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'Asthma' is a complex disease that encapsulates a heterogeneous group of phenotypes and endotypes. Research to understand these phenotypes has previously been based on longitudinal wheeze patterns or hypothesis-driven observational criteria. The aim of this study was to use data-driven machine learning to identify asthma and wheeze phenotypes in children based on symptom and symptom history data, and, to further characterize these phenotypes. The study population included an asthma-rich population of twins in Sweden aged 9-15 years (n = 752). Latent class analysis using current and historical clinical symptom data generated asthma and wheeze phenotypes. Characterization was then performed with regression analyses using diagnostic data: lung function and immunological biomarkers, parent-reported medication use and risk-factors. The latent class analysis identified four asthma/wheeze phenotypes: early transient wheeze (15%); current wheeze/asthma (5%); mild asthma (9%), moderate asthma (10%) and a healthy phenotype (61%). All wheeze and asthma phenotypes were associated with reduced lung function and risk of hayfever compared to healthy. Children with mild and moderate asthma phenotypes were also more likely to have eczema, allergic sensitization and a family history of asthma. Furthermore, those with moderate asthma phenotype had a higher eosinophil concentration (β 0.21, 95%CI 0.12, 0.30) compared to healthy and used short-term relievers at a higher rate than children with mild asthma phenotype (RR 2.4, 95%CI 1.2-4.9). In conclusion, using a data driven approach we identified four wheeze/asthma phenotypes which were validated with further characterization as unique from one another and which can be adapted for use by the clinician or researcher., Competing Interests: FC declares that she receives salary from IQVIA, Nordics, Sweden. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. The other authors have no conflict of interest to declare.

We evaluated the in silico expression and circulating levels of interleukin (IL)37 in patients with different forms of multiple sclerosis (MS) and also upon treatment with different disease-modifying drugs. The combined interpretation of the resulting data strengthens and extends the current emerging concept that endogenous IL37 plays an important role in determining onset and progression of MS. The in silico analysis revealed that production of IL37 from cluster of differentiation (CD)4+ T cells from MS patients was reduced in vitro as compared to healthy controls. The analysis of the datasets also demonstrated that "higher" levels of IL37 production from PBMC entailed significant protection from MS relapses. In addition, the in vivo part of the study showed that IL37 was selectively augmented in the sera of MS patients during a relapse and that treatment with the high potency disease-modifying drug fingolimod significantly increased the frequency of patients with circulating blood levels of IL37 (6/9, 66%) as compared to patients receiving no treatment ( n = 48) or platform therapy ( n = 59) who had levels of IL37 below the limit of the sensitivity of the assay. This finding therefore anticipates that fingolimod may at least partially exert its beneficial effects in MS by upregulating the production of IL37., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Broad and potent neutralizing antibodies (bnAbs) with multiple epitope specificities evolve in HIV-1-infected children. Herein, we studied two antiretroviral-naive chronically HIV-1 clade C-infected monozygotic pediatric twins, AIIMS_329 and AIIMS_330, with potent plasma bnAbs. Elite plasma neutralizing activity was observed since the initial sampling at 78 months of age in AIIMS_330 and persisted throughout, while in AIIMS_329 it was seen at 90 months of age, after which the potency decreased over time. We evaluated potential viral characteristics associated with the varied immune profiles by generating single genome-amplified pseudoviruses. The AIIMS_329 viruses generated from the 90-month time point were neutralization sensitive to bnAbs and contemporaneous plasma antibodies, while viruses from the 112-month and 117-month time points were resistant to most bnAbs and contemporaneous plasma. AIIMS_329 viruses developed resistance to plasma neutralizing antibodies (nAbs) plausibly by N160 glycan loss and V1 and V4 loop lengthening. The viruses generated from AIIMS_330 (at 90 and 117 months) showed varied susceptibility to bnAbs and autologous contemporaneous plasma antibodies, while the viruses of the 112-month time point, at which the plasma nAb specificities mapped to the V2 glycan, V3 glycan, and CD4 binding site (CD4bs), were resistant to contemporaneous plasma antibodies as well as to most bnAbs. Chimeric viruses were constructed from 90-month-time-point PG9-sensitive AIIMS_329 and AIIMS_330 viruses with swapped V1V2 regions of their respective evolved viruses (at 112 and 117 months), which led to higher resistance to neutralization by PG9 and autologous plasma antibodies. We observed the evolution of a viral pool in the AIIMS_330 donor comprising plasma antibody neutralization-sensitive or -resistant diverse autologous viruses that may have contributed to the development and maintenance of elite neutralizing activity. IMPORTANCE Herein, we report the longitudinal development of bnAbs in a pair of chronically HIV-1 clade C-infected monozygotic pediatric twins, AIIMS_329 and AIIMS_330, who acquired the infection by vertical transmission. The plasma from both donors, sharing a similar genetic makeup and infecting virus, showed the evolvement of bnAbs targeting common epitopes in the V2 and V3 regions of the envelope, suggesting that bnAb development in these twins may perhaps be determined by specific sequences in the shared virus that can guide the development of immunogens aimed at eliciting V2 and V3 bNAbs. Characterization of the neutralization-sensitive and -resistant viruses coevolving with bNAbs in the contemporaneous AIIMS_330 plasma provides information toward understanding the viral alterations that may have contributed to the development of resistance to bnAbs. Further longitudinal studies in more monozygotic and dizygotic twin pairs will help in delineating the role of host and viral factors that may contribute to the development of bnAbs., (Copyright © 2019 American Society for Microbiology.)

Objective: There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings., Research Design and Methods: Subjects from the TrialNet Pathway to Prevention Study ( N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years., Results: At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody-positive, 13% for single autoantibody-positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody-positive, 12% for single autoantibody-positive, and 0.5% for initially autoantibody-negative subjects., Conclusions: Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody-positive identical twins and multiple autoantibody-positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins., (© 2018 by the American Diabetes Association.)

We aim to examine if circulating micro-RNA and cytokine levels associate with dementia diagnosis and cognitive scores. To test our hypothesis, we use plasma donated from 48 monozygotic twin pairs in 1997 and 46 micro-RNAs and 10 cytokines were quantified using microfluidic RT-qPCR and multiplex solid-phase immunoassays, respectively. Micro-RNA and cytokine profiling were examined for associations with dementia diagnoses in a longitudinal registry study or with cognitive scores at baseline. Thirty-six micro-RNAs and all cytokines were detected consistently. Micro-RNA profiles associate with diagnoses and cognitive scores at statistically significant levels while cytokine only showed trends pointing at chronic inflammation in twins having or developing dementia. The most notable findings were decreased miR-106a and miR-210, and increased miR-106b expression in twins with a dementia diagnosis. This pioneering evaluation of micro-RNA and cytokine and dementia diagnosis suggests micro-RNA targets in vasculogenesis, lipoprotein transport, and amyloid precursor protein genes.

Objective: Human leucocyte antigen (HLA)-DRB1*13 alleles are associated with protection from anticitrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA). It is, however, unknown at which phase of disease development (seroconversion, ACPA maturation, disease onset or outcome) these alleles are most important. We therefore examined the effect of HLA-DRB1*13 on: ACPA presence (systemic autoimmunity associated with RA) in individuals with and without RA, on ACPA characteristics and on clinical outcome measures., Methods: The effect of HLA-DRB1*13 on ACPA presence in subjects with or without RA (non-RA) was assessed in the Swedish twin registry (n=10 748). ACPA characteristics were studied in patients with ACPA-positive RA from the Swedish Epidemiological Investigation of RA (EIRA, n=1224) and the Dutch Leiden Early Arthritis Clinic (EAC, n=441). Disease activity at inclusion and disease outcome (disease-modifying antirheumatic drugs (DMARD)-free sustained remission and radiographic progression) was assessed in patients with RA from the EAC., Results: HLA-DRB1*13 is associated with protection from ACPA-positive RA (prevalence 16% vs 28% in ACPA-negative non-RA), but not with significant protection from ACPA in individuals without RA (prevalence: 22%, p value 0.09). HLA-DRB1*13 is associated with lower ACPA-levels (EIRA: 447 U/ml versus 691 U/ml, p value= 0.0002) and decreased citrullinated epitope recognition (EIRA: p<0.0001). No association between HLA-DRB1*13 and disease activity or outcome was found., Conclusions: These data indicate that HLA-DRB1*13 mainly affects the onset of ACPA-positive RA in ACPA-positive non-RA individuals. In RA, HLA-DRB1*13 influences ACPA characteristics but not the disease course. This implies that therapeutic strategies aimed at emulating the HLA-DBR1*13 protective effect may be most effective in ACPA-positive healthy individuals at risk for RA., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Congenital leukemia is a rare disease. The majority of cases of this disease are acute myelogenous leukemia (AML). Congenital acute lymphoblastic leukemia (ALL) is rare and most often is of B cell lineage. Rarely, some cases have been designated biphenotypic or mixed phenotype acute leukemia (MPAL). Herein, we report a preterm newborn referred to us as a result of the appearance of blue-violaceous dermal nodules on her body at birth. She was a twin and the product of an in vitro fertilization (IVF) pregnancy. Physical examination showed jaundice, hepatosplenomegaly, and peripheral facial nerve palsy in addition to dermal nodules. Bone marrow aspiration showed 40% blasts of lymphoid lineage; skin biopsy and its immunohistochemistry revealed myeloblastic infiltration of the dermis. Cytogenetic analysis (46,XX), fluorescence in situ hybridization (FISH) analysis, and cranial magnetic resonance were normal. The patient was diagnosed with congenital MPAL, and an association between IVF and congenital leukemia was suggested., (Copyright © 2013. Published by Elsevier B.V.)

Unlabelled: Bordetella pertussis or whooping cough is a vaccine-preventable disease that still remains a serious infection in neonates and young infants. We describe two young infants, monozygotic twins, with a severe B. pertussis pneumonia of whom one needed extracorporeal membrane oxygenation. Diagnostic work-up of unexplained hematuria and proteinuria during the illness revealed low serum complement component 3 (C3) levels. During follow-up, C3 levels remained low (400-600 mg/L). Extensive analysis of the persistent low C3 levels revealed an unknown heterozygous mutation in the C3 gene in both siblings and their mother. This C3 mutation in combination with the specific virulence mechanisms of B. pertussis probably contributed to the severe disease course in these cases., Conclusion: We propose that genetically caused complement disorders should be considered when confronted with severe cases of B. pertussis infection.

The innate immune response from diamniotic and dichorionic twin brothers congenitally infected with Trypanosoma. cruzi (strain DTU-V) who displayed different clinical symptomatology was studied. While Brother I manifested severe cardiac and digestive disorders, the Brother II showed slight splenomegaly. The secretion level of IL-1β, TNF-α, IL-12, IL-10, IFN-α and IL-6 cytokines produced after stimulation of peripheral blood cells with TLR-2, TLR-4 and TLR-9 ligands was determined pre- and post-benznidazole treatment. Cells from 10 uninfected infants born to mothers seropositive for Chagas disease were included as control. The obtained data show that the cells of Brother I secreted lower levels of the pro-inflammatory cytokines IL-1β and TNF-α (upon TLR-2 and TLR-4 stimulation) relative to those secreted by cells from Brother II and uninfected controls. The cells from Brother II secreted high levels of the IL-1β cytokine following TLR-2 stimulation relative to uninfected controls. The cells from both brothers secreted a higher level of IL-6, following TLR-4 stimulation, than that secreted by uninfected infant cells. After treatments, the cytokine secretion levels were similar in both children and comparable to those of uninfected donors. Treatment success in Brother I and treatment interruption in Brother II was detected by the use of serological biomarkers (KMP11, HSP70, PFR2, Tgp63) as well as follow-up done by PCR. Therefore, the Brother II required a second treatment. The data presented suggest that benznidazol treatment allows the innate immune system to reach a fully functional status similar to that of uninfected subjects., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A twin pair affected by juvenile myelomonocytic leukemia (JMML) with the same somatic PTPN11 mutation and abnormal chromosome 7 in bone marrow samples but distinct prognostic gene expression signatures, received a matched-unrelated donor and matched-unrelated cord blood transplant, respectively. Both twins fully engrafted, but after 6 months, the twin with an acute-myeloid-like (AML-like) signature at diagnosis rejected the graft and had an autologous reconstitution. A second transplant with an unrelated 5/6-HLA-matched-loci cord blood performed after 4 months from rejection was unsuccessful. After 25 months from diagnosis, the twin with the AML-like gene expression signature died of liver failure while on progression of his JMML. The other twin, who had a non-acute-myeloid-like (non-AML-like) gene expression signature at diagnosis is in complete hematological remission with full donor chimera. This observation suggests a biological diversity of JMML also in patients with a common genetic background.

Objective: To assess the genetic effect on the occurrence of rheumatoid arthritis (RA) associated autoantibodies., Methods: A co-twin control study of 27 monozygotic (MZ) and 51 dizygotic same sexed (DZss) RA discordant twins., Outcome Measures: The probandwise concordance rate of anti-keratin antibodies (AKA), anti-cyclic citrullinated peptide antibodies (ACPA), IgA- and IgM rheumatoid factor (IgA-RF and IgM-RF). The odds ratio for these autoantibodies based on both conditional and unconditional logistic regression adjusting for the two major genetic risk factors as well as smoking., Results: The probandwise concordance rates (95% CI) of ACPA, AKA, IgM-RF and IgA-RF were 78.6 (55.4-92.4), 16.7 (0.6-58.4), 30.0 (7.3-60.6), 42.1 (14.5-71.1) in MZ twins and 25.0 (10.3-44.4), 0.0 (0.0-27.7), 10.5 (1.4-31.5) and 22.2 (6.8-45.0) in DZss twins. In twin pairs discordant for both RA and autoantibodies the OR of ACPA, AKA, IgM-RF and IgA-RF was 5 (0.5-236.5) 9 (1.3-394.5) 272 (3.5-593.2) and 10 (1.4-434.0) in MZ twin pairs and 17 (4.4-146.1) 20 (3.2-828.0) 33 (5.5-1342.4) and 577 (7.4-1149.2) in DZss twin pairs. In multiple logistic regression analysis on ACPA, the MZ/DZ OR was 21.1 (3.3-213.5) when adjusting for age, sex, ever smoking, PTPN22 1858 T-allele, Shared Epitope (SE) and SE-smoking interaction., Conclusion: There is a genetic contribution to ACPA generation independent of both SE and PTPN22 1858 T-allele. Environmental factors may trigger the expression of IgA-RF, ACPA and AKA in healthy persons who are predisposed to RA., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The Twin Research Registry (TRR) at SRI International is a community-based registry of twins established in 1995 by advertising in local media, mainly on radio stations and in newspapers. As of August 2012, there are 3,120 same- and opposite-sex twins enrolled; 86% are 18 years of age or older (mean age 44.9 years, SD 16.9 years) and 14% less than 18 years of age (mean age 8.9 years, SD 4.5); 67% are female, and 62% are self-reported monozygotic (MZ). More than 1,375 twins have participated in studies over the last 15 years in collaboration with the University of California Medical Center in San Francisco, the University of Texas MD Anderson Cancer Center, and the Stanford University School of Medicine. Each twin completes a registration form with basic demographic information either online at the TRR Web site or during a telephone interview. Contact is maintained with members by means of annual newsletters and birthday cards. The managers of the TRR protect the confidentiality of twin data with established policies; no information is given to other researchers without prior permission from the twins; and all methods and procedures are reviewed by an Institutional Review Board. Phenotypes studied thus far include those related to nicotine metabolism, mutagen sensitivity, pain response before and after administration of an opioid, and a variety of immunological responses to environmental exposures, including second-hand smoke and vaccination for seasonal influenza virus and Varicella zoster virus. Twins in the TRR have participated in studies of complex, clinically relevant phenotypes that would not be feasible to measure in larger samples.

Objective: To evaluate the value of maternal IgM to cytomegalovirus (CMV) as a predictive factor of fetal infection in fetuses with sonographic markers., Methods: Observational study (2006-2011) including a consecutive series of 19 fetuses with sonographic markers of fetal infection and confirmed infection by positive CMV-DNA in amniotic fluid or fetal blood. We evaluated the status of maternal CMV IgM at the time of sonographic suspicion., Results: During this 6-year study period, CMV infection was diagnosed in 19 fetuses from 18 pregnancies, including 16 singletons, both twins of a monochorionic diamniotic pregnancy and one twin of a dichorionic pregnancy. Sonographic suspicion was established on the basis of one or more of the following: brain abnormalities (14), fetal hydrops (4), hyperechogenic bowel (4), pericardial effusion (1), cardiomegaly (1), oligoanhydramnios (4), and placentomegaly (2). Maternal IgG antibodies were positive in all cases but maternal IgM antibodies were negative in 56% of pregnancies. Five of the 10 pregnancies with negative maternal IgM were diagnosed in the second trimester and five in the third trimester., Conclusion: In around half of fetuses with confirmed CMV infection ascertained by sonographic markers, maternal IgM antibodies are negative and should therefore not be used as a diagnostic parameter., (© 2012 John Wiley & Sons, Ltd.)

Monozygotic (MZ) twins discordant for complex diseases may help to find disease mechanisms that are not due to genetic variants. Intermittent allergic rhinitis (IAR) is an optimal disease model because it occurs at defined time points each year, owing to known external antigens. We hypothesized that MZ twins discordant for IAR could help to find gene expression differences that are not dependent on genetic variants. We collected blood outside of the season from MZ twins discordant for IAR, challenged their peripheral blood mononuclear cells (PBMC) with pollen allergen in vitro, collected supernatants and isolated CD4+ T cells. We identified disease-relevant mRNAs and proteins that differed between the discordant MZ twins. By contrast, no differences in microRNA expression were found. Our results indicate that MZ twins discordant for IAR is an optimal model to identify disease mechanisms that are not due to genetic variants., (© 2012 John Wiley & Sons A/S.)

We examined the risk of atopic diseases in twins born after assisted reproduction. Data on atopic diseases and assisted reproduction in 9694 twin pairs, 3-20 years of age, from the Danish Twin Registry were collected via multidisciplinary questionnaires. The risk of atopic diseases in twins born after assisted reproduction was compared with the risk in twins born after spontaneous conception using logistic regression and variance components analysis. Children born after assisted reproduction did not have a different risk of atopic outcomes (adjusted odds ratios [95% confidence intervals] for asthma: 0.95 [0.85, 1.07], P = 0.403; hay fever: 1.01 [0.86, 1.18], P = 0.918; and atopic dermatitis: 1.02 [0.81, 1.11], P = 0.773 respectively) compared with children born after spontaneous conception. Assisted reproduction did not modify the heritability of atopic diseases. This study does not support an association between assisted reproduction and development of atopic diseases. This result must be confirmed in subsequent studies, preferably of singleton populations., (© 2011 Blackwell Publishing Ltd.)

Perinatal hemolytic disease occurs secondary to a hemolytic phenomenon of immune origin resulting in fetal or neonatal anemia. A 38-year-old pregnant woman was referred to the Department of high risk Obstetrics, Hospital Universitario La Paz Madrid because of presenting a dichorionic diamniotic twin pregnancy spontaneously, pre-pregnancy diabetes poorly controlled and severe alloinmunization anti-D. Her first pregnancy ended in a normal delivery at term; in the period of 4 years, she has three newborn with 36, 34 and 40 weeks respectively, who die with a week of life. After that, two intrauterine fetal death occur at 26 weeks of gestation. The patient who is RhD negative, suffers anti-D inmunization with a antibody titration of 1/1024 with 14 weeks of gestation. Twelve plasmapheresis, eight doses of anti-D inmunoglobulins and intrauterine transfusions has been the treatment received. A severe anemia is found during the ultrasound control of the middLe cerebral artery peak systolic velocity in both twins since the 16th week. It remains stable thanks to the treatment. Finally at the 28th week of gestation, pregnancy is terminated with a cesarean section. The twins are born alive and premature, but with good general state. The measurement of the middle cerebral artery peak systolic velocity predicts moderate-severe fetal anemia cases, which are the most important in the clinical management because of the need of active treatment or finish the pregnancy.

We describe monozygotic twins with immune thrombocytopenia (ITP) associated to antiphospholipid antibodies with a dissimilar clinical expression. The first patient was diagnosed to have ITP at 63 years old and was treated with corticosteroids. She presented ulterior exacerbations of thrombocytopenia requiring intravenous immunoglobulin and subsequent treatment with rituximab. She ultimately had a favorable response without thrombotic events during follow-up. The second patient who had a history of three spontaneous abortions and endometrial adenocarcinoma in complete remission was evaluated for severe thrombocytopenia, ITP was diagnosed at the age of 63. She was treated with steroids and had a favorable response. After few months she developed deep venous thrombosis and pulmonary embolism requiring anticoagulation therapy without hemorrhagic events. Both patients were found to have antiphospholipid antibodies and HLA DR4 (DRB1*04) and HLA DR5 (DRB1*12). The association of those two entities in monozygotic twins could support the presence of common predisposing genes. However, with both patients being genotipically identical, the clinical expression was different. Those cases highlight the possibility that environmental factors may affect the expression of those disorders.

We report a case of 7-year-old monozygotic twin patients with atopic dermatitis. The HLA haplotypes were HLA A2, A11, B27, B61, DR1, and DR4. Both serum IgE levels and cedar pollen radioallergosorbent test (RAST) scores were high in the twins (elder/younger sister: IgE: 5170/3980 IU/ml and Japansese cedar pollen: >100/64.0) in contrast to low mite and food RAST scores (Dermatophagoides Pterygonium; 0.59/0.4 and egg white 9.24/4.6). The patients showed positive immediate (20 min in both sisters) and delayed (24 hours in elder sister, 24, 48, 72 hours in younger sister) reactions to a scratch test with Japanese cedar pollen. Skin lesions on the face were aggravated and extended to the trunk and extremities during the Japanese cedar pollen season and gradually subsided in summer. Oral provocation with egg white or cow milk showed no exacerbations, and topical corticosteroid did not improve the eczema. In contrast, successful protection from severe scratching behaviors was achieved by use of topical anti-allergic eye drops and wearing nightgowns made by the mother.

One of identical twin girls was born with ulcers on her leg, and shortly after birth developed a flaccid blister on the leg. Subepidermal blister with vacuolar degeneration of basal cell layer and the heavy infiltration of mononuclear cells in the upper dermis were observed in the blister lesion. She also had generalized livedo. Her identical twin sister did not exhibit ulcers or blisters, but was born with milia on her limbs. Their mother was found to have lupus erythematosus with positive anti-Ro/SSA antibodies and developed Sjögren syndrome. We emphasize neonatal blistering and congenital milia unique manifestations of neonatal lupus erythematosus., (© 2010 Wiley Periodicals, Inc.)

Objective: We verified whether oxidative stress indices (oxidized low-density lipoproteins and malondialdehyde) and inflammatory biomarkers (circulating C-reactive protein, interleukin-6, tumour necrosis factor-α, serum amyloid A and soluble intercellular vascular cell adhesion molecule) are increased in the umbilical vein of placental insufficiency induced intra-uterine growth restricted neonates., Study Design: The prospective cohort study, involving 3 tertiary care centers, consists of 200 consecutively recruited pregnant women carrying twins. We chose the twin pregnancy model because both fetuses share the same maternal environment, thereby avoiding potential confounding factors when comparing oxidative stress and inflammation biomarkers. We analysed only twin pairs with one with intra-uterine growth restriction (N=38) defined as fetal growth<10th percentile with abnormal Doppler of the umbilical artery. Blood samples were taken at birth from the umbilical vein. Intra-pair comparisons on the biomarkers were performed using the Student paired t-test., Results: We observed increased cord blood levels of oxidized low-density lipoproteins, (2.394 ± .412 vs 1.296 ± .204, p=.003) but not of malondialdehyde in growth restricted neonates when compared to their normal counterparts. Although indices of inflammation tended to be increased in cord blood from growth restricted newborns, the difference did not reach statistical significance., Conclusion: In the twin model, intra-uterine growth restriction is associated with low-density lipoprotein oxidation without apparent dysregulation of inflammation biomarkers., Condensation: Increased oxidized low-density lipoproteins are observed in growth restricted twins compared to their co-twins with normal growth at birth., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Introduction: The objective of this study is to determine if multiple systemic autoimmune diseases (SAID) share gene expression pathways that could provide insights into pathogenic mechanisms common to these disorders., Methods: RNA microarray analyses (Agilent Human 1A(V2) 20K oligo arrays) were used to quantify gene expression in peripheral blood cells from 20 monozygotic (MZ) twin pairs discordant for SAID. Six affected probands with systemic lupus erythematosus (SLE), six with rheumatoid arthritis (RA), eight with idiopathic inflammatory myopathies (IIM), and their same-gendered unaffected twins, were enrolled. Comparisons were made between discordant twin pairs and these were also each compared to 40 unrelated control subjects (matched 2:1 to each twin by age, gender and ethnicity) using statistical and molecular pathway analyses. Relative quantitative PCR was used to verify independently measures of differential gene expression assessed by microarray analysis., Results: Probands and unrelated, matched controls differed significantly in gene expression for 104 probes corresponding to 92 identifiable genes (multiple-comparison adjusted P values < 0.1). Differentially expressed genes involved several overlapping pathways including immune responses (16%), signaling pathways (24%), transcription/translation regulators (26%), and metabolic functions (15%). Interferon (IFN)-response genes (IFI27, OASF, PLSCR1, EIF2AK2, TNFAIP6, and TNFSF10) were up-regulated in probands compared to unrelated controls. Many of the abnormally expressed genes played regulatory roles in multiple cellular pathways. We did not detect any probes expressed differentially in comparisons among the three SAID phenotypes. Similarly, we found no significant differences in gene expression when comparing probands to unaffected twins or unaffected twins to unrelated controls. Gene expression levels for unaffected twins appeared intermediate between that of probands and unrelated controls for 6535 probes (32% of the total probes) as would be expected by chance. By contrast, in unaffected twins intermediate ordering was observed for 84 of the 104 probes (81%) whose expression differed significantly between probands and unrelated controls., Conclusions: Alterations in expression of a limited number of genes may influence the dysregulation of numerous, integrated immune response, cell signaling and regulatory pathways that are common to a number of SAID. Gene expression profiles in peripheral blood suggest that for genes in these critical pathways, unaffected twins may be in a transitional or intermediate state of immune dysregulation between twins with SAID and unrelated controls, perhaps predisposing them to the development of SAID given the necessary and sufficient environmental exposures.

Aim: To examine the relationship between asthma, type 2 diabetes and increased body mass index (BMI) in adult twins., Methods: We performed record linkage between questionnaire-defined asthma and BMI, and hospital discharge diagnoses of type 2 diabetes in 34,782 Danish twins, 20-71 years of age., Results: The risk of asthma was increased in subjects with type 2 diabetes relative to nondiabetic subjects both in men (13.5%vs 7.5%), P = 0.001 and in women (16.6%vs 9.6%), P = 0.001. The result remained significant after adjustment for age, BMI, smoking, symptoms of chronic bronchitis, marital status and zygosity, men: OR = 1.70 (1.07-2.70), P = 0.026; women: OR = 1.88 (1.24-2.85), P = 0.003. In this analysis, BMI remained a highly significant predictor for asthma independently of diabetes status in women, P < 0.000 but not in men, P = 0.336. Significant positive genetic correlations were found between asthma and type 2 diabetes, 0.20 (0.01-0.40), P = 0.047; between asthma and BMI in women, 0.15 (0.07-0.22), P < 0.000; and between BMI and type 2 diabetes, 0.40 (0.29-0.43), P < 0.000., Conclusions: Asthma, type 2 diabetes and increased BMI are strongly associated in adults, particularly in women. These results suggest a common aetiology for asthma and metabolic syndrome., (© 2010 John Wiley & Sons A/S.)

Familial features of sarcoidosis and observations in monozygotic twins affected by the condition suggest the presence of a genetic predisposition. Various genetic associations have been described with genes coding for proteins involved in immune regulation in particular at the level of interaction between T-lymphocyte and antigen presenting cell. We review the various genetic targets described with techniques ranging from classic human lymphocyte antigen genotype to genome wide linkage scans. The 6p21 region has been highlighted, which includes relevant genes such as MHC class II, BTNL2 and TNFα. These studies show that the genetics of sarcoidosis are complex, that patient sub-groups exist, which may explain some of the heterogeneity in the results of genetic studies and that the interactions between genetic and environmental factors remains to be elucidated., (Copyright © 2011 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Jr(a) is a high-frequency antigen found in all ethnic groups. However, the clinical significance of the anti-Jr(a) antibody has remained controversial. Most studies have reported mild hemolytic disease of the newborn and fetus (HDNF) in Jr(a)-positive patients. Recently, fatal cases of HDNF have also been reported. We report the first case of HDNF caused by anti-Jr(a) alloimmunization in twins in Korea. A 33-yr-old nulliparous woman with no history of transfusion or amniocentesis was admitted at the 32nd week of gestation because of vaginal bleeding caused by placenta previa. Anti-Jr(a) antibodies were detected in a routine laboratory examination. An emergency cesarean section was performed at the 34th week of gestation, and 2 premature infant twins were delivered. Laboratory examination showed positive direct antiglobulin test and Jr(a+) phenotype in the red blood cells and the presence of anti-Jr(a) antibodies in the serum in both neonates. The infants underwent phototherapy for neonatal jaundice; this was followed by conservative management. They showed no further complications and were discharged on the 19th postpartum day. Preparative management to ensure the availability of Jr(a-) blood, via autologous donation, and close fetal monitoring must be performed even in cases of first pregnancy in Jr(a-) women.

Background: The role of genetics in allergy development is well accepted. However, studies could not delineate the mode of inheritance or what is specifically being inherited. The purpose of this study was to determine the effect of genetics on the development of allergy manifestation, serum IgE level, and sensitization to specific allergens., Methods: Fifty-eight twin sets (age 7 months to 11 years) were evaluated for allergy by medical history, family history, physical examination, serum total IgE level, and percutaneous testing to selected common allergens., Results: In 25 monozygotic (MZ) sets, concordance of atopy was significantly higher than in 33 dizygotic (DZ) sets (84.6% vs 62.5%). The age at onset tended to be earlier when the mother was allergic than when the father was (23.5 months vs 30.5 months). When both twins were allergic, the intra-pair difference in age at onset was within <6 months in 50% of MZ sets versus 31.8% in DZ sets. Total IgE level in twins showed a very strong correlation in MZ sets (r 0.92), but only a moderate correlation among DZ sets (r 0.57). Skin test positivity to specific allergens did not show a significant concordance between twins in either group., Conclusion: Our study indicates that the genetic influence was strongest on the inheritance of IgE phenotype, the development of the atopic tendency, the age of onset, and to some extent on the specific allergy manifestation. The effect seemed less on determining the specific offending allergen(s), suggesting possible roles of epigenetic and environmental factors., (Copyright 2009 SEICAP. Published by Elsevier Espana. All rights reserved.)

Objectives: The aim of this study was to investigate the extent of concordance in the number of leucocytes and their cytokine secretion after ex vivo stimulation in a twin population discordant for the amount of periodontal breakdown., Material and Methods: Venous blood was collected from 18 adult twin pairs (10 monozygotic and eight dizygotic twins). Each twin pair consisted of a diseased twin (proband) and his/her co-twin. In venous blood, leucocytes were counted. The cytokines interleukin (IL)-1beta, IL-6, IL-8, IL-10 and IL-12p40 were assessed after stimulation of monocytic cells, while IL-13 and interferon (IFN)-gamma were determined after lymphocytic stimulation., Results: In the study population as a whole, probands showed higher total numbers of leucocytes and lower IL-12p40 levels compared with their co-twins. In monozygotic twins, no difference was found in the leucocyte counts, but probands secreted more IL-6 than their co-twins; an opposite trend was found for IL-12p40., Conclusion: The results suggest that the observed discordance in periodontal breakdown in the studied monozygotic twin population may be related to the relatively high levels of IL-6 and the low levels of IL-12p40 secretion after ex vivo stimulation of whole-blood cell cultures. This cytokine secretion profile may be regarded as a risk indicator of periodontitis.

Neonatal alloimmune thrombocytopenia (NAIT) is due to an immune-mediated maternal-fetal platelet antigen incompatibility. Central nervous system abnormalities have been reported in infants with NAIT and include intracranial hemorrhage, ventriculomegaly, porencephalic cysts, neuronal migrational disorders, and, rarely, cerebellar lesions. We present the clinical and neuropathological findings from a case of a 3-day-old diamniotic/dichorionic female twin with known bilateral ventriculomegaly born prematurely at 33-1/7 weeks in gestational age. The pregnancy was further complicated by discordant intrauterine growth, intraventricular hemorrhage in the co-twin, and NAIT. At birth, the infant was noted to have diffuse body ecchymoses and petechiae and arthrogryposis. She subsequently developed multisystem organ failure and disseminated intravascular coagulopathy and died on the 3rd day of life. Neuropathological findings at autopsy included a posterior fossa cyst with no gross anatomic evidence of a cerebellum, atrophic pons and medulla with prominent pyramidal tracts and absent olivary nuclei, thinned corpus callosum, and symmetrical dilation of bilateral lateral ventricles. Microscopic examination confirmed the gross findings and revealed no histological evidence of cerebellar tissue, absence of superior and inferior cerebellar peduncles, and acute and chronic germinal matrix hemorrhages. Immunohistochemical studies revealed a focus of reactive gliosis at the base of the posterior fossa cyst with no evidence of cerebellar Purkinje or granule cells. To our knowledge, this is the 1st report with well-characterized neuropathological examination detailing complete cerebellar loss and brain-stem atrophy in a neonate with NAIT.

The pattern of adolescent/young adult Hodgkin lymphoma (YAHL) suggests causation by a relatively late infection with a common childhood virus, but no causal virus has been found. Susceptibility is heritable and linked to lower interleukin 12 (IL12) levels, which can also result from fewer fecal-oral microbial exposures early in life. We studied twin pairs discordant for YAHL to examine exposures capable of altering the IL12 response and T-helper type 1 (Th1)-Th2 balance. One hundred eighty-eight YAHL-discordant twin pairs from the International Twin Study returned questionnaires (70% response). Exposure history of YAHL case-twins was compared with that of their unaffected control-twins using conditional logistic regression for matched pairs to calculate odds ratios (ORs). Behaviors likely to produce oral exposure to microbes conveyed decreases in risk (univariable OR range = 0.2-0.5, P = .003-.11). Significant adjusted ORs were seen for appendectomy (OR = 4.3, P = .001), eczema (OR = 4.2, P = .025), smoking (OR = 2.2, P = .054), and relatively more frequent behaviors associated with oral exposures (OR = 0.1; P = .004). Kappa statistics for intrapair agreement were higher than 0.8 for each significant finding. Our observations support a protective role for increased early oral exposure to the microbiome, suggesting that factors associated with increased Th2 and decreased Th1 cytokines are etiologically relevant to YAHL.

Gastric lesions in primary constitutive immune deficiencies include multifocal atrophic gastritis, erosive pangastritis, and a pattern of gastric lesions reminiscent of graft-versus-host disease. We describe the genetic anomalies in 2 monozygotic twins with an X-linked lymphoproliferative disease (XLP; MIM 308240), a rare familial setting of high susceptibility to Epstein-Barr virus (EBV). Since early childhood, both twin brothers exhibited a severe chronic active atrophic pangastritis. A germline screening of the SH2D1A (MIM 300490) and BIRC4 (MIM 300079) genes was performed, and also a high-resolution whole-genome SNP profiling (Infinium Sentrix Human-1 Genotyping BeadChip, Illumina). A 3 Megabase deletion in the Xq25 region, encompassing the SH2D1A gene, was defined by SNP array genotyping. Histologic analysis of yearly or twice yearly gastric biopsies in both children showed a Helicobacter pylori-negative, Epstein-Barr virus-negative chronic active atrophic pangastritis, with superficial ulcer formation, foveolar hyperplasia, glandular dilatation and ultimately pseudopyloric and intestinal metaplasia. No such chronic active inflammatory gastric lesions have been reported to date in XLP. The similarities between XLP and common variable immunodeficiency (MIM 240500) underscore the need for early recognition and close monitoring of these gastric lesions, with special regard to their neoplastic potential. No infectious cause was determined. We favor a dysimmune mechanism in the development of this chronic atrophic gastritis, presenting a striking similarity to the recently described atrophic autoimmune pangastritis.

This report describes type 1 insulin deficient diabetes mellitus (IDDM) arising in identical twins aged under one year. One twin presented with symptoms and was diagnosed with type 1 IDDM; the diagnosis of type 1 IDDM was simultaneously made in the second twin without clinical symptoms. Both twins were positive for anti-GAD (glutamic acid decarboxylase) antibody at first, and then positive for islet cell antibodies. Interestingly, the twins have four susceptible HLA DR and DQ genes together that are usually recognized separately in IDDM patients in Japan.

Human immunodeficiency virus type 1 (HIV-1) cytotoxic T-lymphocyte escape mutations represent both a major reason for loss of HIV immune control and a considerable challenge for HIV-1 vaccine design. Previous data suggest that initial HIV-1-specific CD8(+) T-cell responses are determined largely by viral and host genetics, but the mechanisms influencing the subsequent viral evolution are unclear. Here, we show a random recruitment of T-cell receptor (TCR) alpha and beta clonotypes of the initial HIV-1-specific CD8(+) T cells during primary infection in two genetically identical twins infected simultaneously with the same virus, suggesting that stochastic TCR recruitment of HIV-1-specific CD8(+) T cells contributes to the diverse and unpredictable HIV-1 sequence evolution.

Problem: Elevated Th1/Th2 cytokine producing CD3(+)/CD4(+) cell ratios were reported in women with a history of recurrent spontaneous abortion (RSA) and multiple implantation failures. We report, significantly elevated Th1/Th2 cell ratios were noticed in a pregnant woman with twin pregnancies complicated with one fetal demise, who had a history of RSA, secondary Sjögren's syndrome (SS), and rheumatoid arthritis., Method of Study: Case report., Results: Peripheral blood Th1/Th2 cell ratios were significantly elevated 3 weeks prior to a fetal demise of twin pregnancies at 20 week gestation. Two weeks after fetal demise, the ratio of intracellular tumor necrosis factor-alpha/interleukin-10 producing CD3(+)/CD4(+) cells in peripheral blood was further increased to three times higher than prior ratio. Elevated Th1/Th2 ratio was down regulated after increasing dose of IVIg treatment. The patient gave birth to a male baby weighing 2650 g at 36 weeks gestation. No serious complications were found in the patient or the baby., Conclusion: Systemic inflammatory immune response pre-exists prior to a fetal demise and the degree of inflammatory immune response got worse with a presence of fetal demise in utero. We infer that the placenta is not an immunological barrier to maternal Th1/Th2 immune responses.

Background: Both genetic and environmental factors are involved in the etiology of bipolar disorder; however, biological markers for the transmission of the bipolar genotype ("endophenotypes") have not been found. Autoimmune thyroiditis with raised levels of thyroperoxidase antibodies (TPO-Abs) is related to bipolar disorder and may be such an endophenotype. This study was intended to examine whether autoimmune thyroiditis is related to the disease itself, to the (genetic) vulnerability to develop bipolar disorder, or both., Method: Blood was collected from 22 monozygotic (MZ) and 29 dizygotic (DZ) bipolar twins and 35 healthy matched control twins to determine TPO-Abs., Results: The TPO-Abs were positive in 27% of the bipolar index twins, 29% of the monozygotic bipolar cotwins, 27% of the monozygotic nonbipolar cotwins, 25% of the dizygotic bipolar cotwins, 17% of the dizygotic nonbipolar cotwins, and in 16% of the control twins. Repeated measures analysis of covariance on log-transformed absolute TPO-Abs values revealed significantly increased mean TPO-Abs levels in discordant twin pairs as compared with healthy twin pairs, whereas no difference was found between bipolar patients and their (discordant) nonbipolar cotwins., Conclusions: This study shows that autoimmune thyroiditis is related not only to bipolar disorder itself but also to the genetic vulnerability to develop the disorder. Autoimmune thyroiditis, with TPO-Abs as marker, is a possible endophenotype for bipolar disorder.

Background: A wide range in antibody titers has been found after immunization with the varicella vaccine, although the basis for these differences has not been described., Methods: To evaluate the contribution of a genetic component in the immune response to the varicella vaccine, concordance for six-week postimmunization antibody titers was evaluated among 248 biologic siblings who participated in varicella vaccine clinical trials by comparing all pairs of siblings (151 pairs) to all possible unrelated, nonsibling pairs created from within this same cohort (30,477 pairs)., Results: Postimmunization antibody titers after 1 varicella vaccine dose were within the range observed historically among healthy vaccinees, with 85.4% of subjects having antibody responses greater than the approximate correlate of protection of 5 gpELISA units. Postimmunization antibody titers within sibling pairs clustered together more than or less than 10 gpELISA units when compared with within nonsibling pairs (P < 0.0001). Postimmunization titers within sibling pairs were also quantitatively closer together than were those within unrelated, nonsibling pairs (P = 0.022). The age-adjusted intraclass correlation coefficient indicated that the heritability of the varicella vaccine immune response is 45% (95% confidence interval of 15-75%)., Conclusions: Similarities in siblings' response to varicella vaccine are supportive of the hypothesis that genetic factors play a role in the antibody response to the varicella vaccine.

The safety and efficacy of adoptive T-cell transfer (ATT) was tested in the context of viral suppression in syngeneic twins discordant for human immunodeficiency virus type 1 (HIV-1) infection. Human leucocyte antigen-matched T cells of seven HIV-negative twins were obtained by lymphapheresis and immediately transfused into the HIV-infected sibling. Four twins received 12 ATTs each, with a mean of 2.10 +/- 0.97 x 10(9) CD4(+) T cells and 1.74 +/- 0.81 x 10(9) CD8(+) T cells. Additional transfers were performed in three more twin pairs to study the short-term kinetics of transfused syngeneic T cells. Mean CD4(+) T-cell counts increased significantly, by 0.133 +/- 0.136 x 10(9) cells/l at 1 h and 0.144 +/- 0.12 x 10(9) cells/l at 3 h post-transfusion (P < 0.0001). Short-term kinetic studies suggested a rapid clearance of transferred T cells from the peripheral blood within minutes due to a distribution to marginal pools. After a mean follow up of 39 months, however, a sustained increase of the mean CD4(+) T-cell count was observed (from 0.232 x 10(9) to 0.523 x 10(9) cells/l) without changes of plasma viraemia. We conclude that ATT combined with highly active antiretroviral therapy is safe and leads to a considerable increase in CD4(+) T-cell numbers. The clearance kinetics of the transfused cells from peripheral blood indicates a very rapid regulation of T-cell homeostasis in HIV infection.

Understanding of the aetiological basis of thyroid autoimmunity may be gained by studying the early stages of the disease process. We aimed to (1) investigate the relationship between thyroid antibody status and Yersinia enterocolitica (YE) infection in euthyroid subjects and (2) explore the relative importance of genetic and environmental risk factors in the acquisition of YE infection. The association between thyroid antibody status and YE infection was explored using a case-control design. Furthermore, thyroid antibody-positive twins were compared with their thyroid antibody-negative co-twin. In 468 twins, IgA and IgG antibodies to virulence-associated outer-membrane proteins (YOPs) of YE were measured. Of these, 147 were thyroid antibody-positive (cases). A total of 147 age- and gender-matched twins were chosen as controls. The prevalence of YOP antibodies was lower among thyroid antibody-positive individuals than among controls. Yersinia infection was not associated with a positive thyroid antibody status: the odds ratio (with 95% CI) for YOP IgA-ab was 0.66 (0.42-1.05), P = 0.078 and for YOP IgG-ab it was 0.95 (0.60-1.50), P = 0.816. Within discordant twin pairs, the thyroid antibody-positive twin did not have an increased risk of Yersinia infection compared to the thyroid antibody-negative co-twin [odds ratio: YOP IgA-Ab: 0.94 (0.49-1.83), P = 0.866, and YOP IgG-Ab: 1.35 (0.72-2.53), P = 0.345]; 41% (95% CI 10-67% of the liability of being YOP antibody-positive was due to genetic effects. In conclusion, Yersinia infection does not confer an increased risk of thyroid antibodies. The genetic contribution in the acquisition of Yersinia infection is modest.

Unlabelled: This paper reports on two male infants with abnormally high levels of serum triacylglycerols (>15.00 mmol/l) and massive accumulation of chylomicrons. Pathological lipidograms were observed during breastfeeding only and were typical of a rare chylomicronaemia syndrome. Laboratory abnormalities were detected accidentally in the otherwise healthy infants. An unrecognized modulating factor in fresh mother's milk caused transitory decreased activity of hydrolytic complex for chylomicrons and very-low-density lipoproteins, probably due to a dysfunction of lipoprotein lipase. The normalization of lipidograms suggested that the catalytic activity of lipoprotein lipase rapidly recovered after weaning. Pathogenesis moved more towards an immune disorder, to the production of (auto)antibodies against a component of the lipolytic system. Mother's milk should be substituted with banked donor human milk, but this is not an unambiguous demand., Conclusion: Fresh mother's milk caused a decrease in the activity of lipolytic enzyme (lipoprotein lipase). The massive hypertriacylglycerolaemia quickly disappeared after weaning. Two infants with this transient chylomicronaemia syndrome were asymptomatic.

We report serial transplantation procedures in 2 sets of brothers with X-linked primary immunodeficiency. The first boy in each family received a T-cell-depleted transplant from a mismatched donor. The recipients then acted as donors for T-replete transplantation of the "tolerized" graft into their HLA-identical brothers with the same disorder. Immune reconstitution was noted to occur at a significantly faster rate in the secondary recipients, and without the occurrence of graft-versus-host disease (GVHD), despite the presence of donor cells mismatched for 1 to 3 HLA antigens. This serial transplantation technique allows the primary recipient of HLA-mismatched donor cells to act as a functionally "HLA-matched" donor for subsequent affected siblings, and should be considered as a therapeutic option in families with congenital disorders.