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Elucidating the basis of chronic disease courses and the development of appropriate treatment methods for inflammatory diseases still represent a big challenge for medical science, as the mechanisms driving aberrant immune reactions are mostly still unknown. Of particular interest is the identification of checkpoints that regulate the function and differentiation of proinflammatory cells during the pathogenesis, along with methods for modulation of specific checkpoints as a treatment approach. Innate receptors, such as members of the natural killer group 2 family (NKG2X), natural cytotoxicity receptors (NCR) or Toll-like receptors (TLRs), play an important role in modulating the immune response. NKG2 member D (NKG2D) is a potent activating receptor of the immune system, known as a sentinel for cellular danger signals presented by cells exposed to endoplasmic reticulum (ER) stress, cell death or an inflammatory cytokine milieu. NKG2A/C bind the non-classical HLA class I molecule, sense changes in ligand expression associated with malignant transformation and cellular stress and their main function is to send inhibitory or activating signals to NK cells and subsets of T cells. In this review, we present our latest knowledge on the understanding of the role of innate receptors in the context of chronic inflammation and autoimmunity with special emphasis on danger sensor receptors NKG2D and NKG2A/C.Die Aufklärung der Grundlagen chronischer Krankheitsverläufe und die Entwicklung geeigneter Behandlungsmethoden von Entzündungskrankheiten sind in der Biomedizin noch immer eine große Herausforderung. Die Mechanismen, die fehlgeleitete Immunreaktionen auslösen, sind größtenteils noch unbekannt. Von besonderem Interesse ist die Identifizierung von Kontrollpunkten oder Checkpoints, welche die Funktion und Differenzierung entzündungsfördernder Zellen während der Pathogenese regulieren, sowie von Methoden zur Modulation spezifischer Checkpoints als therapeutischen Ansatz. Angeborene Rezeptoren wie die Mitglieder der Natural-Killer-Group-2-Familie (NKG2X), natürliche Zytotoxizitätsrezeptoren (NCR) oder Toll-like-Rezeptoren (TLR) spielen eine wichtige Rolle bei der Modulation der Immunantwort. NKG2, Mitglied D (NKG2D) ist ein potenter Aktivierungsrezeptor des Immunsystems, der als Wächter für zelluläre Gefahrensignale bekannt ist, die von Zellen ausgehen, die einem Stress des endoplasmatischen Retikulums (ER), dem Zelltod oder einem entzündlichen Zytokinmilieu ausgesetzt sind. NKG2A/C binden das nichtklassische HLA-Klasse-I-Molekül, erkennen Veränderungen in der Ligandenexpression, die mit Transformation und Tumorzellstress einhergehen, und ihre Hauptfunktion besteht darin, hemmende bzw. aktivierende Signale an NK- und T‑Zellen zu senden. In dieser Übersichtsarbeit werden neue Erkenntnisse zum Verständnis der Rolle angeborener Rezeptoren bei chronischen Entzündungen und Autoimmunität mit besonderem Schwerpunkt auf dem Gefahrensensor-Rezeptor NKG2D und NKG2A/C präsentiert.

Fibroblast growth factor-binding protein 1 (FGFBP1) is a secreted chaperone that mobilizes paracrine-acting FGFs, stored in the extracellular matrix, and presents them to their cognate receptors. FGFBP1 enhances FGF signaling including angiogenesis during cancer progression and is upregulated in various cancers. Here we evaluated the contribution of endogenous FGFBP1 to a wide range of organ functions as well as to skin pathologies using Fgfbp1-knockout mice. Relative to wild-type littermates, knockout mice showed no gross pathologies. Still, in knockout mice a significant thickening of the epidermis associated with a decreased transepidermal water loss and increased proinflammatory gene expression in the skin was detected. Also, skin carcinogen challenge by 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoyl-phorbol-13-acetate resulted in delayed and reduced papillomatosis in knockout mice. This was paralleled by delayed healing of skin wounds and reduced angiogenic sprouting in subcutaneous matrigel plugs. Heterozygous green fluorescent protein (GFP)–knock-in mice revealed rapid induction of gene expression during papilloma induction and during wound healing. Examination of wild-type skin grafted onto Fgfbp1 GFP–knock-in reporter hosts and bone marrow transplants from the GFP-reporter model into wild-type hosts revealed that circulating Fgfbp1-expressing cells migrate into healing wounds. We conclude that tissue-resident and circulating Fgfbp1-expressing cells modulate skin carcinogenesis and inflammation.

Despite intensive scientific research over the past decades, atherosclerosis and atherothrombosis are the leading cause of mortality worldwide. During the recent past it has become clear that atherosclerosis is not merely a lipid-driven disease but a multifactorial process involving chronic inflammation of large arteries. This review article briefly outlines the mechanistic nature of atherosclerosis, presents a synopsis of the current state of the art treatment strategies and finally outlines several therapeutic options, which are in clinical and experimental testing.

SummaryPlatelet-monocyte interactions are strongly implicated in thrombo-inflammatory injury by actively contributing to intravascular inflammation, leukocyte recruitment to inflamed sites, and the amplification of the procoagulant response. Instant blood-mediated inflammatory reaction (IBMIR) represents thrombo-inflammatory injury elicited upon pancreatic islet transplantation (islet-Tx), thereby dramatically affecting transplant survival and function. Developmental endothelial locus-1 (Del-1) is a functionally versatile endothelial cell-derived homeostatic factor with anti-inflammatory properties, but its potential role in IBMIR has not been previously addressed. Here, we establish Del-1 as a novel inhibitor of IBMIR using a whole blood–islet model and a syngeneic murine transplantation model. Indeed, Del-1 pre-treatment of blood before addition of islets diminished coagulation activation and islet damage as assessed by C-peptide release. Consistently, intraportal islet-Tx in transgenic mice with endothelial cell-specific overexpression of Del-1 resulted in a marked decrease of monocytes and platelet-monocyte aggregates in the transplanted tissues, relative to those in wild-type recipients. Mechanistically, Del-1 decreased platelet-monocyte aggregate formation, by specifically blocking the interaction between monocyte Mac-1-integrin and platelet GPIb. Our findings reveal a hitherto unknown role of Del-1 in the regulation of platelet-monocyte interplay and the subsequent heterotypic aggregate formation in the context of IBMIR. Therefore, Del-1 may represent a novel approach to prevent or mitigate the adverse reactions mediated through thrombo-inflammatory pathways in islet-Tx and perhaps other inflammatory disorders involving platelet-leukocyte aggregate formation.Supplementary Material to this article is available online at www.thrombosis-online.com.

Hepatocellular steatosis constitutes the most frequent liver disease in western countries and may progress to steatohepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). The lipid droplet (LD)-associated proteins perilipin, adipophilin, TIP47 ("tail interacting protein of 47 kDa"), S3-12 and myocardial LD protein (MLDP), so-called perilipins 1-5 (PAT family) govern formation, maintenance and degradation of LDs. A lack of perilipin in mice inhibits obesity and a lack of adipophilin or TIP47 inhibit the development of fatty liver disease. In long-term cell culture models as well as in liver biopsies of patients with different acute and chronic liver diseases, LD-associated proteins are sequentially recruited to LDs and regulated via peroxisome proliferator-activated receptor (PPAR) α and PPARγ as well as posttranscriptionally via alternative splicing, LD fusion and lipolysis. Whereas TIP47 and MLDP coat small newly formed LDs in acute microvesicular steatosis, adipophilin constitutes a robust general marker for LDs in many different cell types. Perilipin is important for the long-term storage of lipids in macrovesicular steatosis and controls lipolysis via hormone-dependent phosphorylation. During malignant transformation, increased formation of small LDs and overexpression of adipophilin, TIP47 and MLDP are detected, possibly as the expression of an altered tumor metabolism analogous to a Warburg effect. Adipophilin correlates positively with the proliferation rate of HCC cells. Cultured cells with downregulation of TIP47 or adipophilin via small interfering RNA (siRNA) or small hairpin RNA (shRNA) show less but larger LDs with reduced neutral fat content.

Microfibrillar-associated protein 4 (MFAP4) is localized to elastic fibers in blood vessels and the interalveolar septa of the lungs and is further present in bronchoalveolar lavage. Mfap4 has been previously suggested to be involved in elastogenesis in the lung. We tested this prediction and aimed to characterize the pulmonary function changes and emphysematous changes that occur in Mfap4-deficient ( Mfap4−/−) mice. Significant changes included increases in total lung capacity and compliance, which were evident in Mfap4−/−mice at 6 and 8 mo but not at 3 mo of age. Using in vivo breath-hold gated microcomputed tomography (micro-CT) in 8-mo-old Mfap4−/−mice, we found that the mean density of the lung parenchyma was decreased, and the low-attenuation area (LAA) was significantly increased by 14% compared with Mfap4+/+mice. Transmission electron microscopy (TEM) did not reveal differences in the organization of elastic fibers, and there was no difference in elastin content, but a borderline significant increase in elastin mRNA expression in 3-mo-old mice. Stereological analysis showed that alveolar surface density in relation to the lung parenchyma and total alveolar surface area inside of the lung were both significantly decreased in Mfap4−/−mice by 25 and 15%, respectively. The data did not support an essential role of MFAP4 in pulmonary elastic fiber organization or content but indicated increased turnover in young Mfap4−/−mice. However, Mfap4−/−mice developed a spontaneous loss of lung function, which was evident at 6 mo of age, and moderate air space enlargement, with emphysema-like changes.

In dieser Arbeit wurde der Einfluss zyklischer, uniaxialer Dehnung auf die Expression der im Knochenstoffwechsel wichtigen Proteine c-FBJ murine osteosarcoma viral oncogene homolog (c-FOS), Pleiotrophin (PTN) und Midkine (MDK) in Abhängigkeit von Kollagen Typ 1, Poly-L-Lactid (PLLA) bzw. Fibronektin untersucht. Auch die Rolle der beta1-Integrin-abhängigen Interaktion in diesem Prozess wurde näher analysiert. Für die Versuche wurden humane, mesenchymale Stammzellen sowie eine mesenchymale Stammzelllinie mit Telomerase reverser Transkriptase 4 (hMSC-TERT4) verwendet.

Bullous pemphigoid is the most common autoimmune bullous skin disease which occurs more often at higher age. Clinically it presents with tense blisters and eczematous lesions combined with severe pruritus. The pemphigoid-like diseases include mucous membrane pemphigoid, pemphigoid gestationis and linear IgA disease. Diagnosis is based on immunofluorescence microscopy and confirmatory tests (ELISA, immunoblotting). Classical bullous pemphigoid presents with IgG autoantibodies against BP180 and BP230. Treatment includes topical and systemic corticosteroids and adjuvant immunosuppressants.

Thyroid hormones are of crucial importance for the function of nearly all organ systems. In case of dysfunction of thyroid hormone production and function many organ systems may be affected. The estimation of normal thyroid function is based on determination of TSH and the thyroid hormones T3 and T4. However, international conventions about the normal TSH range are still lacking which bears consequences for patient`s treatment. Hence not unexpected, many patients complain although their thyroid hormone status is in the normal range by clinical estimation. Here, more precise parameters are needed for a better definition of the healthy thyroid status of an individual. Recently, new key players in the system of thyroid hormone action were detected, like specific transporters for uptake of thyroid hormones and thyroid hormone derivatives. DFG, the German Research Foundation supports the priority program Thyroid Trans Act to find answers to the main question: what defines the healthy thyroid status of an individual. The overall aim of this interdisciplinary research consortium is to specify physiological and pathophysiological functions of thyroid hormone transporters and thyroid hormone derivative as new players in thyroid regulation in order to better evaluate, treat, and prevent thyroid-related disease.

Acute zonal occult outer retinopathy (AZOOR) is a rare disease and is part of the white dot syndrome occurring bilaterally and often asymmetrically in young healthy myopic women. Characteristic findings are distinct focal lesions of the outer segments (OS) of the photoreceptor (PR) layer and abnormalities in fundus autofluorescence (FAF) within the lesions. Currently there is a lack of defined disease criteria, such as specific laboratory findings. Also no effective therapy is known which makes it difficult to diagnose, differentiate and treat AZOOR. Supplementation of antioxidants may become part of therapeutic options in AZOOR. A 19-year-old myopic woman presented with unilaterally reduced visual acuity. Due to the clinical features and with the help of FAF, spectral domain optical coherence tomography (SD-OCT) and perimetry the diagnosis of blind spot enlargement syndrome in AZOOR was made. Identification of autoantibodies specific for two retinal antigens (CRALBP and S-Ag) supports the concept of an autoimmunological origin of the disease. Systemic steroids were given but stopped almost 6 weeks later as no improvement was seen. In follow-up controls over 12 months the clinical picture remained unchanged without any further therapy.

Contact allergy is a skin disease that is caused by the reaction of the immune system to low molecular weight chemicals. A hallmark of contact allergens is their chemical reactivity, which is not exhibited by toxic irritants. Covalent binding of contact allergens to or complex formation with proteins is essential for the activation of the immune system. As a consequence antigenic epitopes are formed, which are recognized by contact allergen-specific T cells. The generation of effector and memory T cells causes the high antigen specificity and the repeated antigen-specific skin reaction of contact allergy. New findings reveal that the less specific reaction of the innate immune system to contact allergens closely resembles the reaction to an infection. Therefore, contact allergy can be viewed as an immunologic misunderstanding since the skin contact with chemical allergens is interpreted as an infection. The growing understanding of the molecular and cellular pathologic mechanisms of contact allergy can aid the development of specific therapies and of in vitro alternatives to animal testing for the identification of contact allergens.

Recent publications regarding the function of the T-cell costimulators CD226 and TIGIT as well as the identification of the new costimulatory ligand VISTA are of great interest for an understanding of autoimmune diseases. Both systems display striking similarities to the well-established costimulators CD28/CTLA-4 and PD-1.

Geographic atrophy, the dry form and late manifestation of age-related macular degeneration, is the next challenge following the breakthrough in the treatment of neovascular age-related macular degeneration (AMD). Various interventional pharmacologic approaches with different targets are already being tested in clinical interventional trials. These include reduction of retinal toxins, anti-inflammatory agents, complement inhibition, neuroprotection and alleviation of oxidative stress. Until efficacy and safety is demonstrated, aids for poor vision and further rehabilitative measures remain essential for patients with advanced dry AMD.

The accumulation of hepatocellular lipid droplets, referred to as steatosis, is the most frequent liver pathology in western industrial countries. The surface of lipid droplets is stabilized by amphiphilic proteins of the PAT family (perilipin, adipophilin, TIP47). We recently showed that PAT proteins are differentially expressed in liver.The effects of lipid droplet induction with oleate and of siRNA-mediated downregulation of PAT proteins were evaluated using immunofluorescence microscopy, immunoblot and functional assays.Whereas perilipin, adipophilin and (in only minor amounts) also TIP47 coat lipid droplets in steatotic hepatocytes, adipophilin and TIP47, but not perilipin, are detectable in hepatocellular cell cultures. Likewise, perilipin is not induced after downregulation of adipophilin and TIP47.Common cell culture models show specific differences to human hepatocyte steatosis in vivo. Perilipin may play a role in the long-term storage of fat, which may be only partially reflected by cell culture models.

Sensitization to lipid transfer proteins (LTPs), a pan-allergen in plants, causes severe anaphylactic reactions to foods, especially in the Mediterranean area. A component-based diagnostic approach identified the peach LTP Pru p 3 as a major allergen. We present the case of a 30-year-old LTP-sensitized Spanish woman with a history of severe anaphylactic reaction to grapes, apple and cauliflower in which the detection of specific IgE against the recombinant protein Pru p 3 led to the diagnosis.

Cystic fibrosis (CF) is a common autosomal-recessive inherited disease, which often results in premature death. Due to treatment advances, life expectancy has however continuously improved in recent years. Currently about half of all patients are adults. There are also "atypical" variants of CF with symptoms occurring in late adulthood. CF is caused by a mutation in the gene coding for a chloride ion channel, known as the cystic fibrosis transmembrane conductance regulator (CFTR). This mutation results in abnormally viscous mucosal secretions, leading to multi-organ disease with particular emphasis in the respiratory and digestive tracts. Impaired mucociliary clearance results in bacterial colonization of the airways (e. g. Pseudomonas aeruginosa) and consequently in chronic pulmonary inflammation, inevitably leading to progressive bronchiectasis and combined ventilatory disorders. Typical acute complications are infective exacerbations - the most frequent cause of death in cystic fibrosis - along with allergic bronchopulmonary aspergillosis, haemoptyses and pneumothoraces. Involvement of the gastrointestinal tract generally manifests as exo- and later endocrine pancreatic insufficiency with diabetes mellitus, malabsorption and sometimes biliary liver cirrhosis. Typical acute complications are pancreatitis and ileus. The article describes epidemiology and pathophysiology of CF and focuses on the signs and symptoms, as well as the diagnostic and multi-modal therapeutic strategies used in adult patients.

Sjögren's syndrome is a common autoimmune disorder. Several genetic risk factors such as STAT-4, ILT6 and the haplotype HLA-B8/DR3 have been identified. In addition, there are environmental risk factors, possibly chronic viral infections. In the pathophysiology of Sjögren's syndrome T and B cells infiltrate the salivary and lacrimal glands. As a consequence of the destruction of glandular cells by cytotoxic T cells, production of cytokines and autoantibodies inhibiting glandular function, the production of saliva and tears is decreased. The feeling of dry eyes and mouth is frequently not noticed by the patients. Therefore, Sjögren's syndrome should also be considered when extraglandular manifestations such as vasculitis, polyneuropathy or arthritis occur, even when the patients do not complain of dry eyes and mouth. Establishing the diagnosis of Sjögren's syndrome requires verification of reduced glandular function, for example using Schirmer's test and the Saxon test. The confirmation of Sjögren's syndrome as a cause of sicca syndrome is subsequently performed by the detection of autoantibodies against Ro (SS-A) and La (SS-B) and/or by a salivary gland biopsy.

Amplifications of the c-Rel locus on chromosome 2p13-p16 have been described in distinct lymphoma subtypes, most notably in mediastinal diffuse large B cell lymphoma (DLBCL) and classical Hodgkin´s lymphoma. In B cell lymphomas of the gastrointestinal tract gains of chromosomal material in chromosomal region 2p13-p16 could also be detected using comparative genomic hybridization (CGH). Candidate genes for lymphomagenesis in this region are c-Rel and BCL11A. The objective of this work was to shape out a potential gene dosis effect. For this purpose, 13 lymphomas of the gastrointestinal tract (8 diffuse large cell B cell lymphoma and 5 marginal zone B cell lymphoma) have been analyzed for their genomic status of c-Rel and BCL11A using fluorescence in situ hybridization (FISH). For 3 out of 13 lymphomas a gain of chromosomal material in chromosomal region 2p13-p16 had been detected. By using FISH a gain of gene number copies could be detected 5 lymphomas (3 of which had known gains of chromosomal material in CGH). The relative expression of c-Rel and BCL mRNA was detected using quantitative real time PCR. Furthermore, the expression and intracellular localization of the c-Rel and BCL11A protein were confirmed by using immunohistochemical staining with antibodies not commercially available. There was evidence for a stringen t gene dosis effect of c-Rel and BCL11A in only 2 out of 13 lymphomas. The remaining lymphomas present a heterogenous expression pattern. Maybe there are other regulatory mechanisms leading to constitutive activation of c-Rel and/ or BCL11A.

The von-Hippel-Lindau (VHL) tumor suppressor is a multifunctional protein. VHL mutations are common in sporadic clear cell renal cell carcinoma (ccRCC). Different mutation types may specifically alter pVHL functions, which have significant impact on gene expression and, consequently, on the disease outcome. The aim of this study was to identify gene expression signatures that correlate with specific VHL gene mutation types in RCC.Total RNA and genomic DNA were extracted from 94 frozen clear cell (ccRCC) and 21 papillary RCC (pRCC) specimens from the tumor biobank of Zurich University Hospital. Transcriptome analysis was performed using Affymetrix HG U133A gene chips. All ccRCC tumors were subjected to VHL gene mutation analysis.By applying significance analysis of microarrays genes were identified, which were differentially regulated among the tumor subgroups. Hierarchical clustering based on the expression profile of the most differentially regulated genes resulted in a significant stratification between the two RCC populations. A total of 186 differentially expressed genes were identified by comparing the gene expression profiles of ccRCC with VHL loss-of-function mutations and ccRCC with no gene alterations.The results clearly argue for a significant influence of VHL mutations on gene expression profiles in RCC.

Schizophrenia is characterized by a great heterogeneity of symptoms and functional deficits, especially of cognition. Different phenotypes are thought to result from the interaction of genetic predisposition and environmental factors. Pathophysiological models range from the dopamine and glutamate hypotheses to the hypothesis of free radicals and the hypotheses of neurodevelopment as opposed to neurodegeneration. In addition to the neurobiological approaches, linkage studies and subsequent finemappings deliver evidence with regard to genes potentially involved in schizophrenia. The most important candidate genes, such as dysbindin (DTNBP1), neuregulin (NRG1) and DISC-1 (disrupted-in schizophrenia-1), are thought to influence neurotransmission, as well as the development and maintenance of the structure of neuronal networks. The list of potential candidates includes numerous other genes as well. In conclusion, multiple genetic, neurobiological, and exogenous factors are assumed to interact in the pathogenesis of schizophrenia.

Gout is caused by monosodium urate (MSU) crystal-induced inflammation of the joints and periarticular tissues. MSU crystals activate the NOD-like receptor (NLR) NALP3, which functions as a pattern recognition receptor (PRR). Activated NALP3 mediates interleukin-1b (IL-1b) generation from its inactive pro-form, resulting in the activation of further cells and an IL-8-mediated neutrophil influx into the joint. Based on these new findings on the pathophysiology of gout, an open pilot study has recently demonstrated successful treatment of gout with the soluble IL-1R antagonist anakinra in 10 patients. The physiological role of MSU crystals might be that of a danger signal in peripheral tissues, where they stimulate dendritic cell maturation. The role of PRRs such as the NLR is underlined by NALP3 mutations causing hereditary autoinflammatory syndromes and NOD2 polymorphisms as genetic risk factors for Crohn's disease. In addition to the recognition of danger-associated molecular patterns (e.g. MSU), PRRs confer autoantigen recognition and activation of the innate and adaptive immune system in autoimmune diseases. Detection of RNA and DNA-containing immune complexes by toll-like receptors inducing B-cell activation in systemic lupus erythematosus and of proteinase 3 by the protease-activated receptor-2 inducing dendritic cell maturation in Wegener's granulomatosis have recently been reported.

Sjögren's syndrome (SS) is a common connective tissue disease concerning 0.5 % of the white population. Typical symptoms are dry eyes and a dry mouth. The diagnostics of SS often are difficult, especially during early stages of the disease as long as the leading symptoms have not yet fully developed. Previously employed serum antibodies have neither been sensitive nor specific enough to be able to differentiate SS from different rheumatic diseases. We report on a patient with relapsing corneal erosions. In his case we have been able to support the diagnosis of SS by detecting the anti-alpha-fodrin-antibody as well as antinuclear antibodies.The patient appeared with incomplete closure of the eyelids and corneal ulcers on both eyes. Smears of the conjunctivae from both eyes were sterile. Schirmer's test indicated a decrease in tear production with 5 mm in the right eye and a normal tear production with 19 mm in the left eye. Three months before, the results of this test had been even more pronounced with 1 mm and 3 - 4 mm, respectively. Additionally the patient described relapsing erosions and a dry mouth. We then examined his blood to help diagnose SS. Results were negative for rheumatoid factor, anti-Ro/SSA antibody and anti-La/SSB antibody, but positive for anti-nuclear-antibodies. In order to spare the patient an invasive biopsy we examined the anti-alpha-fodrin-antibody which was positive.Even with negative anti-Ro/SSA and anti-La/SSB antibodies the positive anti-alpha-fodrin-antibody supported the diagnosis of SS. Therefore, we consider it a useful addition to the diagnostics previously employed in the diagnosis of SS (Schirmer's-test, anti-Ro/SSA-AK, anti-La/SSB-AK, rheumatoid factor, eventually biopsy).

Bei einer wesentlichen Anzahl von Patienten mit chronischer Pankreatitis lassen sich genetische und vererbbare Ursachen nachweisen. An eine hereditäre bzw. genetisch bedingte Pankreatitis sollte gedacht werden, wenn keine bekannten Risikofaktoren, z.B. ein chronischer Alkoholmissbrauch für eine chronische Pankreatitis bestehen und wenn eine positive Familienanamnese für eine akut rezidivierende bzw. eine chronische Bauchspeicheldrüsenentzündung oder ein Pankreaskarzinom vorliegt. Patienten mit chronischer Pankreatitis und einer Mutation im kationischen Trypsinogen-Gen haben ein erhöhtes Risiko, im Laufe ihres Lebens an einem Pankreaskarzinom zu erkranken – insbesondere, wenn sie rauchen. Deshalb ist eine engmaschige klinische Verlaufskontrolle in einem spezialisierten Zentrum anzustreben. Die häufigsten genetischen Veränderungen bei Patienten mit positiver Familienanamnese, die mit einer hereditären Pankreatitis assoziiert sind, sind die Punktmutationen R122H, R122C und N29I im kationischen Trypsinogen-Gen. Bei Patienten ohne positive Familienanamnese werden meist Punktmutationen im SPINK1-Gen (N34S-Mutation) oder im CFTR-Gen nachgewiesen. Deren klinische Konsequenzen sind allerdings zum jetzigen Zeitpunkt noch unsicher. Eine molekulargenetische Untersuchung von betroffenen Patienten sollte erwogen werden, wenn Patienten ohne Risikofaktoren vor dem 25. Lebensjahr an einer chronischen Pankreatitis leiden oder ein weiteres Familienmitglied ersten Grades ebenfalls an einer Pankreatitis oder an einem Pankreaskarzinom erkrankt sind. Genetische Untersuchungen nicht erkrankter Verwandter von Patienten mit hereditärer Pankreatitis sollten nur nach ausführlicher genetischer Beratung erfolgen. Eine pränatale Diagnostik wird nicht empfohlen.

Causal treatment options for schizophrenia are lacking due to our restricted knowledge of its etiology and pathogenesis. However, recently three postulated disposition genes for schizophrenia have been increasingly better confirmed: dysbindin, neuregulin-1, and G(72)/DAOA genes. These genes code proteins involved in processes ranging from brain development to the maintenance of glutamatergic transmission in the mature brain. Current interpretation of neuroanatomical findings points at reminiscences of disturbed brain development and a loss of nonneuronal elements, the so-called neuropil, as a correlate of brain atrophy. This reduction in neuropil is mainly caused by synaptic elements. Biochemical findings supporting this show that besides the dopaminergic and serotonergic system, glutamatergic transmission is also disturbed in schizophrenia. All these findings fit very well with the presumed functions of the disposition genes. Hypothesis-free approaches in structural brain imaging and the combination of functional imaging with relevant gene variants open new avenues for using markers from brain imaging to improve the diagnosis of schizophrenia and judge the response to neuroleptic treatment. Despite the enormous increase in knowledge for example in genetic research, the risk variants known until now provide no contribution to early diagnosis of schizophrenia. Furthermore, pharmacogenetics is currently unable to give a clear answer as to whether a single patient is responding to treatment or not.

Periodic fever syndromes comprise a group of disorders characterized by attacks of seemingly unprovoked inflammation. The genetic causes of five hereditary autoinflammatory syndromes have been identified in the last few years: familial Mediterranean fever, the cryopyrinopathies [Muckle-Wells, chronic infantile neurological, cutaneous, articular syndrome (CINCA) and familial autoinflammatory syndromes], TNF-receptor associated periodic syndrome, cyclic neutropenia syndrome and periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. The study of periodic fever syndromes has progressed from clinical characterization to genetic analysis and to the definition of the functional defects linking genes or domains to apoptotic proteins and signal transduction pathways. This new research opens the way for more specific treatment options with a further improvement in prognosis and outcome.

Frasier syndrom is an autosomal dominant, hereditary disease characterized by nephropathy, gonadal dysgenesis and risk of gonadal blastoma in early childhood. To date, in many patients with Frasier syndrome WT1 mutations have been found, occurring exclusively as germ-line mutations of the alternative splicing donor site in intron 9. A Wilms tumor is seen only rarely in this clinical entity. In the present paper we describe the clinical course of a patient with Frasier syndrome confirmed by molecular genetic analysis.Our patient with Frasier syndrome as confirmed by molecular genetic analysis is now 19 years old. The patient became dependent on dialysis due to nethropathy in the form of focal sclerosing glomerulonephritis and terminal renal insufficiency. A kidney transplantation in the left iliac fossa together with new implantation of the ureter according to Dodson. For prophylactic reasons on account of the high risk of gonadal blastoma associated with the disease and sonographically detected microlithiasis in both testicles we performed one year later an inguinal castration. Histology revealed the picture of a severe tubular testicular atrophy with arrested spermatogenesis and focal intratubular germ-line neoplasia.This case report shows that, besides our already published series with Denys-Drash syndrome, WT1 mutations may also be associated with the so-called Frasier syndrome. For children with Frasier syndrome confirmed by molecular genetic analysis and loss of function of the testicles, we recommend performance of a prophylactic castration. We also suggest that phenotypical female patients with focal sclerosing glomerulonephritis be examined for WT1 mutations.

Chronic pancreatitis: Only recently mutations in several genes were found in patients with chronic pancreatitis. In those with a familial chronic pancreatitis mutations of the cationic trypsinogen were identified and the variants N29I and R122H lead to an autosomal dominant disease. In this group of patients the mutation N34S of the trypsin inhibitor SPINK1 was detected. In so-called idiopathic pancreatitis both variants of the SPINK1 and of the CFTR (cystic fibrosis transmembrane conductance regular) were identified. Alterations in both genes were also found in patients with alcoholic chronic pancreatitis. The strongest risk factor for chronic pancreatitis were trypsinogen mutations N29I and R122H mutations. However, both SPINK1 and CFTR increased the risk for chronic pancreatitis to a higher level than alcohol consumption. A genetic investigation should be performed in familial disease and younger age, but also in patients without family history and higher age a mutation could be found. Pancreas cancer: In 10% of the patients with pancreas cancer other members of the family were affected from the disease. Some of them belong to well characterized familial syndroms like HNPCC or Peutz-Jeghers-syndrom. In a minority of the others a genetic factor may be found, too. In sporadic disease the development of the tumor is characterized by continued acquirement of genetic alterations described by the PanIN model (pancreatic intraepithelial neoplesia). This means that the evolution of the neoplasia progresses from normal tissue via epithelial hyperplasy (PanIN 1A), papillary hyperplasy without (PanIN 1B) and with dysplasy (PanIN 2) and carcinoma in situ (PanIN 3) to invasive pancreas cancer. The progression is associated with genetic alterations of the cells (mutations of ki-ras, p16, p53 etc.). This results in deterioration of control of the cell cycle and the apoptosis and explains the malignancy of the disease. These findings may be used in the future to develop newer therapeutic principles in order to improve the dismal prognosis of this disease.

In 1928, Hugo Friedrich Kufs reported on a family with cerebral, retinal, and cutaneous cavernous malformations. Since then, more than 300 families with inherited cavernous malformations have been reported. Genetic studies showed three loci, on chromosomes 7q21-q22 (with the gene CCM1), 7p15-p13 (CCM2), and 3q25.2-q27 (CCM3). The gene product of CCM1 is Krit 1 (Krev interaction trapped 1), a protein interacting with angiogenesis by various mechanisms. Recently, CCM2 has also been identified; its product is a protein which might have a function similar to that of Krit 1. However, the CCM3 gene has still not been found. In this study, we present clinical and genetic findings on 15 German families.

The identification of a specific mutation in the human cationic trypsinogen gene in large kindreds with hereditary pancreatitis was the key to understand the genetic background of chronic pancreatitis. Rapidly, other variants within the same gene were identified-even in small families with a minority of patients. Later, mutations of the most important intrapancreatic trypsin inhibitor SPINK1 were found with high prevalence in patients with idiopathic, tropical and alcoholic chronic pancreatitis. We summarize interesting genetic and biochemical findings, point to clinical features and review recommendations for genetic analysis, follow-up and cancer prevention.

Interactions between low molecular weight compounds with cells of the skin result in reactions with different proteins which enable the uptake, metabolism and efflux of these compounds. It is unlikely, that small molecular weight compounds can achieve pharmacological concentrations within cells by diffusion alone. The pattern of influx proteins of keratinocytes is different from that of hepatocytes. If the balance between these systems is disturbed, the skin may become unable to function as a protective organ which can result in diseases including cancer or-more frequently-allergic contact dermatitis. Recent investigations of the sensitization to fragrances and p-phenylenediamine are discussed. An improved understanding of the metabolism of low molecular weight compounds can lead to new therapeutic strategies. One example is the introduction of photodynamic therapy with topical applied porphyrin precursors.