Belgrade, Serbia Ahvaz Jundishapur Univ Med Sci, Med Phys, Ahwaz, Iran Univ Iowa City, Coll Dent, Div Biostat & Computat Biol, Dept Prevent & Community Dent, Iowa City, IA USA Univ Iowa City, Coll Dent, Div Biostat & Computat Biol, Dept Biomed Engn, Iowa City, IA USA Univ Iowa City, Coll Dent, Div Biostat & Computat Biol, Dept Biostat, Iowa City, IA USA Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Tubingen, Germany Univ Ibadan, Dept Zool, Ibadan, Nigeria Kansas State Univ, Coll Vet Med, Manhattan, KS 66506 USA Univ Tasmania, Sch Technol Environm & Design, Discipline ICT, Hobart, Tas, Australia Childrens Mercy Hosp, Radiol, Kansas City, MO 64108 USA Stockholm Univ, Dept Phys, Stockholm, Sweden Oslo Univ Hosp, Inst Canc Genet & Informat, Oslo, Norway CSIRO, CSIRO Mfg, Pullenvale, Qld, Australia Johns Hopkins Sch Med, Urol, Baltimore, MD USA Univ South Africa, Life & Consumer Sci, Johannesburg, South Africa German Ctr Neurodegenerat Dis, Mech Induced Plast Brain, Bonn, Germany UCL, Inst Child Hlth, Dev Biol & Canc, London, England Simon Fraser Univ, Biomed Physiol & Kinesiol, Burnaby, BC, Canada Univ Manchester, Ctr Hlth Informat, Manchester, Lancs, England Univ Queensland, Sch Human Movement & Nutr Sci, Brisbane, Qld, Australia Albert Einstein Coll Med, Dept Med, New York, NY USA Georgetown Univ, Kennedy Inst Eth, Washington, DC 20057 USA Dermatol Skin & Canc Fdn, Carlton, Vic, Australia Med Coll Wisconsin, Div Hematol, Milwaukee, WI 53226 USA Med Coll Wisconsin, Div Oncol, Milwaukee, WI 53226 USA Med Coll Wisconsin, Div Infect Dis, Milwaukee, WI 53226 USA US FDA, Off Biotechnol Prod, Washington, DC 20204 USA Worcester Polytech Inst, Biomed Engn, Worcester, MA 01609 USA Univ Adelaide, Ctr Orthopaed & Trauma Res, Adelaide, SA, Australia Publ Hlth England, Natl Infect Serv, Bristol, Avon, England Univ Utrecht, Fac Sci Chem, Utrecht, Netherlands Natl Univ Ireland Galway, Pathol, Galway, Ireland Imperial Coll London, NHLI, London, England Danube Private Univ, Neurodegenerat, Krems Donau, Austria Imperial Coll London, Dept Chem, London, England Univ Helsinki, Finnish Museum Nat Hist, Helsinki, Finland Univ Sydney, Sch Life & Environm Sci, Sydney, NSW, Australia Univ Nottingham, Nottingham Digest Dis Ctr, Nottingham, England Univ Toulouse, CNRS, ITAV, USR3505, Toulouse, France ASCR, Inst Mol Genet, CZ Openscreen, Prague, Czech Republic Univ Turku, Inst Biomed, Turku, Finland York Univ, Sch Kinesiol & Hlth Sci, Toronto, ON, Canada Univ Calif Los Angeles, Stein Eye Inst, Ophthalmol, Los Angeles, CA USA Agr & Agri Food Canada, Ottawa Res & Dev Ctr, Ottawa, ON, Canada Helmholtz Zentrum Geesthacht, Mat Design & Characterizat, Geesthacht, Germany Unvers Genova, Internal Med, Genoa, Italy Otto von Guericke Univ, Intelligent Catheter INKS, Magdeburg, Germany Univ Toledo, Canc Biol, 2801 W Bancroft St,Hlth Sci Campus, Toledo, OH 43606 USA CRUK Beatson Inst, Struct Biol, Glasgow, Lanark, Scotland Leibniz Inst Primate Res, Med RNA Biol, Gottingen, Germany Univ Limoges, PEIRENE, EA 7500, Limoges, France Hainan Univ, Vet Med, Haikou, Hainan, Peoples R China UCL, Sch Pharam, Pharmacognosy & Phytotherapy, London, England Univ Oulu, Ecol & Genet Res Unit, Oulu, Finland Rhein Westfal TH Aachen, Inst Biochem & Mol Immunol, Aachen, Germany Univ Stuttgart, Inst Biochem & Tech Biochem, Stuttgart, Germany Peking Univ, Shenzhen Grad Sch, Sch Chem Biol & Biotechnol, Shenzhen, Peoples R China GIGA Res Inst, Med Oncol, Liege, Belgium CHULiege, Liege, Belgium Fdn Bruno Kessler, MPBA, Trento, Italy Hokkaido Univ, Grad Sch Med, Dept Neurobiol, Sapporo, Hokkaido, Japan Univ Leuven, Oncol, Leuven, Belgium Chalmers Univ Technol, Dept Math Sci, Gothenburg, Sweden Radboud Univ Nijmegen, Med Ctr, Dept Neurol, Nijmegen, Netherlands Univ South Australia, Sch Informat Technol & Math Sci, Adelaide, SA, Australia Bio Thera Solut Ltd, Dept Computat Biol, Guangzhou, Guangdong, Peoples R China Inst Invest Biosanitario Granada IBS, Otolaryngol, Granada, Spain Curtin Univ, Sch Mol & Life Sci, Perth, WA, Australia Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England Goethe Univ, Biol DCAL, Inst Pharm, Frankfurt, Germany Univ Lyon, ICBMS, UMR 5246, Lyon, France Inst Pasteur, Dept Genomes & Genet, Paris, France Univ Valencia, Pharmacol, Valencia, Spain Council Agr Res & Econ, Res Ctr Olive Citrus & Tree Fruit, Caserta, Italy Fraunhofer Inst Toxicol & Expt Med ITEM, Preclin Pharmacol & Vitro Toxicol, Hannover, Germany Univ Tasmania, Sch Med, Hobart, Tas, Australia Chugai Pharmaceut Co Ltd, Oncol Lifecycle Management Dept, Tokyo, Japan Univ Lubeck, Inst Neurobiol, Lubeck, Germany NYU, Sch Med, Neurol, New York, NY USA Univ Putra Malaysia, Dept Plant Pathol, Seri Kembangan, Malaysia Univ N Carolina, Biol, Chapel Hill, NC 27515 USA Univ Southampton, Fac Hlth Sci, Southampton, Hants, England Univ Highlands & Islands, Genet & Immunol Res Grp, Inverness, Scotland Heidelberg Univ, Inst Pathol, Heidelberg, Germany Indraprastha Inst Informat Technol, Dept Computat Biol, New Delhi, India Glasgow Caledonian Univ, Sch Hlth & Life Sci, Glasgow, Lanark, Scotland Liverpool John Moores Univ, Pharm & Biomol Sci, Liverpool, Merseyside, England Parkinsons Inst & Clin Ctr, Basic Res, Sunnyvale, CA USA Luxembourg Inst Sci & Technol, Environm Res & 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Kansas, Med Ctr, Family Med Res Div, Kansas City, KS 66103 USA ASTAR, Inst Mol & Cell Biol, Multimodal Mol Biol, Singapore, Singapore Univ Leuven, Dept Chron Dis Metab & Ageing, Leuven, Belgium Int Iberian Nanotechnol Lab INL, Braga, Portugal Anglia Ruskin, Comp & Technol, Cambridge, England Max Planck Inst Biochem, Struct Cell Biol, Planegg, Germany Univ Seville, Dept Comp Architecture & Technol, Seville, Spain Univ Colorado, EBIO, Boulder, CO 80309 USA Univ Manchester, Canc Sci, Manchester, Lancs, England Australian Natl Univ, Res Sch Populat Hlth, Canberra, ACT, Australia Singapore MIT Alliance Res & Technol, Biosyst, Singapore, Singapore Australian Catholic Univ, Mary MacKillop Inst Hlth Res, Musculoskeletal Hlth & Ageing Res Program, Melbourne, Vic, Australia Ruhr Univ Bochum, Gen Surg, St Josef Hosp, Bochum, Germany Northwest A&F Univ, Coll Life Sci, Xianyang, Shaanxi, Peoples R China Australian Natl Univ, Res Sch Biol, Div Plant Sci, Canberra, ACT, Australia Battelle Mem Inst, Clin & Nonclin Res, Columbus, OH USA Southern Methodist Univ, Biol Sci, Dallas, TX 75275 USA Teikyo Univ, Inst Med Mycol, Tokyo, Japan Tempus Labs, Bioinformat, Chicago, IL USA Hunan Univ, Coll Biol, Changsha, Hunan, Peoples R China Inst Cochin, Dept Infect Immun & Inflammat, Paris, France Royal Coll Surgeons Ireland, FutureNeuro Res Ctr Physiol & Med Phys, Dublin, Ireland Univ Jyvaskyla, Gerontol Res Ctr, Jyvaskyla, Finland Heidelberg Univ, Dept Anesthesiol, Heidelberg, Germany Penn State Univ, Biol, University Pk, PA 16802 USA Chinese Acad Sci, Inst Microbiol, State Key Lab Microbial Resources, Beijing, Peoples R China Univ Sci & Technol China, Sch Life Sci, Hefei, Anhui, Peoples R China Michigan State Univ, Anim Sci, E Lansing, MI 48824 USA SUNY Buffalo, Jacobs Sch Med & Biomed Sci, Dept Neurol, Buffalo Neuroimaging Anal Ctr, New York, NY USA Univ Rostock, Inst Biol Sci, Rostock, Germany South China Normal Univ, Sch Environm, Environm Res Inst, Guangzhou, Guangdong, Peoples R China Univ Bari, Dept Vet Med, Bari, Italy Radboud Univ Nijmegen, Med Ctr, Primary & Community Care, Nijmegen, Netherlands EcoHlth Alliance, New York, NY USA Mayo Clin, Cardiovasc Dept, Rochester, MN USA Med Univ Silesia, Sch Med Katowice, Dept Epidemiol, Katowice, Poland Univ Lleida, Anim Sci, Lleida, Spain Univ Florida, Coll Pharm, Pharmaceut Outcomes & Policy, Gainesville, FL USA Pacific Northwest Natl Lab, Earth & Biol Sci Directorate, Richland, WA 99352 USA Univ Edinburgh, Ctr Discovery Brain Sci, Edinburgh, Midlothian, Scotland Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA Univ Penn, Radiol, Philadelphia, PA 19104 USA Humanitas Univ & Res Hosp, Asthma & Allergy Unit, Biomed Sci Personalized Med, Rozzano, Italy Australian Natl Univ, Dept Quantum Sci, Canberra, ACT, Australia Carl von Ossietzky Univ Oldenburg, Ecol Genom, Oldenburg, Germany Int Med Univ, Paediat Dent & Orthodont, Kuala Lumpur, Malaysia Univ Ottawa, Sch Nursing, Ottawa, ON, Canada Maastricht Univ, Dept Educ Support, Maastricht, Netherlands Univ Manchester, Math, Manchester, Lancs, England Kings Coll London, Fac Life Sci & Med, Sch Populat Hlth Sci, London, England Queensland Univ Technol, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia Harbin Med Univ, Publ Hlth Sch, Epidemiol, Harbin, Heilongjiang, Peoples R China UiT Arctic Univ Norway, Dept Chem, Tromso, Norway Cornell Univ, Biol Stat & Computat Biol, Ithaca, NY USA East China Normal Univ, Sch Ecol & Environm Sci, Shanghai Key Lab Urban Ecol Proc & Ecorestorat, Shanghai, Peoples R China Johannes Gutenberg Univ Mainz, Fac Biol, Mainz, Germany Univ Massachusetts, Food Sci, Amherst, MA 01003 USA Max Planck Inst Terr Microbiol, Complex Adapt Traits Res Grp, Marburg, Germany NIHR Biomed Res Ctr Resp, Ctr Exercise & Rehabil Sci, Leicester, Leics, England Yale Univ, Dept Internal Med, Sect Endocrinol, New Haven, CT USA Sardar Patel Univ, Dept Biosci, Anand, Gujarat, India Univ Tokyo, Dept Appl Phys, Tokyo, Japan Univ Cologne, Vivo Res Facil ivRF, Cologne Excellence Cluster Cellular Stress Respon, Cologne, Germany Natl Open Univ Nigeria, Dept Publ Hlth Sci, Lagos, Nigeria Univ Hosp Regensburg, Dept Radiol, Regensburg, Germany Natl Univ Singapore, Geog, Singapore, Singapore Alfaisal Univ, Coll Med, Riyadh, Saudi Arabia Abdelmalek Essaadi Univ, Fac Sci & Techn Tangier, Biomed Genom & Oncogenet Res Lab, Tetouan, Morocco Tech Univ Munich, Fac Sport & Hlth Sci, Exercise Biol Grp, Munich, Germany Univ Santiago de Compostela, Dept Psicoloxia Social Basica & Metodoloxia, Galiza, Spain Griffith Univ, Signal Proc Lab, Brisbane, Qld, Australia Univ Ghent, Dept Neurol, Ghent, Belgium Ghent Univ Hosp, Ghent, Belgium Univ Ghent, Fac Vet Med, Merelbeke, Belgium Albert Einstein Coll Med, Inst Clin & Translat Res, New York, NY USA Anglia Ruskin Univ, Fac Med Sci, Cambridge, England Peking Univ, Coll Chem & Mol Engn, Beijing, Peoples R China Herlev & Gentofte Hosp, Dept Dermatol & Allergy, Hellerup, Denmark Lady Cilento Childrens 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Univ Adelaide, ARCPOH, Adelaide, SA, Australia Pelita Harapan Univ, Fac Med, Cardiol & Vasc Med, Tangerang, Indonesia Inst Mental Hlth, Res Div, Singapore, Singapore UCL, MRC Clin Trials Unit, London, England Univ Padua, Dept Philosophy Sociol Educ & Appl Psychol FISPPA, Padua, Italy Univ Lubeck, Dept Psychiat & Psychotherapy, Lubeck, Germany Dalian Univ Technol, Ctr Mol Med, Dalian, Liaoning, Peoples R China Tianjin United Family Healthcare, Reprod Med, Tianjin, Peoples R China Univ Autonoma Barcelona, Dept Engn Quim Biol & Ambiental, Barcelona, Spain Sao Paulo State Univ UNESP, Dept Anim Sci, Sao Paulo, Brazil Helmholtz Zentrum Munchen, Inst Computat Biol, Canc Syst Biol, Ingolstadter Land Str 1, D-85764 Munich, Germany Univ Tokyo, Dept Cardiovasc Med, Tokyo, Japan Sao Paulo State Univ, Vet Clin, Sao Paulo, Brazil Zhejiang Univ, Inst Biotechnol, Hangzhou, Zhejiang, Peoples R China Aarhus Univ, Dept Mol Biol & Genet, Aarhus, Denmark Univ Manchester, St Marys Hosp, Maternal & Fetal Hlth, Manchester, Lancs, England Univ New Mexico, Internal Med, Albuquerque, NM 87131 USA Mayo Clin, Div Biomed Stat & Informat, Jacksonville, FL 32224 USA King Saud Univ, Plant Prod, Riyadh, Saudi Arabia Polish Acad Sci, Inst Genet & Anim Breeding, Dept Mol Biol, Warsaw, Poland Queensland Univ Technol, Optometry & Vis Sci, Brisbane, Qld, Australia Univ Nottingham, Sch Life Sci, Nottingham, England Canc Council Queensland, Canc Res Ctr, Brisbane, Qld, Australia Umea Univ, Dept Chem, Umea, Sweden Publ Hlth England, Ctr Radiat Chem & Environm Hazards, Bristol, Avon, England Univ Campania L Vanvitelli, DISTABIF, Caserta, Italy Bartshealth, Obstet & Gyanecol, London, England Univ Clermont Auvergne, GReD Lab, Clermont Ferrand, France INRA Abeilles & Environm, Avignon, France Queensland Univ Technol, Sch Publ Hlth & Social Work, Brisbane, Qld, Australia Univ Penn, Psychiat, Philadelphia, PA 19104 USA Novosibirsk State Univ, Res Inst Physiol & Basic Med, Novosibirsk, Russia UCL, Dept Chem, London, England La Trobe Univ, Anim Plant & Soil Sci, Melbourne, Vic, Australia Univ Arizona, Epidemiol & Biostat, Tucson, AZ USA Univ Groningen, Univ Med Ctr Groningen, ERIBA, Groningen, Netherlands Univ Gothenburg, Inst Clin Sci, Dept Radiat Phys, Gothenburg, Sweden SUNY Upstate Med Univ, Biochem & Mol Biol, Syracuse, NY 13210 USA Fundacao Oswaldo Cruz, Ctr Pesquisas Goncalo Moniz, Salvador, Bahia, Brazil Inst Environm Sci & Res ESR, Food Water & Environm Microbiol, Christchurch, New Zealand Univ Otago, Food Sci, Dunedin, New Zealand Florida Atlantic Univ, Biomed Sci, Boca Raton, FL 33431 USA Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia Univ Hosp Wurzburg, Inst Clin Neurobiol, Wurzburg, Germany Inst Trop Med, Publ Hlth, Antwerp, Belgium Univ Thessaly, Sch Hlth Sci, Fac Med, Dept Rheumatol & Clin Immunol, Larisa, Greece Univ Basel, UZB Univ Ctr Dent Med, Dept Orthodont & Pediat Dent, Basel, Switzerland Sorbonne Univ, Museum Natl Hist Nat, Inst Systemat Evolut Biodiversite ISYEB, MNHN,CNRS,UMR 7205,EPHE, Paris, France CNRS, Inst Adv Biosci, Paris, France Univ Western Australia, Sch Mol Sci, Perth, WA, Australia Univ Ft Hare, Biochem & Microbiol, Alice, South Africa Univ Tubingen, Phys, Tubingen, Germany Griffith Univ, Sch Environm & Sci, Brisbane, Qld, Australia Philosoph Theol Hsch Vallendar, Stat & Standardised Methods, Vallendar, Germany Imperial Coll London, Life Sci, London, England Univ Adelaide, Adelaide Med Sch, Adelaide, SA, Australia Univ Nebraska Med Ctr, Dept Pharmacol & Expt Neurosci, Omaha, NE USA Technol Univ Dublin, FOCAS Res Inst, Dublin, Ireland INSERM, Natl Inst Hlth & Med Res, Canc Res Ctr Toulouse, Paris, France Univ Santiago de Compostela, Dept Bioloxia Func, Grp BRAINSHARK, Galiza, Spain Univ Nebraska, Biol, Kearney, NE USA Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona, Spain Univ Pisa, Chem & Ind Chem, Pisa, Italy Univ Manchester, Wellcome Trust Ctr Cell Matrix Res, Manchester, Lancs, England Univ Montpellier, CNRS, Inst Human Genet, Montpellier, France Czech Acad Sci, Inst Organ Chem & Biochem, Prague, Czech Republic CSIC, Natl Ctr Biotechnol CNB, Computat Syst Biol Grp, Madrid, Spain Natl Cheng Kung Univ, Dept Biochem & Mol Biol, Tainan, Taiwan Harvard Med Sch, Schepens Eye Res Inst, Ophthalmol, Boston, MA 02115 USA Lanzhou Univ, Hosp 2, Dept Gen Surg, Lanzhou, Gansu, Peoples R China Univ Technol Sydney, Sch Life Sci, Sydney, NSW, Australia JT Chen Clin, Gynecol, Tokyo, Japan Univ Western Australia, Sch Agr & Environm, Perth, WA, Australia Beijing Normal Univ, Fac Geog Sci, Beijing, Peoples R China Univ Missouri, Elect Engn & Comp Sci, Columbia, MO USA Vrije Univ Amsterdam Med Ctr, Amsterdam Publ Hlth Res Inst, Dept Publ & Occupat Hlth, Amsterdam, Netherlands Semmelweis Univ, Med Biochem, Budapest, Hungary Queen Elizabeth Hosp, Dept Clin Oncol, Hong Kong, Peoples R China Univ Pittsburgh, Chem, Pittsburgh, PA USA GB Pant Inst Post Grad Med Educ & Res, Neurol, New Delhi, India Univ Copenhagen, Vet & Anim Sci, Copenhagen, Denmark Univ Palermo, Biomed Dept Internal & Specialist Med DIBIMIS, Sect Endocrinol, Palermo, Italy UCL, NPP, London, England Univ Florida, Microbiol & Cell Sci, Gainesville, FL USA Univ Salford, Sch Hlth Sci, Manchester, Lancs, England Cardiff Univ, Inst Med Genet, Cardiff, S Glam, Wales INSERM, ICO Canc Ctr, Angers, France Univ Colombo, Fac Med, Microbiol, Colombo, Sri Lanka Beijing Univ Chinese Med, Sch Chinese Mat Med, Beijing, Peoples R China Univ Porto, Fac Pharm, Porto, Portugal Univ Nottingham, Div Primary Care, Nottingham, England Univ Illinois, Pharm Syst Outcomes & Policy, Chicago, IL USA Pontificia Univ Catolica Goias, Escola Ciencias Agr & Biol, Goiania, Go, Brazil China Japan Friendship Hosp, Dept Oncol, Beijing, Peoples R China Boston Univ, Chem, Boston, MA 02215 USA Amer Univ, Environm Sci, Washington, DC 20016 USA Carleton Univ, Neurosci, Ottawa, ON, Canada Univ Regina, Chem & Biochem, Regina, SK, Canada Univ Montreal, Microbiolgy, Montreal, PQ, Canada Univ Leicester, Dept Genet & Genome Biol, Leicester, Leics, England Univ Queensland, Sch Agr & Food Sci, Gatton, Qld, Australia CNRS, BIOM, Paris, France UCL, Hatter Cardiovasc Inst, London, England Flinders Univ S Australia, Sci & Engn, Adelaide, SA, Australia Univ Warwick, Engn, Coventry, W Midlands, England Katholieke Univ Leuven, Ctr Human Genet, Leuven, Belgium Fudan Univ, Dept Macromol Sci, Shanghai, Peoples R China Dokuz Eylul Univ, Biol Educ, Izmir, Turkey Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA Mondo Med, Pulm Dis, Borgomanero, Italy US Naval, Res Lab, Ctr Bio Mol Sci & Engn, Washington, DC USA Univ Oslo, Inst Basic Med Sci, Dept Nutr, Oslo, Norway Peking Univ, Dept Mech & Engn Sci, Beijing, Peoples R China Saarland Univ, Dept Pharm Pharmaceut & Med Chem, Saarbrucken, Germany INSERM, Natl Inst Hlth & Med Res, Skin Res Inst, Paris, France Shanghai Proton & Heavy Ion Ctr, Res & Dev, Shanghai, Peoples R China Univ Georgia, Epidemiol, Athens, GA 30602 USA Univ Freiburg, Med Ctr, Dept Plast & Hand Surg, Freiburg, Germany Sidra Med, Res, Doha, Qatar Rostock Univ, Med Ctr, Dept Oral Maxillofacial & Plast Surg, Rostock, Germany Harvard Med Sch, Brigham & Womens Hosp, Emergency Med, Boston, MA 02115 USA AgResearch, Forage Sci, Palmerston North, New Zealand Univ Calif Los Angeles, Med, Los Angeles, CA USA Arizona State Univ, Biodesign Inst, Virginia G Piper Ctr Personalized Diagnost, Tempe, AZ USA Sheffield Hallam Univ, Res Inst, Mat & Engn, Sheffield, S Yorkshire, England Aneurin Bevan Univ Healthboard, Resp Med, Newport, Shrops, England Univ Calif San Francisco, Neurol Surg, San Francisco, CA 94143 USA Univ Western Australia, UWA Dent Sch, Perth, WA, Australia Fordham Univ, Biol Sci, Bronx, NY 10458 USA Univ Helsinki, Inst Biotechnol, Helsinki, Finland Fujian Normal Univ, Coll Life Sci, Fuzhou, Fujian, Peoples R China Univ Fukui, Dept Frontier Fiber Technol & Sci, Fukui, Japan Univ Southampton, Fac Med, Clin & Expt Sci, Southampton, Hants, England Univ Urbino, Dept Biomol Sci, Urbino, Italy Osped San Luigi, Allergol Unit, Turin, Italy Muljibhai Patel Urol Hosp, Dept Urol, Nadiad, Gujarat, India Univ Granada, Stratig & Paleontol, Granada, Spain Massey Univ, Sch Vet Sci, Auckland, New Zealand CNR, High Performance Comp & Networking Inst, Naples, Italy Univ Childrens Hosp Zurich, Div Metab, Zurich, Switzerland Univ Childrens Hosp Zurich, Childrens Res Ctr, Zurich, Switzerland Univ Melbourne, Biochem & Mol Biol, Parkville, Vic, Australia Inst Pasteur, Leptospirosis Res & Expertise Unit, Noumea, New Caledonia Tsinghua Univ, Sch Life Sci, Beijing, Peoples R China Cheikh Anta Diop Univ UCAD, Sci Fac, Biol Anim Dept, Dakar, Senegal Providence Portland Med Ctr, Earle A Chiles Res Inst, Portland, OR USA Agr & Agri Food Canada, Lacombe Res & Dev Ctr, Lacombe, AB, Canada Alberta Innovates, Performance Management & Evaluat, Edmonton, AB, Canada Univ Malaga, CSIC, Inst Hortofruticultura Subtrop Mediterranea La Ma, IHSM,UMA, Malaga, Spain James Cook Univ, Coll Publ Hlth Med & Vet Sci, Cairns, Qld, Australia European Commiss, Joint Res Ctr, Ispra, Italy Univ Montpellier, Montpellier, France CSIRO, Floreat, WA, Australia Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Guangzhou, Guangdong, Peoples R China Vanderbilt Univ, Pharmacol, 221 Kirkland Hall, Nashville, TN 37235 USA RIKEN, KFU RIKEN Translat Genom Unit, Yokohama, Kanagawa, Japan Univ Tubingen, Neurobiol Vocal Commun, Tubingen, Germany Univ Colorado, UCCS Ctr Biofrontiers Inst, Colorado Springs, CO 80907 USA Fred Hutchinson Canc Ctr, Div Basic Sci, Seattle, WA USA Univ Geneva, Fac Med, Primary Care Unit, Geneva, Switzerland Ernst Moritz Arndt Univ Greifswald, Dept Mol Genet & Infect Biol, Greifswald, Germany East China Univ Sci & Technol, Dept Fine Chem, Shanghai, Peoples R China Ohio State Univ, Surg, Columbus, OH 43210 USA Oragenics, R&D, Tampa, FL USA Natl Environm Agcy, Environm Hlth Inst, Singapore, Singapore Friedrich Loeffler Inst, Inst Diagnost Virol, Greifswald, Germany Queen Elizabeth Hosp, Oncol, Woodville, SA, Australia USDA, Emerging Pests & Pathogens Res Unit, Ithaca, NY USA Univ Freiburg, Med Ctr, Dept Neurosurg, Epilepsy Ctr, Freiburg, Germany Univ Hong Kong, Fac Educ, Informat & Technol Studies, Hong Kong, Peoples R China Univ Tokyo, Grad Sch Agr & life Sci, Agr & Environm Biol, Tokyo, Japan Univ Pittsburgh, Dept Med, Pittsburgh Heart Lung & Blood Vasc Med Inst, Pittsburgh, PA USA Guys & St Thomas NHS Fdn Trust, Directorate Transplant Renal & Urol, London, England Univ Sarajevo, Clin Ctr, Clin Heart Blood Vessel & Rheumat Dis, Sarajevo, Bosnia & Herceg Univ Kent, Sch Math Stat & Actuarial Sci, Canterbury, Kent, England Tokyo Inst Technol, Dept Life Sci & Technol, Tokyo, Japan Univ Appl Sci Munich, Laser Ctr Dept Appl Sci & Mechatron, Munich, Germany CIC NanoGUNE, Nanodevices, San Sebastian, Spain Vrije Univ Amsterdam Med Ctr, Gynaecol, Amsterdam, Netherlands Cardiff Univ, Med Sch, Div Populat Med, Cardiff, S Glam, Wales Karolinska Inst, Dept Med, Solna, Sweden Natl Inst Genet, Ctr Informat Biol, Mishima, Shizuoka, Japan Murdoch Univ, Harry Perkins Inst Med Res, Perth, WA, Australia Univ Limerick, Phys Educ & Sport Sci, Limerick, Ireland Ruhr Univ Bochum, Campus Clin Gynecol, Univ Str, Bochum, Germany Southwest Med Univ, Sch Publ Hlth, Epidemiol & Biostat, Luzhou, Sichuan, Peoples R China Beijing Canc Hosp, Minist Educ Beijing, Key Lab Carcinogenesis & Translat Res, Ctr Mol Diagnost, Beijing, Peoples R China Chinese Acad Sci, Chengdu Inst Biol, Herpetol Dept, Chengdu, Sichuan, Peoples R China Key Lab Nano Biol Effects & Safety, Beijing, Peoples R China NIBR, PK Sci, Basel, Switzerland Daejeon St Marys Hosp, Pain Ctr, Daejeon, South Korea Univ Western Ontario, Sch Hlth Studies, London, ON, Canada Univ Aberdeen, Hlth Psychol Grp, Aberdeen, Scotland Univ Colorado, Anesthesiol, Anschutz Med Campus, Boulder, CO 80309 USA Univ Antwerp, UZA Antwerp Univ Hosp, Crit Care Med, Edegem, Belgium Aarhus Univ Hosp, Endocrinol, Aarhus, Denmark Univ Pretoria, Ctr Transport Dev, Ind & Syst Engn, Pretoria, South Africa Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA Pontificia Univ Catolica Goias, Med Pharmaceut & Biomed Sci Sch, Goiania, Go, Brazil Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden UCL, Clin Educ & Hlth Psychol, London, England KRIBB, Dev & Differentiat Res Ctr, Daejeon, South Korea Univ dArtois, Lab Barriere Hematoencephal, Arras, France AstraZeneca, IMED Biotech Unit, Discovery Sci, Quantitat Biol, Cambridge, England Pacific Northwest Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA Coventry Univ, Appl Maths Res Ctr, Stat Phys Grp, Coventry, W Midlands, England Wilton Ctr, Invista Performance Technol, Cleveland, England Thunen Inst Forest Genet, Genome Res, Grosshansdorf, Germany Lebanese Amer Univ, Nat Sci, Byblos, Lebanon Takeda, Evidence & Value Generat, Osaka, Japan King Abdullah Int Med Res Ctr, Stem Cell & Regenerat Med, Riyadh, Saudi Arabia Univ Bahri, Ind Pulp & Paper, Khartoum, Sudan Univ Queensland, Mater Med Res Inst, Mater Res Inst, Brisbane, Qld, Australia Colorado State Univ, NREL, Ft Collins, CO 80523 USA Rzeszow Univ Hosp, Ob Gyn Dept, Rzeszow, Poland Univ Leeds, Fac Biol Sci, Leeds, W Yorkshire, England Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA Carl von Ossietzky Univ Oldenburg, Neurosci, Oldenburg, Germany UNSW, St George & Sutherland Clin Sch, Microbiome Res Ctr, Sydney, NSW, Australia NYU, Sch Med, Dept Biochem, New York, NY 10016 USA NYU, Sch Med, Dept Mol Pharmacol, New York, NY USA Univ Mississippi, Med Ctr, Med Infect Dis, Jackson, MS 39216 USA Tampere Univ, Fac Social Sci Psychol, Tampere, Finland Univ Cyprus, Dept Biol Sci, Nicosia, Cyprus Goethe Univ, Inst Med Microbiol & Infect Control, Frankfurt, Germany Charite Med Univ Berlin, Inst Radiol, Berlin, Germany Univ Cologne, Univ Hosp Cologne, Internal Med 1, Cologne, Germany Univ Calif Los Angeles, Sch Dent, Sect Periodont, Los Angeles, CA 90024 USA Aalborg Univ Hosp, Dept Clin Biochem, Aalborg, Denmark Manipal Acad Higher Educ, Pharm Practice, Manipal, Karnataka, India Univ Tokyo, Inst Med Sci, Dept Radiol, Tokyo, Japan Cukurova Univ, Family Med, Fac Med, Adana, Turkey Catholic Univ Korea, Coll Med, Dept Humanities & Social Med, Seoul, South Korea Univ Ghent, Food Technol Safety & Hlth, Ghent, Belgium UNSW Sydney, Sch Biol Earth & Environm Sci BEES, Sydney, NSW, Australia St Vincent Shoulder & Sports Clin, Res Unit, Vienna, Austria Cornell Univ, Biomed Engn, Ithaca, NY USA Leibniz Inst Plant Genet & Crop Plant Res IPK, Res Grp Bioinformat & Informat Technol, Gatersleben, Germany Univ Europea Madrid, Sch Doctoral Studies, Madrid, Spain CSIRO Mfg, Biomed Mfg, Melbourne, Vic, Australia Depaul Univ, Biol Sci, Chicago, IL 60604 USA Konkuk Univ, Dept Anim Sci & Technol, Seoul, South Korea Chang Gung Univ, Grad Inst Med Mechatron, Taoyuan, Taiwan Korea Univ, 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Biochem & Mol Biol, 1430 Tulane Ave, New Orleans, LA 70112 USA NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA NIH, NCBI, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA LOreal Res & Innovat, Aulnay Sous Bois, France Lund Univ, Dept Psychol, Malmo, Sweden Catholic Univ Louvain, Inst Rech Expt & Clin, Brussels, Belgium Georgia State Univ, Neurosci Inst, Atlanta, GA 30303 USA Univ Melbourne, Ophthalmol, Surg, Parkville, Vic, Australia Univ Western Australia, Ctr Ophthalmol & Visual Sci, Perth, WA, Australia Iran Univ Med Sci, Med Phys, Fac Med, Tehran, Iran Salk Inst Biol Studies, Cellular Neurobiol, La Jolla, CA USA Imperial Coll London, Fibrosis Res Grp, London, England Univ Texas MD Anderson Canc Ctr, Genitourinary Med Oncol, Houston, TX 77030 USA Univ Liege, GIGA Neurosci, Liege, Belgium Univ Crete, Sch Med, Urol, Iraklion, Greece Flinders Univ S Australia, Flinders Med Ctr, Dept Clin Pharmacol, Adelaide, SA, Australia Max Planck Inst Immunobiol & Epigenet, Bioinformat, Breisgau, Germany Cardiff Univ, Sch Psychol, Cardiff, S Glam, Wales Imperial Coll London, Chem Engn, London, England Lund Univ, Skane Univ Hosp, Clin Sci, Malmo, Sweden Sahlgrens Acad, Inst Clin Sci, Dept Mol & Clin Med, Gothenburg, Sweden Univ Cent Lancashire, Sch Pharm & Biomed Sci, Preston, Lancs, England Hosp Univ Doctor Peset, Psychiat & Clin Psychol, Valencia, Spain Ctr Biol Mol Severo Ochoa, Genome Dynam & Funct, Madrid, Spain Unvivers Hosp Lille, Dept Intens Care, Lille, France Kansai Med Univ, Surg, Osaka, Japan Univ Toulouse, Inst Natl Polytech Toulouse, Ecole Natl Super Agron Toulouse, Lab Genom & Biotechnol Fruit, Toulouse, France UiT Arctic Univ Norway, Inst Psychol, Tromsto, Norway Queens Univ, Ctr Publ Hlth, Belfast, Antrim, North Ireland Univ Manchester, Ctr Primary Care & Hlth Serv Res, Manchester, Lancs, England Griffith Univ, Menzies Hlth Inst, Gold Coast, Qld, Australia Anglia Ruskin Univ, FHSCE, Cambridge, England Univ Lleida, Dept Expt Med, Lleida, Spain NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA Albany Med Coll, Immunol & Microbial Dis, Albany, NY 12208 USA Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia Univ Kent, Sch Biosci, Canterbury, Kent, England Univ Bourgogne Franche Comte, INSERM, LNC, UMR 1231, Besancon, France Ritsumeikan Univ, Coll Life Sci, Dept Biotechnol, Shiga, Japan Kent State Univ, Biol Sci, Kent, OH 44242 USA Natl Inst Infect Dis, Dept Safety Res Blood & Biol Prod, Tokyo, Japan European Inst Marine Studies, Lab Microbiol Extreme Environm, Plouzane, France Univ Iowa, Dept Pharmacol, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USA Natl Univ Singapore, Biol Sci, Singapore, Singapore Conservatoire Natl Arts & Metiers, Lab GBA, EA4627, Paris, France Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA Lomonosov Moscow State Univ, Belozersky Inst Physicochem Biol, Moscow, Russia Jikei Univ, Sch Med, Dept Mol Biol, Tokyo, Japan Univ South Wales, Genom & Computat Biol, Treforest, Wales Duke Univ, Med Ctr, Obstet & Gynecol, Durham, NC USA Univ Technol Sydney, Climate Change Cluster, Sydney, NSW, Australia Nagoya Univ, Grad Sch Med, Dept Radiol, Nagoya, Aichi, Japan Western Sydney Univ, Sch Sci & Hlth, Sydney, NSW, Australia TEI Epirus, Dept Speech & Language Therapy, Ioannina, Greece Indiana Univ Purdue Univ, Orthopaed Surg, Indianapolis, IN 46202 USA Oniris, Vet Pathol, Nantes, France Royal Vet Coll, Pathobiol & Populat Sci, Hatfield, Herts, England Univ Ghent, Lab Pharmaceut Biotechnol, Ghent, Belgium Norwegian Inst Nat Res, Terr Ecol, Trondheim, Norway Univ Calif Merced, Mol & Cell Biol, Merced, CA USA Univ Dublin, Trinity Coll Dublin, Sch Engn, Ctr Transport Res, Dublin, Ireland Lund Univ, Inst Clin Sci, Nephrol, Malmo, Sweden Univ Birmingham, Mech Engn, Birmingham, W Midlands, England Lund Univ, Inst Clin Sci, OB GYN, Lund, Sweden Fdn Jimenez Diaz Hosp, Nephrol & Hypertens, Madrid, Spain Queensland Univ Technol, Sch Chem Phys & Mech Engn, Brisbane, Qld, Australia Otto von Guericke Univ, Psychol, Magdeburg, Germany Univ Med Ctr Gottingen, Dept Expt Neurodegenerat, Gottingen, Germany Harvard Med Sch, Spaulding Rehabil Hosp, Phys Med & Rehabil, Boston, MA 02115 USA Quadram Inst Biosci, Sci Operat, Norwich, Norfolk, England Ostbayer Tech Hsch Regensburg OTH Regensburg, Regensburg Med Image Comp ReMIC, Regensburg, Germany Deakin Univ, Fac Arts & Educ, Melbourne, Vic, Australia Univ Warwick, Warwick Med Sch, Coventry, W Midlands, England INSERM, Natl Inst Hlth & Med Res, Biochem & Mol Biol, Paris, France Univ Liege, Tax Inst, Liege, Belgium Univ Leeds, Sch Mol & Cellular Biol, Leeds, W Yorkshire, England IRCCS Ist Giannina Gaslini, UOC Genet Med, Genoa, Italy Res Diets Inc, Sci, New Brunswick, NJ USA Univ Perugia, Dept Phys & Geol, Perugia, Italy Walter Reed Natl Mil Med Ctr, Cellular Immunol, Bethesda, MD USA Univ Fed Santa Catarina, Biol Sci Ctr, Microbiol Immunol & Parasitol Dept, Florianopolis, SC, Brazil Univ Edinburgh, Royal Infirm, Ctr Liver & Digest Disorders, Edinburgh, Midlothian, Scotland Orion Pharma, Crit Care Proprietary Prod Div, Espoo, Finland MIT, Dept Civil & Environm Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA Univ Turin, Dept Vet Sci, Turin, Italy Univ G dAnnunzio, Dept Psychol Hlth & Territorial Sci, Chieti, Italy NYU, Sch Med, OB GYN, New York, NY USA Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland Univ Turku, Dept Biol, Turku, Finland Tech Univ Berlin, Bioanalyt, Berlin, Germany Univ Goettingen, Inst Phys Biophys 3, Gottingen, Germany Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Translat Res Adv Therapeut & Innovat Oncol TRACTI, Houston, TX 77030 USA Univ Liege, Life Sci, Liege, Belgium Tarbiat Modares Univ, Fac Med Sci, Dept Toxicol, Tehran, Iran ARS, USDA, Stoneville, MS USA Univ Regensburg, RCI Regensburg Ctr Intervent Immunol, Regensburg, Germany Univ Nottingham, Sch Psychol, Nottingham, England NIH, Pathol Lab, Bethesda, MD 20892 USA Univ Carlos III Madrid, Elect Engn, Madrid, Spain Inst Med Mol, Chem Biol, Lisbon, Portugal Univ Costa Rica, CIET, San Jose, Costa Rica Univ Stavanger, Fac Hlth Sci, Stavanger, Norway Erasmus MC, Urol, Rotterdam, Netherlands Univ Edinburgh, Sch Biol Sci, Edinburgh, Midlothian, Scotland German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Inst Bioinformat & Syst Biol IBIS, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany Leiden Univ, Huygens Kamerlingh Onnes Lab, Leiden, Netherlands Univ Vienna, Nutr Sci, Vienna, Austria Kolling Inst Med Res, Med, St Leonards, NSW, Australia Johns Hopkins Sch Med, Biol Chem, Baltimore, MD USA Univ Montreal, Med Nutr & Microbiome Lab, Montreal, PQ, Canada GlaxoSmithKline, Cell & Gene Therapy, Stevenage, Herts, England Univ Trieste, Life Sci, Trieste, Italy Rhein Westfal TH Aachen, Dept Radiol, Aachen, Germany Univ Duisburg Essen, Univ Hosp Essen, West German Canc Ctr, Dept Med Oncol, Essen, Germany Med Univ Vienna, Obstet & Gynecol, Vienna, Austria FHI 360, Social & Behav Hlth Sci Div, Washington, DC USA KU Leuven VIB, Switch Lab, Leuven, Belgium Bielefeld Univ, Fac Technol, Bielefeld, Germany Capital Med Univ, Beijing Shijitan Hosp, Dept Clin Nutr, Dept Gastrointestinal Surg, Beijing, Peoples R China Meiji Univ, Dept Agr Chem, Kawasaki, Japan Yonsei Univ, Coll Med, Microbiol, Seoul, South Korea Johnson & Johnson EAME, Maidenhead, Berks, England Penn State Coll Med, Pediat, Hershey, PA USA Univ N Carolina, Dept Social Med, Chapel Hill, NC 27515 USA Univ Western Australia, ARC CoE Plant Energy Biol, Perth, WA, Australia Wageningen Univ, Div Human Nutr & Hlth, Wageningen, Netherlands Kings Coll London, Dept Neuroimaging, London, England Univ Murcia, Biochem & Mol Biol, Murcia, Spain Old Dominion Univ, Dept Biol Sci, Norfolk, VA 23529 USA Monash Univ, Biochem & Mol Biol, Melbourne, Vic, Australia Chinese Acad Sci, Inst Genet & Dev Biol, Beijing, Peoples R China Univ Pittsburgh, Pharmacol & Chem Biol, Pittsburgh, PA USA Univ Lausanne, Ctr Integrat Genom, Lausanne, Switzerland Univ Queensland, Sch Pharm, Brisbane, Qld, Australia Leibniz Inst Plant Genet & Crop Plant Res IPK Gat, Genebank, Gatersleben, Germany Piramal Imaging, Res & Dev, Berlin, Germany Univ Leeds, Civil Engn, Leeds, W Yorkshire, England Univ Missouri, Chem & Biochem, St Louis, MO 63121 USA US Geol Survey, Coastal & Marine Geol Program, Pacific Coastal & Marine Sci Ctr, Santa Cruz, CA USA Ajinomoto Genet Res Inst, Moscow, Russia Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, Dept Plant Biotechnol, Krakow, Poland Univ Puerto Rico, Engn Sci & Mat, Mayaguez, PR USA Univ Regina, Dept Chem & Biochem, Regina, SK, Canada Argonne Natl Lab, Ctr Nanoscale Mat, 9700 S Cass Ave, Argonne, IL 60439 USA Univ Sunshine Coast, Sunshine Coast Mind & Neurosci Thompson Inst, Sippy Downs, Qld, Australia Chinese Peoples Liberat Army Gen Hosp, Dept Gastroenterol & Hepatol, Beijing, Peoples R China Griffith Univ, Griffith Ctr Social & 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Maximilians Univ Munchen, Phys Chem, NanoBioSci, Munich, Germany Bandung Inst Technol, Sch Pharm, Med Chem, Bandung, Indonesia Univ Luxembourg, Life Sci Res Unit, Luxembourg, Luxembourg Lund Univ, Skane Univ Hosp, Dept Gastroenterol, Malmo, Sweden Millennium Hlth, Translat Genet, San Diego, CA USA Aristotle Univ Thessaloniki, Med Dept 2, Clin Res & Evidence Based Med Unit, Thessaloniki, Greece Jan Kochanowski Univ Humanities & Sci, Piotrkow Trybunalski Branch, Dept Psychol, Kielce, Poland McMaster Univ, Engn Phys, Hamilton, ON, Canada Marche Polytech Univ, Dept Agr Food & Environm Sci, Ancona, Italy Kuwait Univ, Fac Med, Microbiol, Kuwait, Kuwait Fujita Hlth Univ, Dept Breast Surg, Toyoake, Aich, Japan North West Reg Spinal Injuries Ctr, Spinal Injuries Ctr, Southport, Merseyside, England Luxembourg Inst Hlth, Competence Ctr Methodol & Stat, Luxembourg, Luxembourg Nestle Inst Hlth Sci SA, Metab Hlth, Ecublens, Vaud, Switzerland Ctr Inflammat Res VIB, Ghent, Belgium Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium Univ Lisbon, Inst Educ, Curriculo Formacao Prof & Tecnol, Lisbon, Portugal Univ Edinburgh, Ctr Inflammat Res, Edinburgh, Midlothian, Scotland Univ Melbourne, Sch BioSci, Parkville, Vic, Australia Northumbria Univ, Comp & Informat Sci, Newcastle Upon Tyne, Tyne & Wear, England Univ Valencia, Endocrinol, Valencia, Spain INRS, Inst Armand Frappier, Laval, PQ, Canada Univ Laval, INAF, Sch Nutr, Quebec City, PQ, Canada Univ Konstanz, Dept Biol, Constance, Germany Univ Cote dAzur, LAMHESS, Nice, France Scion, Syst Ecol, Christchurch, New Zealand CUNY, Grad Sch Publ Hlth & Hlth Policy, Epidemiol & Biostat, New York, NY 10021 USA Univ Queensland, Sch Dent, Brisbane, Qld, Australia George Inst Global Hlth, Renal & Metab Div, Sydney, NSW, Australia Wuhan Univ, Coll Chem & Mol Sci, Wuhan, Hubei, Peoples R China Griffith Univ, Sch Environm & Sci, Gold Coast, Qld, Australia Univ Minnesota, Radiat Oncol, Minneapolis, MN USA Goethe Univ, Fac Med, Frankfurt, Germany 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Tradit Chinese Med, Inst Interdisciplinary Med Sci, Shanghai, Peoples R China McMaster Univ, Biol, Hamilton, ON, Canada Univ S Florida, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL USA Hacettepe Univ, Inst Canc, Med Oncol, Ankara, Turkey City Univ Hong Kong, Dept Elect Engn, Hong Kong, Peoples R China Natl Taiwan Univ, Dept Entomol, Taipei, Taiwan Chinese Acad Agr Sci, Inst Environm & Sustainable Dev Agr, Ecol Secur, Beijing, Peoples R China Florida State Univ, Inst Mol Biophys, Chem & Biochem, Tallahassee, FL USA Peking Univ, Shenzhen Grad Sch, State Key Lab Chem Oncogen, Lab Computat Chem & Drug Design, Shenzhen, Peoples R China Univ Helsinki, Fac Pharm, Div Pharmaceut Chem & Technol, Drug Res Program, Helsinki, Finland Tohoku Univ, Microbial Biotechnol, Sendai, Miyagi, Japan Tianjin Med Univ, Sch Basical Med Sci, Dept Pharmacol, Tianjin, Peoples R China Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA Natl Hlth Res Inst, Inst Mol & Genom Med, Zhunan, Taiwan Univ Oxford, Physiol Anat & Genet, Oxford, England George Washington Univ, Phys, Washington, DC USA Univ Nebraska, Sch Biol Sci, Lincoln, NE USA Toronto Gen Hosp, Res Inst, Dept Lab Med & Pathobiol, Toronto, ON, Canada Univ Texas Dallas, Biol Sci, Richardson, TX 75083 USA NYU, Dept Chem, New York, NY USA Shandong Univ, Sch Math & Stat, Jinan, Shandong, Peoples R China Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Hefei, Anhui, Peoples R China Purdue Univ, Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA NIBSC, Adv Therapies, Ridge, Herts, England Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Pulm & Crit Care Med, Shanghai, Peoples R China Charite Med Univ Berlin, Dermatol & Allergy, Berlin, Germany Univ Hosp St Etienne, Hematol, St Etienne, France Inland Norway Univ Appl Sci, Inst Biotechnol, Elverum, Norway Univ Jordan, Pediat, Amman, Jordan Inst Pasteur, Mol Mycol Unit, Paris, France Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci, Med Res Council Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales Zurich Univ Appl Sci, Social Work, Zurich, Switzerland Jawaharlal Nehru Univ, Sch Life Sci, New Delhi, India Univ Burgundy Franche Comte, LE2I, Dijon, France Univ Roehampton, Life Sci, London, England Ghent Univ Hosp, Gen & HPB Surg, Ghent, Belgium Univ Wurzburg, Insect Fungus Symbiosis Lab, Wurzburg, Germany Radboud Univ Nijmegen, Behav Sci Inst, Nijmegen, Netherlands Fraunhofer WKI, Applicat Ctr HOFZET, Hannover, Germany UCL, Struct & Mol Biol, London, England Univ Amsterdam, Dev Psychol, Amsterdam, Netherlands Aalborg Univ, Hlth Sci & Technol, CNAP, SMI, Aalborg, Denmark VA Pittsburgh Healthcare Syst, Ctr Hlth Equity Res & Promot, Pittsburgh, PA USA Cedars Sinai Med Ctr, Neurosurg, Los Angeles, CA 90048 USA Sun Yat Sen Univ, Sch Data & Comp Sci, Guangzhou, Guangdong, Peoples R China Dezhou Univ, Shandong Prov Key Lab Biophys, Guangzhou, Guangdong, Peoples R China Maison Teledetection, Inst Rech Dev, UMR Espace DEv, Montpellier, France Xiamen Univ, Sch Life Sci, Xiamen, Fujian, Peoples R China Nanjing Univ, Sch Med, Jinling Hosp, Natl Clin Res Ctr Kidney Dis,Dept Med Imaging, Nanjing, Jiangsu, Peoples R China Univ Kent, Sch Social Policy Sociol & Social Res, Canterbury, Kent, England Univ Fed Minas Gerais, Infect Dis & Trop Med, Belo Horizonte, MG, Brazil Univ Minho, Sch Med, Life & Hlth Sci Res Inst ICVS, Braga, Portugal Univ Montreal, Biochim & Med Mol, Montreal, PQ, Canada Johns Hopkins Bloomberg Sch Publ Hlth, Epidemiol, Baltimore, MD USA Max Planck Inst Biol Ageing, Metab & Genet Regulat Ageing, Cologne, Germany Univ Swaziland, Hlth Sci, Kwaluseni, Eswatini Queensland Univ Technol, Inst Future Environm, Brisbane, Qld, Australia Ctr Sci Monaco, Dept Biol Med, Monaco, Monaco HELIOS Hosp, Urol, Bad Saarow Pieskow, Germany Tech Univ Carolo Wilhelmina Braunschweig, Inst Microbiol, Braunschweig, Germany Univ Barcelona, Barcelona Ctr Maternal Fetal & Neonatal Med, Fetal i D Fetal Med Res Ctr, IDIBAPS BCNatal,Hosp Clin, Barcelona, Spain Univ Barcelona, Hosp St Joan de Deu, Barcelona, Spain Friedrich Loeffler Inst, Inst Bacterial Infect & Zoonoses, Jena, Germany Charite Med Univ Berlin, Neurol, Berlin, Germany Dublin City Univ, Natl Inst Cellular Biotechnol, Mol Therapeut Canc Ireland, Dublin, Ireland Schoen Clin Roseneck, Prien Am Chiemsee, Germany Univ Med Ctr Hamburg Eppendorf, Inst Sex Res & Forens Psychiat, Hamburg, Germany Nankai Univ, Sch Math Sci, Tianjin, Peoples R China Nankai Univ, LPMC, Tianjin, Peoples R China Univ Oxford, Oncol, Oxford, England Royal Holloway Univ London, Class, Egham, Surrey, England Cornell Univ, Clin Sci, Ithaca, NY USA Univ KwaZulu Natal, Pharmaceut Chem, Westville Campus, Durban, South Africa Royal Coll Surgeons Ireland, Med, Dublin, Ireland Univ Oslo, Dept Immunol, Oslo, Norway Bermuda Inst Ocean Sci, Marine Nitrogen Cycling Lab, St Georges, Bermuda Kanazawa Univ, Inst Liberal Arts & Sci, Kanazawa, Ishikawa, Japan World Hlth Org Reg Off Africa, Brazzaville, Rep Congo Univ Hosp BesanCon, Infect Control Dept, Besancon, France Galapagos NV, Clin Dev, Mechelen, Belgium Univ Tasmania, Integrated Marine Observing Syst, Hobart, Tas, Australia Georg August Univ Gottingen, Albrecht von Haller Inst Plant Sci, Dept Systemat Biodivers & Evolut Plants, Gottingen, Germany Univ Occupat & Environm Hlth, Dept Psychiat, Fukuoka, Fukuoka, Japan IMDEA Food, Program Precis Nutr & Aging, Madrid, Spain Radboud Univ Nijmegen, Med Sch, IQHealthcare, Nijmegen, Netherlands Maastricht Univ, Dept Cardiovasc Surg, Maastricht, Netherlands German Diabet Ctr, Inst Clin Biochem & Pathobiochem, Dusseldorf, Germany Juntendo Univ, Grad Sch Med, Dept Radiol, Tokyo, Japan Deakin Univ, Sch Informat Technol, Melbourne, Vic, Australia Max Planck Inst Eusenforschung, Dept Interface Chem & Surface Sci, Dusseldorf, Germany Edge Hill Univ, Dept Psychol, Ormskirk, England Aga Khan Univ, Psychiat, Karachi, Pakistan KRIBB, Korean Bioinformat Ctr, Seoul, South Korea Cardinal Hlth Specialty Solut, Hlth Econ & Outcomes Res, Dallas, TX USA Klinikum Univ Munchen, Div Clin Pharmacol, Munich, Germany Univ Pittsburgh, Neurol Surg, Pittsburgh, PA USA Rhein Westfal TH Aachen, Dept Child & Adolescent Psychiat Psychosomat & Ps, Aachen, Germany Univ Copenhagen, Inst Mol & Cellular Biol, Copenhagen, Denmark St Jude Childrens Res Hosp, Struct Biol, 332 N Lauderdale St, Memphis, TN 38105 USA Royal Shrewsbury Hosp, Colorectal Surg, Shrewsbury, Salop, England Univ Nottingham, Fac Med & Hlth Sci, Nottingham, England Karolinska Inst, Dept Physiol & Pharmacol, Solna, Sweden Chinese Acad Sci, Changchun Inst Appl Chem, State Key Lab Electroanalyt Chem, Jilin, Jilin, Peoples R China Univ British Columbia, Pediat, Vancouver, BC, Canada Chinese Acad Agr Sci, State Key Lab Cotton Biol, Res Base Anyang Inst Technol, Cotton Germplasm Resources,Inst Cotton Res, Beijing, Peoples R China Chinese Univ Hong Kong, Anaesthesia & Intens Care, Hong Kong, Peoples R China Univ Macau, ICMS, Zhuhai, Guangdong, Peoples R China North China Elect Power Univ, Sch Renewable Energy, Beijing, Peoples R China Justus Liegbig Univ, Dept Internal Med, Giessen, Germany Aarhus Univ, Biosci, Aarhus, Denmark Univ Dublin, Trinity Coll Dublin, Irish Longitudinal Study Ageing TILDA, Dublin, Ireland Univ Groningen, Univ Med Ctr Groningen, Hematol, Groningen, Netherlands Vrije Univ Amsterdam Med Ctr, Child Neurol, Amsterdam, Netherlands EBI, EMBL, Cambridge, England Max Planck Inst Marine Microbiol, HGF MPG Joint Res Grp Deep Sea Ecol & Technol, Bremen, Germany Max Planck Inst Human Dev, Ctr Adapt Rat, Berlin, Germany King Faisal Univ, Math, Al Hufuf, Saudi Arabia Griffith Univ, Sch Nursing & Midwifery, Gold Coast, Qld, Australia Iowa State Univ, Roy J Carver Dept Biochemsitry Biophys & Mol Biol, Ames, IA USA Delft Univ Technol, Fac Mech Maritime & Mat Engn, Engn Thermodynam Proc & Energy Dept, Leeghwaterstr 39, NL-2628 CB Delft, Netherlands Univ Nebraska Med Ctr, Coll Allied Hlth Profess, Cytotechnol Educ, Omaha, NE USA Shinko Mem Hosp, Dept Cardiovasc Med, Kobe, Hyogo, Japan Imperial Coll London, Mat, London, England Tech Univ Munich, Dept Surg, Munich, Germany Chinese Acad Agr Sci, Res Inst Pomol, Minist Agr, Lab Qual & Safety Risk Assessment Fruit Xingcheng, Shenyang, Liaoning, Peoples R China James Madison Univ, Commun Sci & Disorders, Harrisonburg, VA 22807 USA Univ Hosp Ulm, Inst Orthopaed Res & Biomech, Ulm, Germany Univ Essex, Sch Hlth & Social Care, Colchester, Essex, England Alpha Altis, Res Serv, Nottingham, England Erasmus MC, Med Oncol, Rotterdam, Netherlands Fed Univ Oye, Dept Ind Chem, Ekiti, Nigeria Duke Univ, Med Ctr, Cell Biol, Durham, NC USA Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England Univ Manchester, Canc Res UK Manchester Inst, Manchester, Lancs, England Helsinki Univ Hosp, Childrens Hosp, Helsinki, Finland Univ Aveiro, CESAM Ctr Environm & Marine Studies, Dept Biol, Aveiro, Portugal Univ Botswana, Psychol, Gaborone, Botswana Univ Fed Bahia, Nursing Sch, Salvador, BA, Brazil Queen Mary Univ London, Biol & Expt Psychol, London, England Natl Univ Pharm, Med Chem Dept, Kharkov, Ukraine Univ Bolton, Dept Educ & Psychol, Bolton, England La Trobe Univ, Dept Chem & Phys, Melbourne, Vic, Australia Gen Hosp Northern Theater Command, Dept Gastroenterol, Shenyang, Liaoning, Peoples R China Doctors Hosp, Dept Nephrol, Athens, Greece Univ Hosp Essen, Pediat 3, Essen, Germany Imperial Coll London, Infect Dis Epidemiol, London, England Sorbonne Univ, Dept Psychiat, Paris, France UNSW Sydney, Educ, Sydney, NSW, Australia Stanford Univ, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA Hannover Med Sch, Clin Laryngol Rhinol & Otol, Hannover, Germany Curtin Univ, Ctr Aboriginal Studies, Perth, WA, Australia Iran Univ Sci & Technol, Biomed Engn Dept, Tehran, Iran Univ Calif San Francisco, Anesthesiol, San Francisco, CA 94143 USA Khalifa Univ Sci & Technol, Mech Engn, Abu Dhabi, U Arab Emirates Univ Florida, Hort Sci, Gainesville, FL USA James Cook Univ, Australian Inst Trop Hlth & Med, Ctr Biodiscovery & Mol Dev Therapeut, Cairns, Qld, Australia Univ Porto, Fac Med, CINTESIS, Porto, Portugal Shaoxing Peoples Hosp, Med Res Ctr, Shaoxing, Zhejiang, Peoples R China NIH, Dept Transfus Med, Bethesda, MD 20892 USA AIIMS, Dept Biotechnol, New Delhi, India Univ Ottawa, Biochem Microbiol & Immunol, Ottawa, ON, Canada Univ Oslo, Inst Clin Med, Div Mental Hlth & Addict, Oslo, Norway Univ Groningen, Univ Med Ctr Groningen, Dept Radiol, Groningen, Netherlands Univ Hong Kong, Sch Nursing, Hong Kong, Peoples R China Tokyo Med Univ, Ibaraki Med Ctr, Urol, Tokyo, Japan Univ Hosp Zurich, Dept Radiat Oncol, Zurich, Switzerland Univ Maryland, Inst Human Virol, Div Immunotherapy, Baltimore, MD 21201 USA Univ Maryland, Dept Surg, Baltimore, MD 21201 USA Stellenbosch Univ, Fac Med & Hlth Sci, Div Mol Biol & Human Genet, Stellenbosch, South Africa China Agr Univ, Coll Biol Sci, Beijing, Peoples R China Osaka Univ, Grad Sch Pharmaceut Sci, Suita, Osaka, Japan Univ Washington, Biochem, Seattle, WA 98195 USA Natl Res Council Italy, Inst Biosci & BioResources, Naples, Italy Univ Lyon, Phys, Lyon, France Univ Basel, Fac Psychol, Ctr Social Psychol, Basel, Switzerland Queen Mary Univ London, Barts Canc Inst, Ctr Mol Oncol, London, England EBI, EMBL, Samples Phenotypes & Ontol Team, Cambridge, England Charles Sturt Univ, Fac Arts & Educ, Bathurst, NSW, Australia Shandong Univ, Helmholtz Inst Biotechnol, Sch Life Sci, State Key Lab Microbial Technol, Jinan, Shandong, Peoples R China Shantou Univ, Dept Biol, Shantou, Guangdong, Peoples R China Shanxi Univ, Inst Biomed Sci, Taiyuan, Shanxi, Peoples R China St Jude Childrens Res Hosp, Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA Harbin Med Univ, Coll Bioinformat Sci & Technol, Harbin, Heilongjiang, Peoples R China NIH, Radiol & Imaging Sci, Bldg 10, Bethesda, MD 20892 USA Georgia Inst Technol, Dept Biol Sci, Atlanta, GA 30332 USA XtalPi Inc, Cambridge, MA USA Consejo Nacl Invest Cient & Tecn, Partner Inst Max Planck Soc, Inst Invest Biomed Buenos Aires IBioBA, Bioinformat, Buenos Aires, DF, Argentina Univ Sydney, Save Sight Inst, Sydney, NSW, Australia Univ South Australia, Canc Res Inst, Australian Ctr Precis Hlth, Adelaide, SA, Australia Jinan Univ, Inst Life & Hlth Engn, Guangdong Higher Educ Inst, Key Lab Funct Prot Res, Guangzhou, Guangdong, Peoples R China Univ Texas Hlth Sci Ctr Houston, Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA Weill Cornell Med, Dept Microbiol & Immunol, New York, NY USA Guangdong Inst Appl Biol Resources, Biotechnol Lab, Guangzhou, Guangdong, Peoples R China Shandong Normal Univ, Coll Life Sci, Jinan, Shandong, Peoples R China Shandong Univ, Life Sci Dept, Jinan, Shandong, Peoples R China South China Agr Univ, Integrat Microbiol Res Ctr, Guangzhou, Guangdong, Peoples R China Liaoning Acad Agr Sci, Crop Mol Improving Lab, Shenyang, Liaoning, Peoples R China Lawson Hlth Res Inst, Med Biophys, London, ON, Canada Univ Melbourne, Infrastruct Engn, Parkville, Vic, Australia Univ Canberra, Fac Hlth, Canberra, ACT, Australia Univ Cambridge, MRC Cognit & Brain Sci Unit, Cambridge, England Emory Univ, Biostat & Bioinformat, Atlanta, GA 30322 USA Johns Hopkins Sch Med, Anesthesiol & Crit Care Med, Baltimore, MD USA Nottingham Trent Univ, Sch Anim Rural & Environm Sci, Nottingham, England Univ Exeter, Biosci, Exeter, Devon, England Hillingdon Hosp NHS Fdn Trust, London, England Univ Glasgow, MRC CSO Social & Publ Hlth Sci Unit, Glasgow, Lanark, Scotland Natl & Kapodistrian Univ Athens, Evaggelismos Athens Hosp, ICU, Athens, Greece Univ Newcastle, Biol Sci, Callaghan, NSW, Australia Coventry Univ, Fac Hlth & Life Sci, Ctr Innovat Res Life Course, Coventry, W Midlands, England Lausanne Univ Hosp, Serv Endocrinol Diabet & Metab, Lausanne, Switzerland Charles Sturt Univ, Sch Community Hlth, Bathurst, NSW, Australia Queens Univ Belfast, Inst Global Food Secur, Belfast, Antrim, North Ireland Natl Univ Singapore, Inst Policy Studies, Singapore, Singapore Univ Penn, Intitute Med & Engn, Philadelphia, PA 19104 USA Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA Univ Michigan, EECS, Ann Arbor, MI 48109 USA Univ British Columbia, Ctr Blood Res, Vancouver, BC, Canada UiT Arctic Univ Norway, Dept Hlth & Care Sci, Fac Hlth Sci, Tromso, Norway Hosp Clin Porto Alegre, Physiotherapy, Porto Alegre, RS, Brazil Univ Paris 05, Med Sch, Paris, France Chinese Acad Agr Sci, Inst Crop Sci, Natl Key Facil Crop Gene Resources & Genet Improv, Beijing, Peoples R China Univ Ghent, Expt Clin & Hlth Psychol, Ghent, Belgium Indian Inst Adv Res, Bioinformat & Struct Biol, Gandhinagar, Gujart, India Bambino Ges Childrens Res Hosp, Lab Mol Med, Rome, Italy Heidelberg Univ, Ctr Infect Dis Parasitol, Heidelberg, Germany Stanford Univ, Elect Engn, Palo Alto, CA 94304 USA Univ Cadiz, Biol, Andalucia, Spain Mansoura Univ Hosp, Gen Surg, Mansoura, Egypt Inst Pasteur, Virol Pole, Dakar, Senegal Cardiff Univ, Div Canc & Genet, Cardiff, S Glam, Wales Ctr Expertise & Biol Diagnost Cameroon, Food Safety & Environm Microbiol, Yaounde, Cameroon Swiss Fed Labs Mat Sci & Technol, Lab Thin Films & Photovolta, Dubendorf, Switzerland Assiut Univ, Assiut Urol & Nephrol Hosp, Fac Med, Assiut, Egypt UCL, GEE, London, England UCL, IHA, London, England Univ Derby, Univ Derby Online Learning, Derby, England SUNY Stony Brook, Family Populat & Prevent Med, Stony Brook, NY 11794 USA Walter & Eliza Hall Inst Med Res, Mol Med Div, Melbourne, Vic, Australia Newcastle Univ, Northern Inst Canc Res, Newcastle Upon Tyne, Tyne & Wear, England German Ctr Neurodegenerat Dis, Clin Dementia Res, Bonn, Germany Sorbonne Univ, CNRS, UMR 7144, Stn Biol, Paris, France Univ Barcelona, Odontoestomatol, Barcelona, Spain Janelia Res Campus, Comp Sci, Ashburn, VA USA Univ Oxford, Ctr Trop Med & Global Hlth, Oxford, England Univ Bern, ARTORG Ctr Biomed Engn Res, Bern, Switzerland Australian Natl Univ, Eccles Inst Neurosci, John Curtain Sch Med Res, Canberra, ACT, Australia John Innes Ctr, Metab Biol, Norwich, Norfolk, England USDA ARS, Genom & Bioinformat Res Unit, Raleigh, NC 27695 USA Med Univ Graz, Inst Med Informat Stat & Documentat, Holzinger Grp, Graz, Austria Ajou Univ, Pharm, Suwon, South Korea City Univ Hong Kong, Sch Energy & Environm, Hong Kong, Peoples R China Univ British Columbia, Sch Kinseiol, Vancouver, BC, Canada Univ Copenhagen, Marine Biol Sect, Dept Biol, Copenhagen, Denmark Univ Vienna, Dept Commun, Vienna, Austria Univ Dundee, Sch Social Sci, Dundee, Scotland Tech Univ Dresden, Inst Bot, Dresden, Germany Univ Oxford, Div Struct Biol, Oxford, England Natl Univ Hlth Syst, Med, Singapore, Singapore Univ Canterbury, Sch Biol Sci, Christchurch, New Zealand Univ Hosp Southern Denmark, Focused Res Unit Mol Diagnost & Clin Res, Odense, Denmark Univ Oxford, Primary Care Hlth Sci, Oxford, England Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA Adnan Menderes Univ Aydin, Fac Nursing, Dept Publ Hlth Nursing, Aydin, Turkey Oasi Res Inst IRCCS, Dept Neurol IC, Troina, Italy Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA Kings Coll London, Kings Ctr Mil Hlth Res, London, England LSHTM, Dept Infect Dis Epidemiol, London, England Leibniz Univ Hannover, BMWZ Organ Chem, Hannover, Germany Xi An Jiao Tong Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Xian, Shaanxi, Peoples R China Univ South Australia, Sch Pharm & Med Sci, Adelaide, SA, Australia Univ Fed Santa Catarina, Dept Phys Educ, Florianopolis, SC, Brazil Southern Med Univ, Nanfang Hosp, Dept Oncol, Guangzhou, Guangdong, Peoples R China Stanford Univ, Hansen Expt Phys Lab, Palo Alto, CA 94304 USA Shenzhen Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp 2, Inst Translat Med, Shenzhen, Guangdong, Peoples R China Univ Hong Kong, Dept Stat & Actuarial Sci, Hong Kong, Peoples R China UCL, Dept Mech Engn, London, England ASTAR, Singapore Immunol Network, Lab Microbial Immun, Singapore, Singapore Cent South Univ, State Key Lab Powder Met, Changsha, Hunan, Peoples R China Univ Aberdeen, Inst Appl Hlth Sci, Aberdeen, Scotland Univ Bridgeport, Biomed Engn, Bridgeport, CT 06601 USA Texas Tech Univ, Hlth Sci Ctr, Pharmaceut Sci, Lubbock, TX 79430 USA Univ Montana, Ecosyst & Conservat Sci, Missoula, MT 59812 USA Univ Goettingen, Dept Syst Neurosci, Gottingen, Germany NHLBI, Lab Syst Genet, Bldg 10, Bethesda, MD 20892 USA Cleveland Clin, Lou Ruvo Ctr Brain Hlth, Imaging, Las Vegas, NV USA Flinders Univ S Australia, Coll Nursing & Hlth Sci, Nutr & Dietet, Adelaide, SA, Australia Univ Padua, Dept Math, Padua, Italy Lund Univ, Fac Law, Lund, Sweden Univ Gothenburg, Dept Microbiol & Immunol, Gothenburg, Sweden NARO, Kachwekano Zardi, Entebbe, Uganda Natl Yunlin Univ Sci & Technol, Bachelor Program Interdisciplinary Studies, Touliu, Yunlin, Taiwan Aarhus Univ, Dept Biomed, Danish Res Inst Translat Neurosci DANDRITE, Aarhus, Denmark Eduardo Mondlane Univ, Math & Comp Sci, Maputo, Mozambique Univ Bern, Dept Old Age Psychiat & Psychotherapy, Bern, Switzerland RAS, Inst Cytol, Lab Cytol Unicellular Organisms, St Petersburg, Russia Beijing Inst Technol, Sch Chem & Chem Engn, Beijing, Peoples R China Univ Queensland, Queensland Alliance Agr & Food Innovat, Brisbane, Qld, Australia Fraunhofer Inst Toxicol & Expt Med ITEM, Inhalat Toxicol, Hannover, Germany Univ Hong Kong, Publ Hlth, Hong Kong, Peoples R China Univ Hlth Network, Anesthesia & Pain Med, Toronto, ON, Canada Univ Toronto, Toronto, ON, Canada Univ Bath, Dept Hlth, Bath, Avon, England Univ Copenhagen, Computat & RNA Biol, Copenhagen, Denmark Fisheries & Oceans Canada, Bedford Inst Oceanog, Dartmouth, NS, Canada Goethe Univ, CEF MC, BMLS, Phys Biol, Frankfurt, Germany Albert Einstein Coll Med, Anat & Struct Biol, New York, NY USA Queensland Govt, Dept Environm & Sci, Brisbane, Qld, Australia Uppsala Univ, Vasc Surg Sect, Dept Surg Sci, Uppsala, Sweden Childrens Canc Hosp, Res, Cairo, Egypt Leibniz Inst Nat Prod Res & Infect Biol, Bio Pilot Plant, Jena, Germany Duy Tan Univ, Inst Res & Dev, Da Nang, Vietnam Univ Helsinki, Helsinki Inst Life Sci HiLIFE, Helsinki, Finland Univ Queensland, Australian Inst Bioengn & Nanotechnol, Brisbane, Qld, Australia George Inst Global Hlth, Sydney, NSW, Australia Griffith Univ, Griffith Inst Drug Discovery, Brisbane, Qld, Australia Dezhou Univ, Coll Phys & Elect Informat, Shandong Prov Key Lab Biophys, Dezhou, Peoples R China Henan Agr Univ, Coll Life Sci, Zhengzhou, Henan, Peoples R China Univ Tokyo, Publ Hlth, Tokyo, Japan Sun Yat Sen Univ, Affiliated Hosp 1, Guangzhou, Guangdong, Peoples R China Univ Illinois, Dept Med, Chicago, IL USA Beijing Inst Microbiol & Epidemiol, State Key Lab Pathogen & Biosecur, Beijing, Peoples R China Minist Hlth, Key Lab Neonatal Dis, Shanghai, Peoples R China Covenant Univ, Dept Phys, Ota, Nigeria Prince Sattam Bin Abdulaziz Univ, Dept Phys Therapy & Hlth Rehabil, Al Kharj, Saudi Arabia Lund Univ, Cognit Sci, Malmo, Sweden Natl Open Univ Nigeria, Dept Publ & Environm Hlth, Abuja, Nigeria Peking Univ, Sch Publ Hlth, Dept Lab Sci & Technol, Beijing, Peoples R China Univ Sydney, Sch Publ Hlth, Menzies Ctr Hlth Policy, Sydney, NSW, Australia Univ Auckland, Dept Elect & Comp Engn, Auckland, New Zealand Beijing Univ Chinese Med, Res Ctr TCM Informat Engn, Beijing, Peoples R China Osped Niguarda Ca Granda, Cardiac Surg, Milan, Italy Univ Vet Med, Clin Horses, Hannover, Germany Harbin Med Univ, Lab Med Genet, Harbin, Heilongjiang, Peoples R China Univ Saskatchewan, Dept Psychol, Saskatoon, SK, Canada Univ Coimbra, Ctr Studies Geog & Spatial Planning CEGOT, Coimbra, Portugal Univ Groningen, Univ Med Ctr Groningen, Epidemiol, Groningen, Netherlands South Cent High Specialty Hosp, Dept Neurol & Neurosurg, Pemex, Mexico Shandong Agr Univ, Coll Informat Sci & Engn, Tai An, Shandong, Peoples R China Curtin Univ, Natl Drug Res Inst, Perth, WA, Australia Wageningen Bioveterinary Res, Bacteriol & Epidemiol, Lelystad, Netherlands Guangdong Second Prov Gen Hosp, Dept Rheumatol & Immunol, Guangzhou, Guangdong, Peoples R China Erasmus MC, Biomed Rngineering, Rotterdam, Netherlands Hiroshima Univ, Grad Sch Biomed & Hlth Sci, Hiroshima, Japan Univ Iceland, Sch Hlth Sci, Reykjavik, Iceland Ohio State Univ, Mat Sci & Engn, Columbus, OH 43210 USA Kathmandu Univ, Sch Med Sci, Dept Physiotherapy, Dhulikhel, Nepal Univ Queensland, Sch Biomed Sci, Brisbane, Qld, Australia Fraunhofer MEVIS, Image Guided Therapies, Bremen, Germany Natl Univ Hlth Syst, Haematol Oncol, Singapore, Singapore Sun Yat Sen Univ, Canc Ctr, Breast Oncol, Guangzhou, Guangdong, Peoples R China Med Coll Wisconsin, Pharmacol & Toxicol, Wauwatosa, WI USA Queensland Univ Technol, Sci & Engn Fac, Sch Chem Phys & Mech Engn, Brisbane, Qld, Australia Univ Turin, Dept Mol Biotechnol & Hlth Sci, Turin, Italy Univ Tehran Med Sci, Sch Rehabil, Physiotherapy Dept, Tehran, Iran Univ Helsinki, Dept Forest Sci, Helsinki, Finland Univ Messina, Human Pathol, Messina, Italy AO Papardo Hosp Messina, Messina, Italy Univ Ibadan, Coll Med, Inst Child Hlth, Ibadan, Nigeria King Faisal Univ, Coll Med, Fac Ophthalmol, Al Hasa, Saudi Arabia Univ Stirling, Inst Social Mkt, Stirling, Scotland Saveh Univ Med Sci, Social Determinants Hlth Res Ctr, Saveh, Iran Gakujutsu Shien Co Ltd, Tokyo, Japan Chinese Acad Sci, Inst Geochem, Guiyang, Guizhou, Peoples R China Univ Plymouth, Med Sch, Plymouth, Devon, England CHU Toulouse, Immunol, Toulouse, France Azorean Biodivers Grp, Ctr Ecol Evolut & Environm Changes, Azores, Portugal Univ Acores, Azores, Portugal RIKEN, Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan Peking Univ, Sch Publ Hlth, Dept Global Hlth, Beijing, Peoples R China Chang Gung Univ, Chang Gung Mem Hosp, Dept Neurol, Linkou Med Ctr, Taoyuan, Taiwan Chang Gung Univ, Coll Med, Taoyuan, Taiwan Univ Malawi, Coll Med, Biomed Sci Dept, Blantyre, Malawi Univ Malawi, Coll Med, Pharm Dept, Blantyre, Malawi Bioself Commun, Biocurat, Marseille, France Peking Univ, Hosp 3, Dept Neurol, Beijing, Peoples R China Ahmadu Bello Univ, Fac Basic Clin Sci, Coll Hlth Sci, Dept Pathol, Zaria, Nigeria Dalhousie Univ, Dept Anesthesia Pain Management & Perioperat Med, Halifax, NS, Canada VisMederi Srl, Siena, Italy UCL, Canc Res UK, London, England UCL, UCL Canc Trials Ctr, London, England Univ Ottawa, Family Med, Ottawa, ON, Canada China Agr Univ, Coll Engn, Beijing, Peoples R China Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, Leiden, Netherlands Sun Yat Sen Univ, Affiliated Hosp 1, Dept Intervent Radiol, Guangzhou, Guangdong, Peoples R China Amer Univ Beirut, Med Ctr, Infect Dis, Beirut, Lebanon Sheffield Hallam Univ, Dept Social Work Social Care & Community Studies, Sheffield, S Yorkshire, England Mechnikov Res Inst Vaccines & Sera, Viral Hepatitis, Moscow, Russia Univ Ottawa, Pediat, Ottawa, ON, Canada Vreden Russian Res Inst Traumatol & Orthopaed, Dept Wound 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Informat Engn, Xiangtan, Hunan, Peoples R China Univ Hlth Network, Mood Disorders & Psychopharmacol, Toronto, ON, Canada Sao Paulo State Univ UNESP, Dept Anim Sci, Sao Paulo, Brazil Sao Paulo State Univ, Vet Clin, Sao Paulo, Brazil

Overlapping synthetic peptides of human SO protein chain. (PDF 193Â kb)

Clinical data and laboratory parameters before and during UDCA-treatment and availability of serum and peripheral blood mononuclear cells in 53 PSC patients included in the study. (DOCX 30Â kb)

Receiver operating curve (ROC) analysis for IgG-antibodies to the four SO-proteins comparing sera from PSC patients with those from healthy donors, PBC, AIH, alcoholic liver disease (ALD), viral hepatitis, ulcerative colitis (CU), Crohn disease (CD), and collagen disorders. (PDF 257Â kb)

Schematic presentation of the enzyme sulphite oxidase (SO) with its different domains, and the immuno-dominant epitopes recognised by PSC sera (aa = amino acid; mo = molybdenum binding site). (PDF 165 kb)

Activity of IgG-antibodies against the four SO-proteins in sera from untreated PSC-patients without and with IBD as well as in patients with pure IBD as determined by ELISA. Individual values (•) and median (―) are given. p

Uveitis is an intraocular inflammatory disease in which autoimmune reactions have been discussed in playing an important role. Many data in this respect derived from the animal model of "experimental autoimmune uveitis", where several organ-specific autoantigens have been described such as the retinal S-antigen and the interphotoreceptor retinoid-binding protein. However, their diagnostic and pathogenic role in humans has been controversially discussed. In recent studies, the possible relevance of betaB1-crystallin, present in lens and ciliary body, has been outlined. We, therefore, wanted to analyse whether sera from patients with uveitis might contain antibodies to lens proteinsHuman lenses from cadaveric eyes were shock frozen, homogenized, and resuspended. The resulting suspension (human lens protein fraction--HLPF) was analyzed for antigenicity by ELISA and Western blotting with patients' sera. A total of 165 patients with uveitis, 54 patients with scleritis and episcleritis, 56 patients with other eye diseases, and 112 healthy blood donors were studied.Twenty-six (49%) of the 53 patients with anterior uveitis, 17 (32%) of the 53 patients with intermediate uveitis and 7 (22%) of 32 patients with posterior uveitis reacted in the ELISA with the HLPF. Antibodies to lens antigens were detected in one-third of patients with panuveitis and retinal vasculitis. In contrast, only 12% of the healthy blood donors were positive in the ELISA. The number of patients with an autoimmune response to alpha-crystallins in Western blot predominated in all investigated groups.These data indicate that antibodies to lens proteins occur in a high incidence in sera from patients with uveitis. Forty-nine percent of the patients with anterior uveitis and only 12% of healthy controls were positive in the ELISA. In our groups of patients and controls the autoantibodies reacted in the Western blot predominantly with alpha-crystallin. Further studies are required to analyze in more detail the clinical and etiopathogenetic relevance of the antilens antibodies in uveitis.

This work compiles information on the principles of diagnostic immunochemical methods and the recent advances in this field. It presents an overview of modern techniques for the production of diag- nostic antibodies, their modification with the aim of improving their diagnostic potency, the different types of immunochemical detection systems, and the increasing diagnostic applications for human health that include specific disease markers, individualized diagnosis of cancer subtypes, therapeutic and addictive drugs, food residues, and environmental contaminants. A special focus lies in novel developments of immu- nosensor techniques, promising approaches to miniaturized detection units and the associated microfluidic systems. The trends towards high-throughput systems, multiplexed analysis, and miniaturization of the diag- nostic tools are discussed. It is also made evident that progress in the last few years has largely relied on novel chemical approaches.

Additional file 7: Table S1. Induction of cytokine release by XS15. Table S2. Antibody responses to XS15.

Additional file 7: Table S1. Induction of cytokine release by XS15. Table S2. Antibody responses to XS15.

Additional file 1. Supplementary Materials and Methods.

Additional file 8: Fig. S1. Impact of XS15 on slanMo-mediated T-cell polarization. Fig. S2. Impact of XS15 on slanMo-mediated IFNγ expression by WT1 peptide-specific CD8+ T cells. Fig. S3. Ex vivo phenotype of granuloma infiltrating cells (GICs). Fig. S4. Ex vivo assessment of regulatory T cells (Treg) in granuloma infiltrating cells (GICs) and PBMCs. Fig. S5. Ex vivo phenotype of checkpoint receptors in granuloma infiltrating cells (GICs) and PBMCs. Fig. S6. Detection of vaccinated peptides in granuloma tissue by mass spectrometry.

Additional file 8: Fig. S1. Impact of XS15 on slanMo-mediated T-cell polarization. Fig. S2. Impact of XS15 on slanMo-mediated IFNγ expression by WT1 peptide-specific CD8+ T cells. Fig. S3. Ex vivo phenotype of granuloma infiltrating cells (GICs). Fig. S4. Ex vivo assessment of regulatory T cells (Treg) in granuloma infiltrating cells (GICs) and PBMCs. Fig. S5. Ex vivo phenotype of checkpoint receptors in granuloma infiltrating cells (GICs) and PBMCs. Fig. S6. Detection of vaccinated peptides in granuloma tissue by mass spectrometry.

Additional file 1. Supplementary Materials and Methods.

Ribavirin wurde als eines der ältesten Virostatika zuletzt v.a. zur Therapie der chronischen Hepatitis C verwendet. Sein genauer Wirkungsmechanismus ist aber unbekannt. Es scheint, dass Ribavirn über keine antivirale Wirkung im Sinne einer direkten Hemmung der HCV-Replikation verfügt, sondern über die Freisetzung verschiedener Zytokine einen Shift von TH2- zu TH1-vermittelter Immunreaktion auslöst. Amantadin wurde zur Behandlung diverser Erkrankungen einschließlich der Prophylaxe einer Influenza eingesetzt. Bei der Therapie der Hepatitis C wurde es mit Ribavirin kombiniert, um dessen Effekt zu verstärken. Sein Stellenwert in der Hepatitis-C-Therapie blieb aber umstritten. Bisher liegen nur wenige Studien vor, die den immunmodulierenden Effekt von Amantadin untersucht haben. Vereinzelt wurde eine Inhibierung der HCV-Replikation durch Amantadin bei an Hepatits C erkrankten Patienten in vivo und in vitro beschrieben, der genaue antivirale Wirkmechanismus von Amantadin in der HCV-Therapie blieb aber bis zuletzt unbekannt. Beide Medikamente werden derzeit bezüglich einer Wirksamkeit zur Therapie einer Covid-19-Erkrankung untersucht. PBMC von 20 gesunden Probanden wurden in vitro kultiviert, um dann sowohl Zellen des erworbenen Immunsystems als auch Natürliche Killerzellen genauer zu untersuchen. Hierbei sollten insbesondere TH1- und TH2-Reaktionen analysiert werden. Drei verschiedene Antigene (BCG, Tetanus-Toxoid und PPD) wurden verwendet, um die PBMC zu unterschiedlichen Immunreaktionen vom TH1- oder TH2-Typ anzuregen; ferner wurde der Einfluss von Ribavirin bzw. Amantadin in unterschiedlichen Konzentrationen innerhalb dieses in vitro-Testsystems untersucht. Ein radioaktiver Proliferationsassay diente der quantitativen Zellproliferationsbestimmung. Die Ausbildung des frühen Aktivierungsmarkers CD69 sowie verschiedener Zelloberflächenmoleküle (CD4, CD8, CD19 und CD56) wurde mittels Durchflusszytometrie nachgewiesen. Ein Zytokin-ELISA diente der Untersuchung der Zytokinproduktion (IL-1, IL-5, IL-6, IL-10, IL-13, IFN-gamma, TNF-alpha, TNF-beta und GM-CSF) unter Einfluss von Ribavirin bzw. Amantadin. Unsere Daten deuten darauf hin, dass es große interindividuelle Unterschiede in der immunologischen Reaktion auf Ribavirin und Amantadin gibt. So zeigten einige der 20 Probanden ähnliche Ansprechverhalten auf beide Wirkstoffe, welche aber in der gesamten Kohorte nicht signifikant waren. Dies erklärt auch, warum die Therapie der Hepatitis C mit diesen Substanzen nur einen marginalen Effekt hatte. In dieser Arbeit wurde eine kleine Probandenkohorte untersucht, in der sowohl TH1- als auch TH2- und TH0-Immunprofile vertreten waren. Die Untersuchung eines größeren Kollektives der jeweiligen Subtypen wäre eine Möglichkeit, um die immunmodulierenden Wirkmechanismen genauer zu verstehen und dann mögliche Therapieresponder von Non-Respondern zu unterscheiden bzw. Ansatzpunkte für künftige Therapien zu ermitteln. Individuelle Prädisposition und immunologische Reaktionsmuster könnten also wichtige Faktoren sein, welche die Wirksamkeit von Ribavirin und Amantadin beeinflussen. Möglicherweise könnte eine prätherapeutische Bestimmung des jeweiligen immunologischen Subtyps helfen, eine auf den Patienten optimal angepasste antivirale Therapie auszuwählen.

HAHA/HAMA Nachweis sowohl unter Patienten mit rheumatischen Erkrankungen (unter oder ohne Therapie) als auch unter den gesunden Probanden. Beeinflussung der Therapie auf die HAHA/HAMA Häufigkeit. Kreuzreaktivität

Die PBC ist eine chronische cholestatische Lebererkrankung, deren Ursachen und Pathomechanismen noch nicht genau geklärt sind. Sie geht mit einer autoimmun bedingten Zerstörung der kleinen intrahepatischen Gallengänge einher und kann in fortgeschrittenen Stadien zu einer Schädigung des gesamten Leberparenchyms bis hin zum Vollbild einer Leberzirrhose führen (Kaplan 1996). Derzeitige Standardtherapie der PBC ist laut aktueller Leitlinie eine Dauertherapie mit UDCS (Strassburg et al. 2017). Aufgrund anderer assoziierter Autoimmunerkrankungen oder einer stattgehabten Lebertransplantation erhält jedoch ein Teil der PBC-Patienten zusätzlich zur UDCS-Therapie eine immunsuppressive Therapie. Bei über 90% der PBC-Patienten sind Autoantikörper gegen mitochondriale Antigene (AMA) nachweisbar, die sehr spezifisch für die Erkrankung sind und daher große diagnostische Bedeutung haben (Kaplan 1996). 2010 wiesen Berg et al. bei PBC-Patienten erstmals auch Antikörper gegen ein rekombinantes Peptid des muskarinischen Acetylcholinrezeptors Typ 3 (Anti-mAchR3- Antikörper) nach. Einige Studien haben gezeigt, dass solche Anti-mAchR3-Antikörper auch die Rezeptoraktivität beeinflussen können (Frischke 2013; Preuss et al. 2014a; Preuss et al. 2014b). Ziel der vorliegenden Arbeit war es, diese funktionelle und die Proliferation beeinflussende Aktivität der Anti-mAchR3-Antikörper bei PBC- Patienten zu re-evaluieren und Änderungen in der Aktivität und Prävalenz der Antikörper im Krankheitsverlauf unter verschiedenen Therapieregimen zu analysieren. Hierfür wurden Seren von 38 PBC-Patienten zum Zeitpunkt der Erstdiagnose bzw. vor Therapiebeginn und im Verlauf der Erkrankung (ohne Therapie, n = 4; unter Therapie mit UDCS, n = 18; unter immunsuppressiver Therapie, n = 16) untersucht. Um sicher zu sein, dass mögliche Effekte auf Antikörper und nicht andere Faktoren in den Patientenseren zurückzuführen sind, wurden aus allen Seren Immunglobuline durch Ammoniumsulfatfällung isoliert. Die Untersuchung der aus den Seren isolierten Immunglobulinfraktionen erfolgte mit einer in der Literatur vorbeschriebenen, teilweise leicht modifizierten Lumineszenz-basierten Methode. Hierbei wurden neben mAchR3- überexprimierenden CHO-Zellen auch Cholangiozyten (TFK-1-Zellen) und Hepatozyten (HEP-G2-Zellen) eingesetzt. Zudem wurde im selben Patientenkollektiv mittels eines 3H-Thymidin-basierten Proliferations-Assay auch die Prävalenz und Aktivität von die Zellproliferation beeinflussenden Antikörpern untersucht. Auch hier wurden entsprechende Verlaufsmessungen durchgeführt. Es konnte besonders mit TFK-1-Zellen und HEP-G2-Zellen eine hohe Prävalenz von rezeptorinhibierenden Anti-mAchR3-Antikörpern von 84% bzw. 63% festgestellt werden. Ein kleiner Prozentsatz der Anti-mAchR3-Antikörper (5% bei den TFK-1-Zellen, 3% bei den HEP-G2-Zellen) zeigte zudem rezeptoraktivierende Aktivität. Mit den CHO-Zellen gelang der Antikörper- Nachweis überraschenderweise trotz der Überexpression des Rezeptors weniger sensitiv. Bei 63% der Patienten ließen sich mit dieser Zelllinie keine funktionell aktiven Anti-mAchR3-Antikörper nachweisen, bei 26% inhibierende und bei 11% aktivierende Antikörper. Grund hierfür ist vermutlich eine Zell- bzw. Organspezifität der nachgewiesenen Anti-mAchR3-Antikörper, die beispielsweise auf zellspezifischen Subtypen des mAchR3 oder zellspezifischen Varianten der nachgeschalteten Signalwege beruhen könnte. Zudem scheint auch der Zustand der Zellen und das intrazelluläre Milieu Einfluss auf die Antikörperwirkung zu haben. Im Verlauf der Erkrankung ergaben sich bei den Messungen mit TFK-1-Zellen und HEP-G2-Zellen unter keiner der Therapieformen signifikante Veränderungen der Antikörper-Aktivität am mAchR3 oder wesentliche Veränderungen der Antikörper-Prävalenz. Bei den weniger sensitiven Messungen mit CHO-Zellen ergab sich lediglich in der Gruppe der immunsupprimierten Patienten im Verlauf eine statistisch signifikante Zunahme der rezeptorinhibierenden Aktivität der Anti-mAchR3-Antikörper, in den übrigen beiden Gruppen ließen sich auch mit den CHO-Zellen keine signifikanten Veränderungen feststellen. Analog zu den für die Erkrankung pathognomonischen AMA scheinen damit auch die funktionellen Anti-mAchR3- Antikörper im Krankheitsverlauf wenig Dynamik bezüglich ihrer Prävalenz und Aktivität zu zeigen. Im 3H-Thymidin-Proliferations-Assay konnte hauptsächlich eine die Proliferation inhibierende Antikörperwirkung auf HEP-G2-Zellen gezeigt werden. Diese Zellen wurden durch die Antikörperfraktionen aller untersuchten Patientenseren in ihrer Proliferation gehemmt. Mit TFK-1-Zellen und CHO-Zellen war deutlich seltener eine Proliferationshemmung zu beobachten (3% bzw. 16%). Ob diese ebenfalls sehr organ- bzw. zellspezifisch die Proliferation inhibierende Wirkung durch Anti-mAchR3-Antikörper oder andere Antikörper aus den Seren der PBC- Patienten verursacht wurde, musste in dieser Arbeit offen bleiben. Im Krankheitsverlauf zeigte die proliferationsbeeinflussende Aktivität der Antikörper bei keiner Zelllinie und keiner Patientengruppe eine signifikante Veränderung. Angesichts der starken Zellspezifität der nachgewiesenen Antikörper könnten künftige Studien an aus Biopsiematerial von PBC-Patienten gewonnen Cholangiozyten und Hepatozyten helfen, die mögliche pathogenetische Bedeutung der Antikörper besser zu verstehen. Diese Studien sollten nach Möglichkeit auch erneute Verlaufsmessungen beinhalten, um zu überprüfen, ob sich die hier gewonnenen Erkenntnisse an diesen Zellen bestätigen lassen.

In verschiedenen Studien wurden Autoantikörper (AAK) gegen den muskarinischen Acetylcholin Rezeptor 3 (mAChR3) bei Patienten mit Sjögren Syndrom (SS) und primärer biliärer Cholangitis (PBC) beschrieben, und es wurde gezeigt, dass diese Antikörper den Rezeptor aktivieren oder inhibieren können, also funktionell aktiv sind. Diese Untersuchungen wurden insbesondere mit Epithelzellen der Speicheldrüsen durchgeführt. Ziel der vorliegenden Arbeit ist es, zu überprüfen, ob AAK gegen den mAChR3 auch bei Patienten mit anderen autoimmunen Lebererkrankungen, wie der primären sklerosierenden Cholangitis (PSC) und der autoimmunen Hepatitis (AIH), oder bei der Virushepatitis (VH) vorkommen, und ihre Wirkung auf die Rezeptorfunktionalität, Zellproliferation und Apoptosemechanismen von Cholangiozyten unter Verwendung der Zelllinie TFK-1, zu analysieren. Ferner sollte mittels Epitop-Mapping geklärt werden, ob es immundominante Epitope gibt, die von IgG und IgM mAChR3 AAK erkannt werden. Darüber hinaus wird der Einfluss des mAChR3 Antigens auf die humorale Immunantwort der Patientenlymphozyten untersucht. Insgesamt wurden 499 Probanden davon 142 PBC-, 50 PSC-, 44 AIH-, 50 VH-, 25 ALD-, 60 SS-Patienten und 129 gesunde Probanden mittels Lumineszenz Assay, Adsorptionstest, ELISA, Durchflusszytometrie, In-Cell Western und mittels 3H-Thymidin-Einbau getestet. In der Durchflusszytometrie haben ein Drittel der 38 PBC- und 74 % der 35 PSC-Patienten IgM-Antikörper gegen mAChR3-exprimierenden TFK-1-Zellen. IgG-Antikörper sind nicht nachweisbar. Immunglobuline (Ig) von 31 % der 142 PBC-, 14 % der 50 PSC- und 44 % der 43 AIH-Patienten stimulieren den mAChR3 auf 1*104 TFK-1-Zellen, haben aber keinen Effekt auf deren Proliferationsrate, Zytokinproduktion oder die Expression der Apoptose Proteine Bcl-2, Bax und Caspase-9. Bei Verwendung des rekombinanten mAChR3 Antigens zeigen Seren von Patienten mit SS, VH und alkohol-induzierte Lebererkrankungen (ALD) im ELISA eine verstärkte IgM-Reaktivität. IgG-Antikörper waren insbesondere bei Patienten mit AIH und SS kaum nachweisbar. IgG-AAK binden bevorzugt an den zweiten zytoplasmatischen und dritten extrazellulären Loop. mAChR3 AAK des IgM-Typus an die angrenzenden Transmembranregionen nach dem zytoplasmatischen Loop Nr.1, an die dritte extrazelluläre Schleife und das nachfolgende C-terminale Ende. Das mAChR3 Antigen aktiviert in vitro CD4+-Lymphozyten von 20 PBC-Patienten, aber inhibiert sowohl deren Th1- als auch deren Th2-Zytokinantwort. Bei 20 Patienten mit AIH führt es zu einer Aktivierung von CD4+- und CD8+-Lymphozyten, einer Stimulation ihrer Proliferation und einer Reduktion der IFN-γ- und IL-10 Produktion. Der Effekt des mAChR3 Antigens auf die PBMC von 20 PSC-Patienten ergibt bereits eine spontane Aktivierung von CD19+-Zellen sowie eine verstärkte IL-6- und verminderte IL-5-Sekretion. In dieser Arbeit wird erstmalig gezeigt, dass Antikörper gegen mACh3R-exprimierende TFK-1-Zellen in Seren von PBC-, PSC-, VH-Patienten aber auch von gesunden Probanden nachweisbar sind. Ig’s von PBC- und PSC-Patienten stimulieren aber spezifisch den mACh3R auf Cholangiozyten. Patienten- und Kontrollseren reagieren, abhängig vom IgG- und IgM-Antikörpertypus, mit unterschiedlichen mAChR3-Epitope Darüber hinaus führt die Inkubation von PBMC von PBC-, PSC- und AIH-Patienten mit dem mAChR3 Antigen in vitro zur Aktivierung unterschiedlicher Zellpopulationen mit Freisetzung verschiedener Zytokine.

Analyse von Anti-Topoisomerase I-Antikörpern und Evaluierung ihrer immundominanten Epitope bei Patienten mit diffus kutaner systemischer Sklerose vor und nach autologer hämatopoetischer Stammzelltransplantation bei 24 Patienten, die im Rahmen einer Studie im Uniklinikum Tübingen behandelt wurden. Korrelationen von Antikörperprävalenz und Höhe von Antikörpertitern. Es kam zu keiner relevanten Abnahme der Prävalenz unter der Therapie, jedoch signifikanter Reduktion der Antikörpertiter. Patienten mit schlechtem Ansprechen hatten vor der Therapie signifikant höhere Antikörpertiter.

Hintergrund: Das Vorkommen verschiedener Autoantikörper bei Patienten mit neuropsychiatrischem systemischem Lupus erythematosus (SLE) hat die Aufmerksamkeit auf einen Zusammenhang zwischen dem Auftreten spezifischer Antikörper und Beteiligung des Nervensystems gerichtet. Ziel der hier vorliegenden Arbeit ist die Untersuchung der Korrelation zwischen dem Auftreten von Autoantikörpern gegen zentrales Nervensystem (ZNS) und klinisch neuropsychiatrischer Manifestationen sowie die Charakterisierung möglicher ZNS-Antigene bei Patienten mit verschiedenen Kollagenerkrankungen, insbesondere unter Berücksichtigung des SLE. Material und Methoden: Seren von Patienten mit unterschiedlichen Erkrankungen wurden mit den Methoden Western Blot und ELISA untersucht. Von den 74 im Western Blot untersuchten Patienten entwickelten 16 eine zerebrale Manifestation im Verlauf und sechs Patienten wiesen zum Zeitpunkt der Untersuchung eine ZNS-Beteiligung auf. Als Antigene wurden ein 100.000 g Überstand (SN) aus Rinderhirn sowie ein in E.coli exprimiertes alpha-Tubulin verwendet. Zur Charakterisierung der Targetantigene wurden monoklonale Antikörper gegen alpha- und beta-Tubulin sowie gegen das Mikrotubuli-assoziierte-Protein 2 (MAP2) eingesetzt. Im ELISA wiesen von insgesamt 112 untersuchten Patienten 41 eine ZNS-Beteiligung zum Zeitpunkt der Untersuchung auf, ein Patient entwickelte eine ZNS-Manifestation im Verlauf. Ergebnisse: Seren von 57% der Patienten reagierten im Western Blot unter Verwendung des 100.000 g SN aus ZNS-Gewebe mit Determinanten mit einem MG von < 50 KD. Auf Höhe des rekomb. alpha-Tubulins (50 kD), zeigten 39% der Seren eine positive Reaktion. Seren von Patienten mit ZNS Manifestation im Verlauf reagierten zu 68,8 % positiv bei einem MG von < 50 kD und zu 37,5% positiv bei 50 kD. Von den Seren der Patienten mit bekannter ZNS Manifestation reagierten 50% bei einem MG von < 50 kD und nur 16,6 % zeigten Reaktionen bei 50 kD, d.h. auf Höhe des alpha-Tubulins. Des Weiteren traten bei 49% der Patienten Banden > 50 kD auf, v. a. bei ca. 66 und 97 kD, sowie gehäuft Reaktionen an der Stelle zwischen Trenn- und Sammelgel (MAP1/2). Seren von Patienten mit ZNS Manifestation im Verlauf reagierten zu 50% positiv bei einem MG > 50 kD. Von den Seren von Patienten mit bekannter ZNS-Manifestation reagierten 33,3% positiv bei einem Molekulargewicht von > 50 kD. Im ELISA reagierten Seren von 19 der 41 Patienten mit ZNS-Beteiligung (46%) mit der Bande 1 (Bereich MAP1/2), 16 (39%) mit der Bande 2 (97 kD) und 15 (37%) mit der Bande 3 (66 kD). Seren von Patienten ohne ZNS-Manifestation reagierten mit diesen Determinanten in 37%, 37% und 34%. Schlussfolgerung: Die in der vorliegenden Arbeit präsentierten Ergebnisse ergaben keine eindeutige Korrelation zwischen einer neuropsychiatrischen Manifestation einer Kollagenerkrankung und Antikörpern gegen ein bestimmtes Antigen aus ZNS-Gewebe, insbesondere auch die bisher beschriebenen Antigene MAP1/2 und alpha-Tubulin. Ihre Beteiligung an der Entstehung eines solchen Krankheitsbildes muss daher weiter offen bleiben. Es wurde aber wieder deutlich, dass bei Kollagenerkrankungen Antikörper gegen verschiedene neuronale Strukturen gebildet werden, deren bessere Charakterisierung zur Klärung beitragen könnte, wie diese Antikörper induziert werden und welche pathogenetische Bedeutung sie haben. Background: The presence of various autoantibodies in SLE patients with neuropsychiatric manifestations has focused attention on a relationship between the occurrence of specific antibodies and involvement of the nervous system. The aim of this work is to investigate the correlation between CNS autoantibodies and clinical onset of neuropsychiatric manifestations as well as characterization of possible CNS antigens in patients with various collagen diseases with special reference to SLE. Material and Methods: Sera from patients with various diseases were examined by Western blot and ELISA methods. Of the 74 patients studied by Western blotting 16 patients developed a cerebral manifestation in the course, six patients showed CNS involvement at the time of testing. As antigens a 100,000 g supernatant (SN) from bovine brain and an in E. coli expressed alpha-tubulin were used. For the characterization of the target antigens monoclonal antibodies against alpha- and beta-tubulin as well as microtubule-associated protein 2 (MAP2) were used. In ELISA 41 of a total of 112 examined patients showed a CNS involvement at the time of examination, one patient developed a CNS manifestation in the course. Results: In Western blot against the 100 000 g SN from CNS tissue most patients (57%) showed a reaction at a MW of < 50 KD. At the height of the recombinant alpha-tubulin 39% of the patients had a positive reaction. Patients with CNS manifestation in the course had a positive reaction from 68.8% at a MW of < 50 kD and 37.5% at 50 kD. Of the patients with known CNS manifestation 50% showed a positive reaction at a MW of < 50 kD, and only 16.6% showed a positive reaction at 50 kD, which is at the level of the alpha-tubulin. Furthermore there were positive bands at > 50 kD in 49% of the patients, especially around 66 and 97 kD, and heaped reactions at the interface between separating and stacking gel (MAP1/2). 50% of the patients with CNS manifestation in the course responded positively at a MW > 50 kD. In the group of patients with known CNS manifestation 33.3% reacted positively to a molecular weight > 50 kD. A total of 112 patients were tested by ELISA, CNS involvement was described in 41 patients. ELISA showed that 19 (46%) of these 41 patients with CNS involvement had antibodies against MAP1/2 (B1), 16 (39%) against B2 (97 kD) and 15 (37%) against B3 (66 kD). Sera from patients without CNS manifestation responded to these determinants in 37%, 37% and 34%. Conclusion: The results presented in this study showed no clear link between a neuropsychiatric manifestation of collagen disease and antibodies to a particular antigen from CNS tissue, in particular the previously described antigens MAP1 / 2 and alpha-tubulin. Their involvement in the emergence of such a disease must therefore remain open. However it became clear again that antibodies against different neural structures are formed in collagen diseases. Their better characterization could help to clarify how these antibodies are induced and what pathogenetic role they have.

Das Hauptaugenmerk dieser Arbeit ist auf die immundominanten Epitope der E2-Untereinheit der Pyruvatdehydrogenase (PDH-E2) gerichtet, die bei der primär biliären Zirrhose das Target der Anti-M2-Antikörper darstellt. Um die Reaktivitäten der PBC-Seren gegen verschiedene potentielle Epitope der PDH-E2 ermitteln zu können, wurde die komplette Länge der PDH-E2 Untereinheit in Form von 35 Peptiden synthetisiert. Jedes dieser linearen Proteine wies eine Länge von 25 Aminosäuren auf und überlappte mit den jeweils 8 Aminosäuren der beiden benachbarten synthetisierten Peptide. Daraufhin testeten wir diese Peptide mit Seren von 91 klinisch, serologisch und histologisch definierten PBC-Patienten, die zuvor ebenfalls auf ihre IgG- und IgM-Reaktivitäten gegen die Antigene M2 und M4 getestet wurden. Die Ergebnisse dieser Arbeit zeigen deutlich, dass das bedeutendste immundominante Epitop (G4-Peptid), das von den antimitochondrialen Autoimmunantikörpern (AMA) erkannt wird, sich in dem katalytisch aktiven Zentrum der PDH-E2 Untereinheit befindet. Ebenso wurde das bisher als immundominantes Epitop geltende Protein 167-184 der inneren Lipoyl-Domäne mit und ohne gebundenes Liponamid synthetisiert und mit denselben Seren der 91 AMA-positiven PBC-Patienten getestet. Jedoch blieb eine gesteigerte Reaktivität gegen die beiden Peptidvarianten aus. Des Weiteren wurden die PBC-Patienten nach komplementbindenden Antikörpern, Krankheitsverlauf, Art der medikamentösen Therapie und Lebertransplantation in verschiedene Gruppen eingeteilt. Anhand der Absorptionsmittelwerte wird ihr Verhalten im Verlauf und unter Therapie dargestellt. Die AMA-Reaktivitäten von Seren mit komplementbindenden Antikörpern und aktivem Krankheitsverlauf werden mit den Reaktivitäten gegen die 35 PDH-E2-Peptide korreliert. Auf diese Weise wurden die Auswirkungen der verschiedenen Therapien auf die AMA untersucht sowie nach Hinweisen für die Identität des M4-Antigens und für prognostisch wertvolle Marker geforscht. AIM: To search for further immunodominant peptides of the pyruvate dehydrogenase complex E2-component (PDC-E2) recognized by antimitochondrial antibodies (AMA) in primary biliary cirrhosis (PBC). METHODS: Sera from 95 patients with PBC were tested by enzyme-linked immunosorbent assay against 33 synthetic overlapping peptides (25 amino acids; aa) covering the entire length of the E2-subunit of PDC-E2. Furthermore, the inner lipoyl peptide 167-184 was used in an unlipoylated and a lipoylated form as well as coupled to ovalbumin. Sera from 11 AMA negative/ANA positive PBC patients, 63 patients with other liver disorders and 22 healthy blood donors served as controls. RESULTS: Of the 95 PBC-sera, 74% reacted with the peptide 475-499 and 58% with the peptide 407-431 located within the catalytic domain of PDC-E2. Patients with other disorders or healthy controls were positive in only up to 18%. Antibodies to the unlipoylated and lipoylated peptide 167-184 within the inner lipoyl domain were found in only 5% and 11% of the PBC sera, respectively; using ovalbumin-coupled peptides, the incidence increased up to 57% (unlipoylated form). CONCLUSION: Peptides within the catalytic site of PDC-E2 rather than the previously reported lipoyl binding peptide 167-184 may represent major immunodominant epitopes recognized by AMA in PBC.

Hintergrund: Autoantikörper spielen bei der Diagnostik und Klassifikation der autoimmunen Hepatitis (AIH) eine wichtige Rolle. Darüber hinaus wird über eine eventuelle Bedeutung von Autoantikörpern bei der Pathogenese der Erkrankung spekuliert. Bei der AIH Typ III kommen Autoantikörper gegen Leber-/Pankreas (LP)- bzw. ein lösliches Leber-Antigen (SLA) vor. Diese Autoantikörper sind krankheitsspezifisch und reagieren im Westernblot unter Verwendung eines 100 000g Überstandes aus Rattenleber mit einem 52 kDa Protein, das mittlerweile als UGA-Suppressor Transfer RNA (tRNA) assoziiertes Protein (tRNP(Ser)Sec) identifiziert wurde. Seren von Patienten mit AIH Typ III erkennen jedoch weitere Proteine, u.a. eine 48 kDa Determinante, die bisher nicht identifiziert werden konnten und auch mit Seren von Patienten beobachtet wurden, bei denen klinisch/histologisch die typische Konstellation einer AIH vorlag, die bisher bekannten relevanten Autoantikörper aber fehlten. Ziel der vorliegenden Arbeit war daher, diese Reaktionsmuster besser zu definieren und hinsichtlich ihrer Spezifität für eine AIH zu überprüfen. Methoden und Ergebnisse: Seren von 11 Patienten mit anti-LP/SLA positiver AIH III sowie von 27 Patienten mit klinisch/histologisch hochgradigem Verdacht auf AIH (n=27) und 58 Patienten mit AIH Typ I wurden im Westernblot gegen den 100 000g Überstand aus Rattenleber getestet. Als Kontrollgruppen dienten Seren von 6 Patienten mit primär-biliärer Zirrhose sowie von 35 Blutspendern. In Seren der AIH III-Patienten wurden neben Antikörpern gegen die LP/SLA-assoziierte 52kDa Determinante weitere Antikörper gegen 66, 60, 48 und 35 kDa-Proteine beobachtet. Weitere Aufreinigung über Sucrosedichtegradientenzentrifugation ergab eine Anreicherung der 66, 48 und 35 kDa Proteine in einer 1.14-Gradientenfraktion, die für weitere Untersuchungen eingesetzt wurde. 45% der Seren der AIH Typ III- Patienten und 81 % der Seren der Patienten mit v.a. AIH reagierten mit der 66 kDa Bande. Zusätzlich kamen bei diesen Patienten gehäuft Reaktionen im Bereich 48kDa (45% bzw. 37%) und 35 kDa (55% bzw. 37%) vor. Patienten mit AIH Typ I hatten Antikörper gegen das 66 kDa Protein in 9% und gegen das 35 kDa Protein in 3% der Fälle. Gesunde Kontrollen waren negativ; von den sechs PBC-Patienten hatten zwei (33%) Antikörper gegen die 66 und/oder die 48 bzw., 35 kDa-Determinante, und bei diesen Patienten bestand klinisch der Hinweis auf ein Überlappungssyndrom mit einer AIH. Um die Antigene besser zu charakterisieren, wurden die entsprechenden Proteinbanden aus den SDS-Gelen ausgeschnitten und einer massenspektrometrischen Analyse unterworfen. Ferner wurde das 66 kDa-Protein über Immunpräzipitation isoliert und ebenfalls der massenspektrometrischen Analyse zugeführt. Diese Untersuchungen führten aber bisher zu keinen aussagekräftigen Ergebnissen. Schlussfolgerung: Die in dieser Arbeit vorgelegten Ergebnisse zeigen, dass bei Patienten mit AIH Typ III weitere Antikörper vorkommen, die mit Proteinen bei 66, 48 und 35 kDa reagieren. Da dieselben Antikörper auch bei Patienten zu beobachten waren, bei denen der hochgradige Verdacht auf eine AIH bestand, jedoch alle bisher bekannten Autoantikörper negativ waren, könnte es sich um ‚neue’ Markerantikörper handeln, die die Definition einer weiteren Subgruppe von Patienten mit AIH erlauben und damit helfen, die serologische Diagnose der AIH zu verbessern. Die Identifizierung dieser Proteine auf molekularer Ebene steht jedoch noch aus. Background: Autoantibodies play in the diagnosis and classification of autoimmune hepatitis (AIH) an important role. In addition to that, there is speculation about a possible role of autoantibodies in the pathogenesis of the disease. In AIH type III autoantibodies against Liver-/pancreas (LP) - or a soluble liver antigen (SLA) occur. These autoantibodies are disease specific and react in Western blot using a 100 000g supernatant from rat liver with a 52 kDa protein, which is identified as a UGA-suppressor transfer RNA (tRNA)-associated protein (tRNP (Ser) Sec). Sera from patients with AIH type III however identify other proteins including a 48 kDa determinant in western blot. This determinant could not be identified yet and observed with sera from patients, with clinically / histologically typical constellation of AIH but without the previously known typical autoantibodies. The aim of this study was to define this new reaction patterns and to review their specificity for AIH. Methods and results: Sera from 11 patients with anti-LP/SLA positive AIH III and from 27 patients with clinically / histologically highly suspected AIH (n = 27) and 58 patients with AIH type I were tested in a Western blot against the 100 000g supernatant from rat liver. Sera from 6 patients with primary biliary cirrhosis, and 35 blood donors served as a control group. In sera of AIH-III patients were observed in addition to antibodies against the LP / SLA-associated 52kDa determinant, antibodies against 66, 60, 48 and 35 kDa proteins. Further purification on sucrose gradient centrifugation led an accumulation of the 66, 48 and 35 kDa proteins in a 1.14-gradient fraction, which was used for further investigations. 45% of the sera of AIH type III patients and 81% of the sera of patients with suspected AIH reacted with the 66 kDa band. Additionally to that we found in these patients frequently responses at 48kDa (45% or 37%) and 35 kDa (55% or 37%). Patients with AIH type I had antibodies against the 66 kDa protein in 9% and against the 35 kDa protein in 3% of cases. Healthy controls were negative. In the group of the six PBC patients two (33%) had antibodies against the 66 and / or 48 or 35 kDa determinant. In these two patients was clinically suspected an overlap syndrome with AIH. To characterize these antigens better, the corresponding protein bands from SDS gels cut out and subjected to mass spectrometric analysis. Furthermore, the 66 kDa protein was isolated by immunoprecipitation and also analysed with mass spectrometry. But this research led to so far to no meaningful results. Conclusion: This study shows that in patients with AIH type III further antibodies that react with proteins at 66, 48 and 35 kDa exist. The same antibodies were also seen in patients with a high suspicion of AIH, but with negative previously known autoantibodies. Therefore the described reactions could bee 'new' marker antibodies, which allow the definition of a new subgroup of patients with AIH. This could be helping to improve the serological diagnosis of AIH. The identification of these proteins on a molecular level is still pending.

Seit ihrer Entdeckung wecken Fullerene auf Grund ihrer chemischen Struktur große Hoffnungen. Zunehmend werden Fullerene besser verstanden und in der Medizin eingesetzt. Dabei können sie vielfältige Rollen einnehmen: Sei es als Transporter, als Verbindungsstück zwischen Medikament und Targeting-Protein, als Kontrastmittel oder als eigenständiges Medikament. Viele bisherige Studien schließen einen generell toxischen Effekt der Fullerene aus. Mehrere Studien beschreiben den Effekt von Fullerenen als Medikament oder als Kontrastmittel. Es gibt jedoch (außer den Zelltoxizitätsstudien) wenige Arbeiten, die sich mit der Interaktion dieser Stoffgruppe mit dem menschlichen Körper selbst beschäftigen. Für das Immunsystem gibt es nur vereinzelte Studien. Auf Grund der geringen Datenlage und der Erkenntnis, dass Fullerene Einfluss auf die angeborene Immunantwort zu haben scheinen, sowie der zunehmenden Anwendung im klinischen Sektor ist es von großer Wichtigkeit, den Einfluss der Fullerene auf den Körper und das Immunsystem besser zu verstehen. In diesem Kontext untersuchte die vorliegende Arbeit den Einfluss von zwei Vertretern der Fullerene (Polyhydroxy-C60 und N-ethyl-polyamin-C60) auf das Immunsystem. Dazu wurden die PBM Zellen aus dem Blut von 20 gesunden Probanden isoliert und kultiviert. In einem in-vitro Testsystem wurde der Einfluss der Fullerene auf diese Zellen getestet. Verschiedene Antigene (BCG, Tetanus Toxin und PPD) stimulierten die PBM Zellen zu unterschiedlichen Immunreaktionen vom TH1-oder TH2-Typ, um mögliche Effekte der Fullerene auch im aktivierten Immunsystem zu klassifizieren. Die Fullerene wurden in unterschiedlichen Konzentrationen zugeführt. Untersucht wurde damit der Einfluss der Fullerene auf die Proliferation von PBM Zellen, die Zytokinproduktion an Hand von IL-1, IL-5, IL-6, IL-10, IL-13, IFN-gamma, TNF-alpha, TNF-beta, GM-CSF mittels Sandwich-ELISA und die frühe Aktivierung der Immunzellen an Hand der CD69-Expression mittels Durchflusszytometrie. Es konnte gezeigt werden, dass die zwei Fullerene die Proliferation von PBMC stimulieren. Eine verstärkte CD69-Expression fand sich aber nur auf NK-Zellen. Auch auf die Produktion T-Zell-assoziierter Zytokine hatten sie keinen Einfluss, während sie die Sekretion von IL-6 signifikant verstärkten. Zusammenfassend können wir sagen, dass die getesteten Fullerene keinen immunsuppressiven Effekt haben und nicht zelltoxisch sind und insbesondere Zellen des spezifischen Immunsystems nicht wesentlich beeinflussen. Dagegen weisen die Befunde durchaus auf eine Aktivierung von Zellen des angeborenen Immunsystems hin (z.B. NK-Zellen). Since the discovery of fullerenes, there are great expectations because of their chemical structure. We get to know more and more about fullerenes and they are more often used in medicine. For example as transporter, as connector between drug and targeting-protein, as contrast agent or as standalone drug. Many studies show no general toxic effect of fullerenes. Some studies describe the effects of fullerenes as drug or contrast agent. There are few studies (except the cell toxicity studies) that deal with the interaction of this element group and the human body itself. Because of the few data and the fact, that fullerenes seem to have an effect on the unspecific immune response, as well as the upcoming use in medicine, it is very important to understand the influence of fullerenes on the human body and the immune system. In this work we studied two fullerenes named Polyhydroxy-C60 and N-ethyl-polyamin-C60 and their influence on the immune system. Therefore PBM-cells were isolated and cultivated from the blood of 20 healthy donors. We checked the influence of fullerenes on the PBM-cells in an in-vitro system. Different antigens (BCG, tetanus toxin and PPD) were used to provoke different immune responses (TH1- or TH2-typ), to classify possible effects of fullerenes in different situations of an immune response. The fullerenes were added in different concentrations. We investigated the influence of the fullerenes on the proliferation of PBM-cells, the cytokine production (IL-1, IL-5, IL-6, IL-10, IL-13, IFN-gamma, TNF-alpha, TNF-beta, GM-CSF via sandwich-ELISA) and the early activation of immune cells by CD69 expression with flow cytometry. We could show an increased proliferation of PBM-cells through the used fullerenes. An increased CD69 expression was only found on natural killer cells. There was no influence of the production of t-cell-associated cytokines, but the secretion of IL-6 was significantly increased. In summary, the used fullerenes do not suppress the immune system and show no cytotoxicity. They especially don’t affect specific/adaptive immune cells. But our data shows definitely an activation of innate immune cells like natural killer cells.

Das Medikament Umckaloabo (Eps®7630) stellt einen ethanolischen Auszug aus den Wurzeln von Pelargonium sidoides und P. reniforme dar, einer südafrikanischen Geranienart, die in der dortigen traditionellen Medizin zur Behandlung von Infektionskrankheiten eingesetzt wird. Es ist in Deutschland zur Behandlung von Bronchitiden zugelassen. Chemische Analysen des Pflanzenauszuges ergaben ein großes Spektrum an Polyphenolen. In bisherigen experimentellen Studien wurde bei Zugabe von Umckaloabo u.a eine erhöhte IFN-gamma-Synthese in virusinfizierten Zellen nachgewiesen sowie eine Aktivierung von Zellen des angeborenen Immunsystems einhergehend mit einer Freisetzung von TNF-alpha, IL-1, IL-12, Il-18 und IFN-alpha/gamma und Stickoxiden. Ziel der vorliegenden Arbeit war daher, die Wirkung von Umckaloabo auf Zellen des erworbenen Immunsystems in vitro zu analysieren mittels PBMC (peripheral blood mononuclear cells) von insgesamt 20 gesunden Probanden. Durch kostimulierende Antigene (BCG, purified protein derivative [PPD] und Tetanus-Toxoid [TT]) wurden TH1- bzw. TH2-Immunreaktionen provoziert und der Einfluss von Umckaloabo in unterschiedlichen Konzentrationen innerhalb dieses in-vitro-Testsystems untersucht. Zum Einsatz kamen Proliferationsassays, Methoden zur quantitativen Zytokinbestimmung mittels Sandwich-ELISA, sowie durchflusszytometri¬sche Detektionsmethoden zum Nachweis verschiedener Zelloberflächenmoleküle (CD3, CD4, CD8, CD19, CD45, CD56) sowie des frühen Aktivierungsmarkers CD69 und der Expression des für regulatorische T-Zellen (Treg) charakteristischen intrazellulären Proteins Foxp3. Umckaloabo führte in Konzentrationen von 1 bis 1000 µg/ml zu einer signifikanten Steigerung der Proliferation von Lymphozyten: Ohne Kostimulation und bei Kostimulation mit PPD um den Faktor 10, bei Kostimulation mit TT um den Faktor 2. Durchflusszytometrisch konnte gezeigt werden, dass insbesondere die CD4-positiven T-Helferzellen zunahmen, etwas weniger auch die CD8-positiven zytotoxischen T- bzw. CD56-positiven natürlichen Killer (NK)-Zellen. CD19-positive B-Zellen wurden dagegen kaum beeinflusst. In einer Konzentration von 10 µg/ml führte Umckaloabo zu einem signifikanten Anstieg der Expression von CD69, d.h. einer Aktivierung dieser Zellsubpopulationen. Die Analyse der Zytokinproduktion ergab, dass die für Makrophagen typischen Zytokine wie IL-1, IL-6 und TNF-alpha bei 10 µg/ml signifikant anstiegen, ebenso bei Kostimulation durch PPD oder TT. Die Ausschüttung von TNF-alpha bei Kostimulation mit TT wurde bei 10 µg/ml signifikant gehemmt, die von IFN-gamma signifikant gesteigert. Die durch TT induzierte Produktion der TH2-typischen Zytokine IL-5 und IL-13 wurde durch Umckaloabo bei 1 µg/ml signifikant gehemmt. Die Ausschüttung von IL-10 durch Umckaloabo wurde bei 1 µg/ml signifikant gesteigert, ebenso bei Kostimulation mit PPD, während die IL-10-Spiegel bei den starken Kostimuli TT bzw, BCG durch Zugabe von Umckaloabo nicht verändert wurden. Die durchflusszytometrische Analyse der regulatorischen T-Zellen ergab eine deutliche Zunahme des Anteils an Treg innerhalb der Population der CD4-positiven Zellen bei Zugabe von Umckaloabo, die in schwächerer Ausprägung auch bei Kostimulation mit TT bzw. PPD zu sehen war. Zusammenfassend konnten die angeführten experimentellen Untersuchungen zeigen, dass Umckaloabo in einem in-vitro-System komplexe Wirkungen auf PBMC hat. Es führt in erster Linie zu einer Aktivierung von Makrophagen, TH1-Zellen und NK-Zellen, während TH2-Reaktionen inhibiert werden. Darauf könnte durchaus der in vivo beschriebene positive Effekt bei Infektionskrankheiten zurückzuführen sein. Ferner scheint die Substanz Treg zu aktivieren, was möglicherweise erklärt, dass das Medikament nur in seltenen Fällen zu Überreaktionen führt. Die vorliegende Arbeit ist somit ein Beitrag, den bisher nur empirisch belegten immunstimulierenden Einsatz von Umckaloabo wissenschaftlich zu untermauern, macht aber auch weiteren Forschungsbedarf deutlich. Anzustreben sind insbesondere eine Zuordnung der immunologischen Effekte zu bestimmten Komponenten des Extraktes sowie prospektive Studien unter Einnahme von Umckaloabo. Ectracts of the Geraniacea Pelargonium sidoides have been traditionally used for the treatment of respiratory tract infections in southern Africa. Nowadays, the modern equivalent termed Eps®7630 (trademark: Umckaloabo), an ethanolic extract of the roots of the plant is succesfully used in phytotherapy. Numerous clinical studies have provided evidence of the beneficial effects of Eps®7630 therapy in patients afflicted with bronchitis, sinusitis and rhinopharyngitis but the molecular mechanisms that provide these effects are not yet known. Therefore it is promising that Eps®7630 alone as well as several of its major constituents could be recently shown to have effects on innate immunity in vitro, e.g. they enhanced the release of TNF-alpha and iNO in Leishmania-infected macrophages. Therefore, aim of this project was to study the influence of Eps®7630 in adaptive immune responses in vitro by means of FACS, proliferation and cytokine assays. PBMC of 20 healthy donors were isolated and cultivated with different concentrations of Umckaloabo. Addition of different antigen stimuli (BCG, PPD and tetanus toxoid) provocated different immunologic reactions (TH1 respectively TH2). In these in-vitro studies we could show that addition of Umckaloabo in concentrations from 1µg/ml up to 1000 µg/ml significantly enhanced proliferation of different kinds of lymphocytes, especially of CD-4 positive cells and Treg -cells. Analysis of cytokines showed a significantly enhanced secretion of IL-1, IL-6, TNF-alpha and IL-10. We could prove that Umckaloabo does not only influence the innate immune system but also influences lymphocytes by different mechanisms. Enhancing of TH1 reactions could be a possible mechanism of antiviral effects of Umckaloabo.

Hintergrund: Antimitochondriale Antikörper (AMA), insbesondere Anti-M2, gelten als pathognomonisch für die primär-biliäre Zirrhose (PBC). In der vorliegenden Arbeit werden neue mitochondriale Antigen-Antikörpersysteme vorgestellt, die bei Patienten mit klinisch/ histologisch hochgradigem Verdacht auf PBC und positiven AMA aber negativen Befunden für Anti-M2 zu beobachten waren. Methoden und Ergebnisse: Es wurden 73 Anti-M2 negative Seren von Patienten mit PBC, 22 Anti-M2 positive Seren, insgesamt 88 Seren von Patienten mit anderen Autoimmun- oder Lebererkrankungen sowie 30 Seren von gesunden Blutspendern untersucht. Vierzehn von 43 (33%) Anti-M2 negativen Seren von Patienten mit PBC, die im Westernblot gegen einen 100 000g Überstand von submitochondrialen Partikeln aus Rinderherz getestet wurden, reagierten mit einer Determinante bei 60 kD, die sich in der Saccharose-Dichtegradientenzentrifugation bei 1,18-1,20 anreichern ließ. Nach Isolierung durch Elektoelution aus dem Gel konnten in dieser Bande mittels massenspektrometrischer Analysen F1-ATPase und Komplex III der mitochondrialen Atmungskette identifiziert werden. Von den Seren der Vergleichsgruppen reagierten auch 70% der Anti-M2 positiven Seren mit der 60 kD Bande. Seren von gesunden Probanden und Patienten mit anderen Erkrankungen waren dagegen vollständig negativ. Schlussfolgerung: Die hier vorgelegten Untersuchungen lassen darauf schließen, dass es bei der PBC neben den Anti-M2 Antikörpern weitere spezifische antimito-chondriale Antikörper gibt, die bisher allerdings ausschließlich im IFT und Westernblot nachgewiesen werden können. Diese Befunde tragen einerseits zur Verbesserung der serologischen Diagnostik bei, könnten aber auch neue Aspekte zur Aufklärung der Ätiopathogenese dieser chronischen Erkrankung eröffnen. Background: Antimitochondrial antibodies (AMA), especially anti-M2, are considered to be pathognomonic for primary biliary cirrhosis (PBC). In this work new mitochondrial antigen-antibody-systems are described which could be found in the sera of patients with clinically/ histologically defined PBC and presence of AMA in IFT but no reaction with the PBC-specific M2-antigen in ELISA and Western blotting. Methods and results: 73 anti-M2 negative sera from patients with PBC, 22 anti-M2 positive sera from patients with PBC and all together 88 sera from patients with other autoimmune diseases or diseases of the liver, as well as 30 sera of healthy donors have been investigated. Fourteen of 43 (33%) anti-M2 negative sera from patients with PBC which had been tested against a 100 000 g supernatant of submitochondrial particels from beef heart (BH SMP SN) recognized an antigen of 60 kd. This antigen could be enriched by Sucrose Density Gradient Centrifugation at 1,18-1,20. After isolation by electroelution out of stainded polyacrylamid gels, in this 60 kd band F1-ATPase and complex III of the mitochondrial electron transport chain could be identified by mass spectrometry (MALDI-TOF). In the control groups, 70 % of anti-M2 positive sera reacted as well with the 60 kd antigen, however none of the sera from healthy donors and patients with other diseases than PBC recognized the antigen. Conclusion: These results suggest additional specific antimitochondrial antibodies other than anti-M2 antibodies in patients with PBC. These antibodies have been shown so far exclusively in IFT and Western blotting. Recognition of these antibodies may improve serologic diagnosis of PBC in the future as well as clarify the ethiopathogenetic understanding of this chronic disease.

Aprotinin wird sowohl in systemischer Applikationsform als auch lokal als Bestandteil von Fibrinklebern zur perioperativen Blutungsverringerung angewendet. Als Fremdantigen kann es das Immunsystem sensibilisieren und bei Reexposition anaphylaktische Nebenwirkungen verursachen. Die vorliegende Arbeit sollte die zelluläre Immunreaktion bei Patienten untersuchen, die Aprotinin erst- und einmalig in systemischer, lokaler oder kombinierter Applikationsform erhielten. Es wurde die Proliferation der aus peripherem Patientenblut gewonnenen Lymphozyten mit dem Antigen Aprotinin im Lymphozytenproliferationstest (LTT) bestimmt, und zwar vor Exposition sowie eine, vier und zwölf Wochen nach Exposition. Desweiteren wurden die Zytokine IL-1, IL-6, TNF-a, IL-4, IL-5, IL10, IL-12, g-IFN und GM-CSF in den Überständen der Lymphozytenkulturen und in den Patientenseren mittels ELISA sowie die Expression der Zytokin mRNA in den Lymphozyten mittels PCR bestimmt. Die Lymphozytenproliferation zeigte unabhängig vom Applikationsmodus in allen drei Gruppen beginnend 4 Wochen nach Exposition eine Sensibilisierung des Immunsystems. Die Zytokinspiegel in Überständen in Aprotininstimulierten Lymphozyten nach ein- und erstmaliger Gabe veränderten sich in den drei Gruppen im Verlauf nicht signifikant, IL-6 und IL-10 wurden allerdings auffällig häufig produziert. Eine eindeutige Zuordnung der Immunantwort zu Typ1- bzw. Typ2-Reaktion ließ sich nicht nachweisen. In Einzelfällen scheint Aprotinin aber Typ2-Reaktionen (IL-5) zu stimulieren. Die Zytokine in den Patientenseren zeigten keine wesentlichen Veränderungen. Diese Daten zeigen, daß Aprotinin immunkompetente Zellen und insbesondere TH1/Typ1- bzw. TH2/Typ2-Reaktionen in der Gesamtheit nicht signifikant beeinflußt, aber in Einzelfällen eine TH2-Antwort induzieren kann. Dazu würde passen, daß zwar gelegentlich Nebenwirkungsreaktionen in Form von anaphylaktischen Reaktionen auftreten, diese jedoch im Hinblick auf die häufige Applikation von Aprotinin doch sehr selten sind. Dennoch sollte, wie bereits von anderen Autoren gefordert, eine eventuelle frühere Aprotiningabe sorgfältig evaluiert werden. Eine mögliche Reexposition sollte nur unter strenger Indikationsstellung und unter Anaphylaxieprophylaxe erfolgen. Aprotinin, a well-known protease-inhibitor, is applied systemically and locally as fibrin sealant to decrease peri-operative bleeding. As foreign antigen it can sensitize the immune system and cause anaphylactic reactions. Therefore, the present study was designed to examine the cellular immune reaction in patients having received Aprotinin for the first time and uniquely either systemically, locally or both. The lymphocyte proliferation in response to the antigen Aprotinin was determined in the lymphocyte transformation test (LTT) before as well as one, four and twelve weeks after exposition. Furthermore, the production of the cytokines IL-1, IL-6, TNF-a, IL-4, IL-5, IL-10, IL-12, g-IFN and GM-CSF in lymphocyte culture and in patients' sera was determined on protein level by ELISA as well as on mRNA level by RT-PCR. Lymphocyte proliferation showed independently of the application mode in all three groups (Aprotinin application locally, systemically or both) a sensitization of the immune system beginning four weeks after exposition. The cytokine levels in culture supernatants of aprotinin-stimulated lymphocytes after the first and unique application did not show significant alterations. However, IL-6 and IL-10 were remarkably frequently produced. A clear subclassification of the immune response into Th1/type1- and /or Th2/type2-reaction on the basis of the cytokine patterns could not be done. However, in individual cases Aprotinin preferentially seemed to induce type2-reactions which could be seen at the increased IL-5 production. The cytokines in the patients' sera did not show any substantial changes. These data indicate that Aprotinin does not significantly affect immune-competent cells and in particular Th1/type1 and/or Th2/type2- reactions. However, in individual cases a Th2/type2-reaction can be induced, an observation which goes in line with the fact that some but very few patients show occasional side effects in form of anaphylactic reactions. Nevertheless, in view of the broad and frequent applications of Aprotinin these side effects are very rare. Yet, the earlier exposition to Aprotinin, as already demanded by other authers, should be evaluated carefully. A possible reexposition should take place under strict observation and accompanied by prophylactic means against anaphylactic reactions.

Der Verlauf von Eosinophilen Leukozyten im Blut und Anti-ML-1-IgG-Subklassen über 24 Monate wurde im Sinne einer retrospektiven Anwendungsbeobachtung bei Mammakarzinom-Patientinnen einer onkologischen Schwerpunktpraxis untersucht, die sich erstmals einer Behandlung mit dem Mistelpräparat ABNOBAviscum Mali (R) unterzogen. Zielsetzung der Untersuchung ist die Bereitstellung eines größeren Datenmaterials dieser Verlaufsparameter und eine Auswertung unter explorativen Gesichtspunkten. Im Verlauf der 24-monatigen Behandlung bildeten alle Patientinnen IgG-Antikörper gegen ML-1. Der individuelle Verlauf der IgG-Subklassenmuster erwies sich als ausgesprochen vielgestaltig und korrelierte nicht mit anderen Patienten- oder Verlaufscharakteristika. Die Bildung von Antikörpern der Subklassen 1 und 3 ging zeitlich der Subklasse 4 voran, die Subklasse 2 wurde nur bei 18 % der Patientinnen gebildet und nahm im Verlauf der Behandlung wieder ab. In einer logarithmischen Modellrechnung nahm sowohl der Titer für IgG1 wie für die IgG4 vom 3. zum 24. Monat signifikant zu. Auch die (nicht logarithmischen) Titer-Mittelwerte der Subklassen 1 und 4 sowie der Subklassen 2 und 4 sowie 2 und 3 waren signikant positiv korreliert (p< 0,01). Keine signifikante Korrelation bestand zu den Eosinophilen. Die Eosinophilenzahlen waren sowohl 1 Monat wie auch 24 Monate nach Behandlungsbeginn signifikant erhöht. Trotz der hohen Immunogenität des verwendeten Mistelextraktes zeigt sich eine gute Verträglichkeit ohne schwerwiegende Nebenwirkungen. Die Untersuchung bestätigt die vorbeschriebene hohe Penetranz einer frühen Eosinophilie und einer Anti-ML1-IgG-Bildung unter Behandlung mit VAE. Das zur Zeit der höchsten Eosinophilie noch seltene Auftreten lektinspezischen IgG und das im Verlauf der Antikörperbildung eher späte Auftreten von solchen der Subklasse 2 und 4 unterstützt die Annahme, dass die Eosinophilie durch das Vielstoffgemisch des VAE über das unspezifische Immunsystem getriggert wird. Verwendet man die Subklassenverteilung als Surrogatmarker für die Typ1/Typ2-Polarisierung des Immunsystems so entwickelt sich während einer 24monatigen Behandlung mit VAE eine parallele Stimulation beider Wege. Weitere Untersuchungen sind erforderlich, um den Stellenwert von Eosinophilie und Anti-ML1-IgG-Bildung in der Behandlung mit VAE zu erhellen. Eosinophilic leukocytes and mistletoe-lectin specific anti-ML-1-IgG subclasses were monitored in breast cancer patients during 24 months of treatment with a mistletoe extract (ABNOBAviscum Mali (R)) in an ambulatory oncologic setting and evaluated retrospectively. The aim is to provide a pool of data on these parameters and perform an explorative analysis. During 24 months of treatment, all patients developed IgG antibodies against mistletoe lectin I (ML-1). The individual patterns of IgG-subclass distribution were highly variable and did not correlate with other parameters. The production of IgG1 and IgG3 began earlier than that of IgG4. IgG2 reached a maximum prevalence of only 18% and declined later. In a logarithmic model, the titer of IgG1and IgG4 increased significantly between the month 3 and month 24. A significant positive correlation was found for the non-logarithmic mean of IgG1 with IgG4, IgG2 with IgG4 and IgG2 with IgG3 (p< 0,01). No significant correlation of IgG-subclass levels existed with eosinophils. The eosinophils themselves where significantly elevated in month 1 and month 24. Despite of a high immunogenic potential of the used mistletoe extract, no severe adverse reactions were observed. This study underlines the earlier described high potency of mistletoe extracts to induce anti-ML1-IgG and elevations in eosinophilic counts. Given the fact that the eosinophily occurs much earlier in the treatment course than the subsequent conversion for IgG2 and IgG4 antibodies, it is assumed that eosinophily is triggered by mechanisms of the unspecific immune system in response to mistletoe components. When using the IgG-subclass distribution to estimate the polarisation of the immune response to mistletoe, a co-stimulation of both Typ-1- and Typ-2- paths is observed within 24 months of treatment with mistletoe extracts. Further studies are needed to examine the significance of eosinophily and anti-ML1-IgG production during treatment with mistletoe extracts.

In der vorliegenden Arbeit wurden verschiedene Verfahren zum Nachweis von Anti-Neutrophil-Cytoplasmic Antibodies (ANCA) verglichen und die Prävalenz dieser Antikörper bei verschiedenen Erkrankungen (autoimmune Lebererkrankungen, Vaskulitiden) sowie ihre Assoziation mit anderen serologischen Markern untersucht. Für den Immunfluoreszenztest (IFL) wurden Objektträger mit Granulozyten von 10 verschiedenen Spendern angefertigt und ausgetestet; ferner wurden unterschiedliche Fixationsmethoden (Äthanol vs. Methanol und Formalin) untersucht. Die Patientenseren wurden zusätzlich im ELISA und Westernblot gegen Granulozyten getestet. Nur von zwei der getesteten zehn Spender konnten Granulozyten isoliert werden, die sich zum Nachweis von ANCA im Immunfluoreszenztest (IFL) eigneten. Fixation mit Methanol führte zu reproduzierbareren Ergebnissen als die mit Äthanol oder Formaldehyd. ANCA mit einem perinukleären Fluoreszenzmuster (pANCA) waren vor allem bei Patienten mit primär sklerosierender Cholangitis (PSC), autoimmuner Hepatitis (AIH), chronisch entzündlichen Darmerkrankungen und Vaskulitiden nachweisbar, ein zytoplasmatisches Fluoreszenzmuster (cANCA) war in erster Linie bei Patienten mit primär-biliärer Zirrhose und M. Wegener zu beobachten. Unter standardisierten Testbedingungen, lag bei der PSC die Prävalenz der ANCA bei 79%, bei der AIH bei 73%, bei Patienten mit chronisch entzündlichen Darmerkrankungen bei 56%(M. Crohn) bzw. 86% (Kolitis ulcerosa). 87% der PBC Patienten waren AMA positiv, 40% von ihnen zeigten ein cANCA Muster. Bei diesen Patienten waren IgM- und Gesamtbilirubinspiegel signifikant häufiger erhöht als bei ANCA negativen. Der ELISA mit Granulozyten eignete sich nicht zur Detektion von ANCA. Bei der Untersuchung von Patientenseren mit dem Westernblot konnten zwei Determinanten bei 35 und 95kD identifiziert werden, mit denen spezifische Seren von Patienten mit PSC und Kolitis ulcerosa reagierten. Diese Befunde machen einerseits die Problematik in der Standardisierung des Nachweises von ANCA deutlich, belegen aber andererseits, dass mit Hilfe eines gut etablierten Testsystems der Nachweis von p- oder cANCA einen sinnvollen Parameter in der Diagnostik nicht nur der Vaskulitiden sondern auch der autoimmunen Lebererkrankungen darstellt. Der Nachweis identischer Determinanten mit Westernblot bei Patienten mit PSC und Kolitis ulcerosa weist auf einen gemeinsamen Antigenkomplex und damit möglicherweise einen gemeinsamen pathogenetischen Mechanismus bei beiden Krankheitsbildern hin. Der Nachweis von ANCA mit einem atypischen zytoplasmatischen Muster bei Patienten mit PBC die nicht mit den bekannten AMA-Spezifitäten zu korrelieren scheinen, könnte auf einen weiteren zytoplasmatischen Antigen/Antikörperkomplex bei dieser Erkrankung hinweisen, der möglicherweise mit der Krankheitsaktivität korreliert. Eine weitere Identifizierung der Targetantigene von ANCA wäre daher ein wichtiger Schritt in der Einordnung ihrer diagnostischen und ätiopathogenetischen Relevanz. In the following study, several different methods for the detection of anti-neutrophil-cytoplasmic antibodies (ANCA) were compared with each other and the prevalence of these antibodies in various diseases (autoimmune liver diseases, vasculitis) as well as their association with other serological markers was examined. Microslides with granulocytes from 10 different persons were made and tested with the immunofluorescence test (IFL); furthermore, different methods of fixation (ethanol vs. methanol and formalin) were examined. The patient’s serums were further tested in ELISA and Western blot for granulocytes. Granulocytes could only be isolated in two of the ten donors, which were then suitable for the detection of ANCA in the immunofluoresence test (IFL). Fixation with methonal produced more reiterable results than fixation with ethanol or formaldehyde. ANCA with a perinuclear fluorescent pattern (pANCA) were observed mostly in patients with primary sclerosing cholangitis (PSC), autoimmune hepatitis, inflammatory bowel diseases, and vasculitis; a cytoplasmic fluorescent pattern (cANCA) was observed primarily in patients with primary-biliariy cirrhosis and Wegener’s granulomatosis. Under standardised test conditions, the prevalence of ANCA in PSC stood at 79%, in AIH at 73%, and in patients with inflammatory bowel diseases at 56% and 86% for Crohn’s disease and ulcerative colitis respectively. 87% of the PBC patients were AMA-positive; 40% showed a cANCA pattern. These patients had a significant, more frequently heightened IgM and total bilirubin level than those patients who were ANCA-negative. The ELISA with granulocytes was not suitable for the detection of ANCA. In the examination of patient serums with Western blot, two determinants were identified at 35 and 95kD that reacted with specific serums from patients with PSC and ulcerative colitis. These results demonstrated on the one hand the problems associated with the standardisation of the detection of ANCA, however, on the other hand, these results verify that, with the help of a well established test system, the detection of pANCA or cANCA offers a useful parameter in the diagnosis not only of vasculitis but also of autoimmune liver diseases. The detection of identical determinants with Western blot in patients with PSC and ulcerative colitis indicates an antigen complex common to both, and therefore potentially indicates a pathogenetic mechanism common to both illnesses. The detection of ANCA with an atypical cytoplasmic pattern in patients with PBC that do not appear to correlate with known AMA-specificities could indicate an additional cytoplasmic antigen/antibody complex in connection with this illness that possibly correlates with illness activity. A further identification of the target antigen of ANCA would therefore be an important step towards the classification of its diagnostic and aetiopathogenetic relevance.