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Introduction: Neuromyelitis optica (NMO) and Multiple Sclerosis (MS) have been reported in different populations. NMO is more frequent in non-Caucasians, and clinical phenotype differences between populations are likely influenced by genetic susceptibility. In Brazil, it has been reported that NMO patients have a mainly European ancestry background. Like other autoimmune diseases, NMO has a multifactorial origin (i.e., genetics, environmental and infectious factors). Regarding the genetics of NMO, epidemiological findings suggest that a polygenic background has an important role in the development of this type of disease. In this context, various genes have been studied, such as those involved in the synthesis of the T cell beta chain receptor, the VH2-5 gene, myelin basic protein, the CTLA-4 gene, and the interleukin-1 gene., Materials and Methods: We performed a study with the main objective of identifying candidate genes involved in the susceptibility to develop NMO in a Mexican population., Result: We included 35 patients with an NMO diagnosis according to the Wingerchuk 2006 criteria. The mean age of the patients was 43.3 years old (20-67), and 80 percent of the patients were women. The presence of HLA-DRB1*03 and HLA-DRB1*10 alleles were more frequent in NMO patients than in controls (n=198; p=0.03 and 0.005, respectively)., Conclusion: There were no differences in the other alleles that have been described in MS subjects, such as HLA-DRB1*04, HLA-DRB1*08 and HLA-DRB1*13. These findings may support the hypothesis that implicated immune-genetics as a key factor in development of this type of disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background & Aims: The Alaska Native population is one of few populations in the world with a high prevalence of autoimmune hepatitis. The objective of this study was to determine the frequency and HLA and clinical associations of autoantibodies in Alaska Native people with autoimmune hepatitis., Methods: Alaska Native individuals with autoimmune hepatitis were recruited in clinics conducted statewide. Sera were tested for the presence of autoantibodies described in either autoimmune hepatitis or rheumatic disease. Associations between autoantibodies and HLA alleles and clinical features were assessed., Results: Seventy-one patients were included. At the study visit, 34 patients (47.9%) had antibodies to double-stranded DNA by immunofluorescence; 27 (38.0%) had anti-neutrophil cytoplasmic antibodies; and 11 (15.5%) had anti-Ro antibodies. Only one person had antibodies against soluble liver antigen, and in that person, anti-Ro was absent. Associations were found between autoantibodies and HLA alleles, including positive associations between HLA DR3 and anti-double-stranded DNA antibodies and between HLA DR14 and antineutrophil cytoplasmic antibodies. There was no association between autoantibodies and clinical outcomes., Conclusions: As in other populations, the prevalence of anti-double-stranded DNA antibodies and antineutrophil cytoplasmic antibodies is high in Alaska Native people with autoimmune hepatitis. In contrast to data from other populations, there is a lower prevalence of anti-soluble liver antigen and a lack of association between anti-Ro and anti-soluble liver antigen. In addition, the HLA profile and associations with autoantibodies are unique. No clear prognostic implications of autoantibodies have emerged in this population., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Familial clustering of juvenile autoimmune liver disease (AILD), including autoimmune hepatitis and autoimmune sclerosing cholangitis (ASC), is rare, despite a high prevalence of autoimmune disorders in AILD families., Methods: To investigate this discrepancy, we measured autoantibodies diagnostic for AILD, anti-nuclear, anti-smooth muscle, anti-liver kidney microsomal type 1, anti-liver cytosol type 1, and anti-soluble liver antigen antibodies, and human leukocyte antigen profiles in 31 patients and 65 of their first-degree relatives (FDR). The autoantibody profile was compared with that of 42 healthy subjects (HS)., Results: Autoantibodies were detected in 71% (22/31) patients. Anti-nuclear antibody or anti-smooth muscle antibody were present in 4/65 FDR (6.2%). HS were negative for all autoantibodies. The frequencies of homozygous HLA DRB1*0301 (DR3) genes and haplotype A1-B8-DR3 were higher in the patients (25% and 43%) than in FDR (9% and 27%) and HS (0% and 16%). The frequencies of disease-protective genes DR4 and/or DR15 were lower in the patients (25%) than in FDR (42%) and HS (42%). Only 1 family contained 2 patients with AILD, 1 with ASC and 1 with primary sclerosing cholangitis. Both patients possessed A1-B8-DR3 genes, the ASC being homozygous and the primary sclerosing cholangitis heterozygous. Six FDR had nonhepatic autoimmune disorders, none being autoantibody positive., Conclusions: Homozygosity for DR3 plays a major role in the predisposition to juvenile AILD. Diagnostic autoantibodies for AILD are rare among patients' FDR and not linked to clinical manifestation of AILD.

Background/aims: To study the clinical features of elderly Chinese patients with autoimmune hepatitis., Materials and Methods: The clinical features of 36 patients diagnosed at age >60 years were compared with those of 39 patients aged <50 years., Results: The M:F ratio was 1:35 (>60 years) vs. 3:36 (<50 years). The patients >60 years had a higher frequency of cirrhosis at presentation than the patients <50 years (52.8% vs. 15.4%, p=0.001). The patients >60 years also had a significantly increased incidence of ascites at presentation (41.7% vs. 10.3%, p=0.001) and lower serum albumin levels (p=0.037). There were significant differences between older and younger patients with respect to the frequencies or titers of anti-nuclear antibody (46.2% vs. 83.3%, p=0.011). HLA DR3 positivity occurred more frequently in the patients <50 years than in those >60 years (59.0% vs. 19.4%, p<0.001), whereas HLA DR4 occurred more often in the patients >60 years (63.9% vs. 25.6%, p=0.001). Treatment failure occurred more frequently in the patients <50 years (28.2% vs. 9.1%, p=0.041). However, there were no significant differences between the groups with respect tomode of onset, other clinical signs at presentation biochemical parameters, and smooth muscle antibody positivity., Conclusion: Elderly patients have a greater frequency of cirrhosis at presentation, anti-nuclear antibody, HLA DR4 positivity than patients <50 years, and they have a lower occurrence of treatment failure. Conventional corticosteroid regimens may be an effective management for older patients with autoimmune hepatitis.

We report that a significant number of autistic children have serum levels of IgA antibodies above normal to the enzyme tissue transglutaminase II (TG2), and that expression of these antibodies to TG2 is linked to the (HLA)-DR3, DQ2 and DR7, DQ2 haplotypes. TG2 is expressed in the brain, where it has been shown to be important in cell adhesion and synaptic stabilization. Thus, these children appear to constitute a subpopulation of autistic children who fall within the autism disease spectrum, and for whom autoimmunity may represent a significant etiological component of their autism., (Copyright © 2011, International Society for Autism Research, Wiley-Liss, Inc.)

Objectives: To determine the prevalence of Raynaud's phenomenon (RP) in patients with primary Sjogren's syndrome (pSS) and to identify clinical and immunological characteristics associated with this manifestation. Since increased interferon-gamma (INF-gamma) has been associated with RP, we also compared the INF-gamma production in pSS patients with or without RP., Methods: RP was diagnosed if pSS patients presented with characteristic sequence of skin color changes of the digits. In uncertain cases noninvasive vascular tests were performed by ultrasound examination. The secretion of INF-gamma by peripheral blood mononuclear cells was assessed by enzyme-linked immunospot analysis. Further, we examined the expression of different lymphocyte activation markers (CD25, CD45RO, CD69) on CD4+ T-cells by flow cytometric analysis., Results: Thirty-six of 108 patients with pSS had RP. In these patients we found a significantly increased number of INF-gamma-secreting peripheral blood mononuclear cells compared with patients without RP or to healthy controls. Further, in patients with RP a significantly increased percentage of CD25-positive T-helper cells was detectable. In addition we found an association of leukopenia, thyroiditis, and lower C3 levels with RP in pSS patients., Conclusions: These results suggest a pathogenic role of INF-gamma in pSS patients with RP. Whether the RP is immune-mediated or whether INF-gamma directly causes vasospasm still remains to be elucidated.

Ancestral haplotype (AH) 8.1(HLA-A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501, DQB1*0201) seems to be associated with susceptibility to autoimmune diseases. Different mechanisms are probably involved in increasing autoimmunity, such as unbalanced cytokine production and the lack of C4A protein. So AH 8.1 modifies immune response in many ways. In this study we demonstrate that IgG2 serum levels were significantly lower in 8.1 AH carriers than in 8.1 AH non-carriers. On the contrary, as regards IgG1, IgG3, IgG4 serum levels, no significant differences were observed between the two groups. In AH 8.1 carriers low IgG2 levels might take to slower clearance of the infectious agent and hence to a lasting presence of it. The persistence of infectious antigens could determine an increased production of autoantibodies with a higher risk of cross-reactions.

Background: Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is almost universal, but the natural history of recurrent HCV in the allograft is highly variable. Our study had two aims: 1) to assess the impact of different pre- and postLT factors on graft and patient survival in HCV transplant recipients and 2) to create a model which may predict the patients at risk for HCV-related graft cirrhosis at 5 years postLT., Methods: A total of 168 LTs were considered for this study. Univariate and multivariate Cox proportional hazards regression model was used, as well as logistic regression analysis to create a model of prediction of HCV cirrhosis within 5 years after LT., Results: Predictive factors for both decreased graft and patient survival included patients recently transplanted (2000-2004), induction without azathioprine, short-term therapy with mycophenolate mofetil and prednisone (< or =6 months), presence of early cholestasis, histologically proven early recurrence of hepatitis C. Recipient human leukocyte antigen DR3 positivity, presence of early cholestasis, and donor age >50 years were identified as independent predictors of graft cirrhosis within 5 years. A predictive model was established in order to calculate at 6 months a risk score for graft HCV cirrhosis within 5 years postLT using a formula that included the identified independent predictors. The area under receiver operating characteristic curve was 0.83, indicating a good ability to predict medium-term HCV allograft cirrhosis., Conclusion: This model may be a useful tool for better identifying high-risk HCV patients who should be selected for early initiation of antiviral therapy.

Objective: In Caucasian type 1 autoimmune hepatitis patients with a main susceptibility of human leukocyte antigen DR3 and DR4, elderly patients have a higher frequency of concurrent autoimmune disease and cirrhosis at presentation. However, in Japanese patients, the disease is dominantly associated with DR4, and their clinical features may be different from those of previous reports. In this study, we assessed the clinical features of Japanese elderly patients with type 1 autoimmune hepatitis., Methods: We investigated 160 consecutive patients with type 1 autoimmune hepatitis, consisting of 34 elderly patients (> or = 65 years) and 126 younger patients (< 65 years)., Results: There were no differences in form of clinical onset, frequencies of concurrent autoimmune disease, positive proportions of anti-nuclear antibody and/or anti-smooth muscle antibody, and human leukocyte antigen DR status between the two groups. However, the elderly patients had lower serum levels of albumin (p=0.0049), and higher frequencies of cirrhosis (F4) and pre-cirrhosis (F3) (p=0.014) compared with the younger patients. In contrast, in elderly patients, the cumulative incidental rate of the normalization of serum alanine aminotransferase levels within 6 months after the introduction of initial treatment was higher in those treated with prednisolone > or = 20 mg/day than those treated only with ursodeoxycholic acid (p=0.001)., Conclusion: We speculate that more years may pass between the occurrence of the disease and the presentation in Japanese elderly patients than in younger patients, and we considered that, even in elderly patients, those with advanced fibrosis should be treated with prednisolone in order to prevent progress of the disease into liver failure.

Background: Peripartum and postpartum dermatologic lesions may or may not be an indicator of morbidity or mortality for either the fetus or mother., Case: Postpartum dermatologic lesions occurred in a 41-year-old multipara, 1 week after a repeat cesarean delivery for severe intrauterine growth restriction and nonreassuring fetal testing. The diagnosis, using histopathologic techniques, and the pharmacologic management are discussed., Conclusion: This case raises intriguing questions regarding prompt diagnosis, treatment, and the counseling of patients with dermatologic lesions with respect to current and future pregnancy outcomes.

Aim: To report on our large German collective and updated data of 142 patients with autoimmune hepatitis (AIH) type 1., Methods: Key investigations performed were liver biopsy, serum autoantibodies as well as serum markers such as IgG and elevated transaminases. Antinuclear antigen (ANA) and smooth muscle antigen (SMA) autoantibodies characterized type 1 AIH. Type 3 (AIH) was solely characterized by the occurrence of soluble liver antigen/liver-pancreas antigen (SLA/LP) autoantibodies either with or without ANA or SMA autoantibodies., Results: Most prevalent HLAs were A2 (68 patients, 48%), B8 (63 patients, 44%), C7 (90 patients, 63%), DR3 (49 patients, 38%), DR4 (49 patients, 38%) and DQ2 (42 patients, 30%). Compared to the Italian and North American patients, we found fewer patients with a DQ2 subtype. Furthermore, the B8-DR3-DQ2 human leucocyte antigen (HLA) was also less prominent compared to the North American patients. However, prevalences of B8, DR3, DR4, DR7, DR11 and DR13 were comparable to the Italian and North American patients. Furthermore, we report on an additional subgroup of patients with SLA/LP positive AIH. Generally, in this subgroup of patients the same HLA subtypes were favoured as the AIH type 1., Conclusion: Although HLA subtypes were comparable between these three collectives, the German patients were distinct from the Italian and North American patients with respect to DQ2 and from the North American patients with respect to B8-DR3-DQ2 HLA. A clinical correlation, e.g. difference in severity or treatability of AIH type 1, has yet to be determined.

Objectives: Determine the frequency, clinical phenotype, and prognostic implications of antibodies against cyclic citrullinated peptides in patients with type 1 autoimmune hepatitis., Methods: Three hundred and ninety-five serum samples from 179 patients were tested by enzyme-linked immunosorbent assay, and findings correlated with clinical and histological features, frequency of HLA DR3 and DR4, and treatment outcome., Results: Twenty patients (11%) had antibodies against cyclic citrullinated peptides. Seropositivity was associated with a higher frequency of rheumatoid arthritis (RA) (25 vs. 0%, P < 0.001). Patients with antibodies against cyclic citrullinated peptides also had a significantly greater occurrence of histological cirrhosis at presentation (47 vs. 20%, P = 0.01) and death from hepatic failure than seronegative patients (25 vs. 9%, P = 0.04). Cirrhosis at presentation occurred more commonly in the patients with antibodies against cyclic citrullinated peptides and RA than in the other patients (100 vs. 21%, P = 0.005)., Conclusions: Antibodies against cyclic citrullinated peptides occur in a subgroup of patients with type 1 autoimmune hepatitis who have a greater occurrence of cirrhosis at presentation and death from hepatic failure. Their presence with RA at accession characterizes a subgroup with cirrhosis.

In animal models autoreactive CD8(+) T cells are crucial in the development of type 1 diabetes (T1D); however, their role in human T1D is still not known. To address the role of CD81 T cells we performed a pilot study by investigating CD8(+) T cell-mediated cytokine secretion after in vitro stimulation with 94 preproinsulin (PPI) peptides. We were able to show that CD8(+) T cells contribute to a strong IFNgamma reactivity against PPI in human T1D. Further investigations defining epitope specificity, cytokine secretion, and cytotoxic capacity are important to clarify their role in T1D development.

Background: This study was designed to examine the effects of hexavalent chromium [Cr(VI)] on the immunological pattern of shoe, hide, and leather industry workers, moving from the hypothesis that some haplotypes (HLA-B8,DR3) can be important hidden risk cofactors., Methods: Workplaces of 20 firms were monitored for total and respirable dusts and for total and hexavalent chromium. Cr(VI) on materials was also measured. Assay of chromium levels in blood and urine of 44 serological human leukocytes antigen (HLA)-typed workers (20 exposed, 15 HLA-B8,DR3-negative/5-positive and 24 non-exposed, 18 HLA-B8,DR3-negative/6-positive subjects) was performed by atomic absorption, and lymphocyte subsets (FACS-analysis), mitogen-mediate lympho-proliferation ([3H]thymidine incorporation), cytokine levels (ELISA), natural killer (NK) cytotoxic activity (51Cr-release assay) were determined., Results: The environmental parameter levels are lower than threshold limit value-time-weighted average (TLV-TWA); in the materials, the Cr(VI) values exceeded the levels allowed. The peripheral blood mononuclear cells (PBMC) proliferation and the T-helper1 (TH1) cytokine pattern of subjects chronically exposed were significantly raised; addition in vitro of Cr(VI) further stimulated these parameters and in general the entire TH1 system and NK activity. The TH2 system was unaltered. In the HLA-B8,DR3-positive workers, immunologically "low responders", the addition of Cr(VI) in vitro caused a further reduction of the considered parameters in the exposed subjects with a dramatic deficit of the TH1 system., Conclusions: Results indicate the unsuitability of TLV-TWA as a line of demarcation between safe and dangerous Cr(VI) concentrations and the importance of individual genetic susceptibility for occupational and preventative medicine. In particular, the presence of the HLA-B8,DR3 alleles can represent an important cofactor of immunotoxic susceptibility consequent to chronic low-dose Cr(VI) exposure.

The present case report refers to a multiorgan autoimmune disease manifesting following thymectomy performed for a benign thymoma. This disease is characterized by hypothyroidism, severe myasthenia, polymyositis and alopecia which are organ-specific diseases probably with a different time of onset but which are all an expression of the same immunopathologic process occurring in individuals who have a genetic predisposition. Characteristic of the present case is not only the association of the different immunopathologic clinical pictures but also the rather difficult differential diagnosis between a hypothyroidism-related myopathy and polymyositis. It was possible to formulate the diagnosis by integrating the results of clinical and laboratory evaluation with the therapeutic outcome. The onset of the syndrome was attributed to the withdrawal, following surgery, of the inhibitory effects of the thymoma on some clones of autoreactive lymphocytes.

We studied the human leukocytes antigens in 18 Egyptian children with biliary atresia (BA) without extrahepatic congenital malformations. There was a significant increased frequency of both B8 and DR3 (83.3% and 94.4% in patients with BA compared with 6.5% and 14.9% in the general population, respectively). Ten patients had the B8/DR3 haplotype. Our results support the hypothesis that genetic factors may play a role in susceptibility to BA.

Purpose: Cross-sectional data from the Wisconsin Epidemiologic Study of Diabetic Retinopathy indicated that patients with HLA-DR4, but not DR3, were more likely to have prevalent proliferative retinopathy than those without both antigens. We describe the relation of HLA-DR3 and DR4 antigens to the 14-year incidence and progression of diabetic retinopathy and macular edema in this cohort., Design: A population-based cohort study., Participants: A probability sample of male and female patients receiving primary care for diabetes in 11 counties of southern Wisconsin., Methods: Participants were invited for a baseline examination in 1980 to 1982, with follow-up examinations at 4, 10, and 14 years later. At the 4-year examination, a random sample of participants (n = 428) diagnosed with diabetes before the age of 30 and taking insulin were selected for HLA-DR typing., Main Outcome Measures: Fourteen-year incidence and progression of diabetic retinopathy and macular edema based on masked stereoscopic fundus photographic grading., Results: There was no relation between HLA-DR3 and DR4 status with the 14-year incidence and progression of diabetic retinopathy, progression to proliferative retinopathy, and incidence of macular edema. Patients with either HLA-DR3 or DR4 were less likely to progress to proliferative retinopathy compared with those who were negative for both, although these relations were not statistically significant. The associations did not vary after adjusting for hypertension status, baseline retinopathy, and glycosylated hemoglobin levels, or after stratifying by duration of diabetes (less than 10 years vs. 10 years or more) and age at diagnosis of diabetes (less than 15 years vs. 15 years or more). Furthermore, 10-year mortality and 14-year nephropathy rates did not differ by HLA-DR3 or DR4 status, suggesting that selective mortality did not explain the pattern of associations seen., Conclusions: In contrast to the initial cross-sectional findings, these data suggest that HLA-DR3 or DR4 status is unrelated to 14-year incidence and progression of diabetic retinopathy. The discrepancy may be related to increasing homogeneity of retinopathy and diminishing power to detect small differences, but it may also reflect the uncertain and inconsistent effects of HLA-DR3 or DR4 on the development and progression of diabetic retinopathy.

We describe the clinical course of a girl with onset of type I diabetes mellitus at the age of 3 years. At the age of 10, coeliac disease and shortly thereafter a vitamin B12 deficiency anemia (Imerslund-Gräsbeck-syndrome) was diagnosed. Her younger sister also suffered from Imerslund-Gräsbeck-syndrome when she was 11 year old. This unusual, so far not described association of rare diseases suggests a common autoimmune etiology.

The prevalence and clinical and laboratory associations of IgM, IgG and IgA rheumatoid factors (RF) were determined in 352 patients with systemic lupus erythematosus (SLE). IgM, IgG, and IgA class RF were detected in 17.9%, 20.5%, and 20.5% of the sera, respectively. RF were associated with sicca syndrome, hypergammaglobulinemia, high titer of antinuclear antibodies, anemia, SSA- and SSB-antibodies, and with the presence of HLA-DR3. RF correlated negatively with nephritis and livedo racemosa. Moreover, we observed an association of RF and parameters of inflammatory activity such as elevated erythrocyte sedimentation rate (ESR) and leukopenia. Analysis of immunoglobulin classes revealed that laboratory parameters of inflammatory activity, SSA- and SSB-antibodies and HLA-DR3 correlated with IgA RF only. IgA RF define a subgroup of SLE patients characterized by distinct autoimmune phenomena and high disease activity in the absence of nephritis.

Linear IgA disease and chronic bullous disease of childhood are both subepidermal autoimmune blistering diseases. Class I and II major histocompatibility locus (MHC) antigen typing was performed on 60 patients (26 chronic bullous disease of childhood, 34 adult linear IgA disease), and the findings were correlated with the clinical course. The typing was performed using a lymphocyte microcytotoxicity assay, and the results were compared with a reference population of U.K. organ donors. Analysis of the tumour necrosis factor (TNF) locus was performed using sequence-specific oligonucleotides on a dot blot in 51 patients and compared with a random control population and human lymphocyte antigen (HLA) DR3 matched controls. The disease was found to be significantly associated with HLA Cw7 (chi2 = 19.24, P = 0.001), B8 (chi2 = 9.89, P = 0.04) and DR3 (chi2 = 10.47, P = 0.014), all components of the common Caucasian haplotype. There was also a close association between the disease and possession of HLA DR2 or 3 (chi2 = 16.34, P = 0.001). A reduction in the incidence of DR1 and DR4 (alleles carrying the rheumatoid motif) was observed, which is more marked in the children (chi2 = 8.34, P = 0.039). In the childhood group there was an increased frequency of B8, DR3 and DQ2 compared with the adults which included five of 26 who were homozygous for these antigens, a feature not seen in the adults, which may account for the differences seen between the two groups. Possession of HLA B8, DR3 and DQ2 probably facilitates earlier presentation of the disease as there is no evidence from our results that the adults and children differ fundamentally in their MHC associations. The rare TNF2 allele was found in 29 of 51 patients (expected 8.2, chi2 = 18. 3, P = 0.0001). This was more marked in the children (19 of 26). Patients with the TNF2 allele had a longer disease duration (5.3 years TNF2, 3.0 years TNF1).

Renal allograft survival is prolonged after pretransplantation blood transfusion. The aim of this study was to test retrospectively the development and persistence of microchimaerism after pretransplantation blood transfusion and to assess whether the type of blood transfusion (partially matched [= sharing of at least one HLA-B and one HLA-DR antigen between blood donor and recipient] versus mismatched) influences the (continued) presence of donor-type cells. A sensitive nested PCR technique based on HLA-DRB1 allele-specific amplification using sequence-specific primers (detection level: one donor cell among 10(5) recipient cells) for detection of donor cells was implemented in our laboratory. We studied 21 patients for microchimaerism in the peripheral blood compartment, following blood transfusion. Our preliminary data show that microchimaerism was detectable up to 8 weeks after blood transfusion. In all patients receiving a partially matched blood transfusion, donor-type cells were detected in the first week after transfusion, in 7/8 patients 2-4 weeks after transfusion, and in some patients up to 8 weeks after transfusion. After mismatched transfusion a tendency to shorter duration of microchimaerism was observed.

A 59-year-old woman developed an acute and severe thrombocytopenia (platelet count below 10.10(9).L-1) with active bleeding, 6 days after a massive transfusion for intraoperative haemorrhagic shock. The diagnosis of post-transfusion purpura (PTP) was confirmed by the presence of an allo-antibody directed against HPA-1a platelet antigen. The patient and her daughter had a rare HPA-1b platelet phenotype, but also belonged to the HLA DR3 phenotype, frequently associated with PTP. This case shows the therapeutic difficulties of postoperative PTP. Despite active bleeding, this syndrome requires the discontinuation of transfusions of incompatible platelets. Transfusion of phenotyped platelets is often inefficient. Red cell concentrates must be platelet and plasma free. Immunomodulating therapy can shorten the time course. Preventive measures, particularly autologous transfusions, are necessary for subsequent haemorrhagic surgery or parturition.

The number of lymphocytes in the blood is constant, pointing to an effective control of circulating lymphocyte values. The mechanisms of this regulation are uncertain, although it is likely that the number of blood lymphocytes is conditioned by hormones, homing factors and cytokines whose production is at least partly restrained by genetic factors. Particularly genetic factors linked to major histocompatibility complex (MHC) appear to be involved. In human beings a decreased number of blood lymphocytes has been described in healthy subjects carrying the Human Leucocyte Antigens (HLA) haplotype HLA-B8,DR3. In the present study, to inquire into the mechanisms of this lymphocyte decreased number, we have performed an analysis of blood subset values in these subjects. When the absolute values of lymphocytes were analysed according to HLA phenotype, HLA-B8,DR3 positive subjects (N = 26) displayed significantly lower values as compared to HLA-B8,DR3 negative ones (N = 282). The analysis of lymphocyte subpopulations performed by flow cytometry in 72 subjects did not show significant changes in lymphocyte subset percentages between HLA-B8,DR3 positive subjects and negative ones. Thus, the decrease of circulating lymphocytes seems to be due to a reduction of cell number affecting all lymphocyte subsets rather than a single cell subpopulation. The analysis of in vitro spontaneous apoptosis performed by flow cytometry in a smaller sample of subjects showed a significant increase of spontaneous apoptosis in lymphocytes from HLA-B8,DR3 positive individuals suggesting a possible explanation for the deviation from normal lymphocyte count observed in these subjects. However it is intriguing that a decreased number of blood lymphocytes can be observed in healthy HLA-B8,DR3 positive subjects but also in autoimmune diseases linked to this haplotype like systemic lupus erythematosus and insulin-dependent diabetes. Furthermore, in our opinion, this finding is to be kept in mind in evaluating hematological parameters in healthy subjects.

The association between myasthenia gravis (MG) and TAP polymorphisms was studied in 79 Swedish patients and 155 unrelated controls. TAP typing was performed by ARMS-PCR technique and stratification analysis was used to determine if the TAP associations were independent or secondary to linkage disequilibrium with DQ2 and DR3. TAP1 and TAP2 alleles did not confer independent risk for MG. TAP2*0101 was, however, positively associated with MG in patients with an early onset of disease compared to patients with a late onset of disease. TAP1 and TAP2 alleles did not confer risk in MG patients negative for DQ2. In conclusion, susceptibility to MG is not primarily conferred by TAP alleles in the extended DR3 haplotype.

To evaluate the predictive factors of insulin requirement in newly diagnosed patients with unclassifiable diabetes, 54 consecutive patients, aged less than 35 years, were prospectively followed for 3 years or more. At entry, haemoglobin HbA1c, basal and stimulated C-peptide concentrations, HLA phenotype, islet cell antibodies (ICA) status, and serum levels of soluble CD8 antigen (sCD8) were evaluated. After a median time of 9 (range 2-32) months, 31 patients (group 1) required insulin therapy, whereas 23 patients (group 2) remained non-insulin-requiring after 36 months. Group 1 patients were younger (P < 0.05) and had higher HbA1c and sCD8 serum levels (P < 0.0001), respectively), a higher frequency of ICA positivity and of HLA DR3 and/or DR4 phenotype (P < 0.005 and P < 0.0001, respectively), and lower C-peptide concentrations (P < 0.005 and P < 0.0001, basal and stimulated, respectively) than group 2. The sensitivity, specificity, positive and negative predictive value, and overall accuracy for the subsequent insulin requirement were: sCD8 serum levels (> 737 U/ml), 100%, 65%, 79%, 100% and 85%, respectively; stimulated C-peptide (< 0.60 nmol/l), 71%, 96%, 96%, 74% and 81%, respectively; and ICA positivity (> 20 JDFU), 45%, 91%, 87%, 55% and 65%, respectively. Thus, higher sCD8 serum levels, low stimulated C-peptide concentrations and ICA positivity are the most powerful predictors of subsequent recourse to insulin therapy in young, newly detected patients with unclassifiable diabetes.

Objective: To study the human leukocyte antigen (HLA)-DQ heterodimers in the susceptible DR haplotypes for patients with insulin-dependent diabetes mellitus (IDDM) in Taiwan., Research Design and Methods: Extended class II HLA haplotypes were studied in 57 unrelated IDDM patients, 31 simplex IDDM families, and 105 unrelated control subjects recruited from the same area in Taiwan. Class II HLA genotyping was based on PCR-SSO DNA typing techniques. Extended class II HLA haplotypes were deduced unequivocally by the Taiwanese pedigree studies., Results: DR3/DR3, DR3/DR4, and DR3/DR9 genotypes were strongly associated with IDDM susceptibility in this population. In addition to the reported DR3/DR4 in Caucasians, the heterozygotic effect of DR3/DR9 for IDDM was remarkable in the Taiwanese population. Extended HLA haplotypes studies revealed that DRB1*0301/DQA1*0501/DQB1*0201, DRB1*0405/DQA1*0301/DQB1*0302, and DRB1*0405/DQA1*0301/DQB1*0401 were the susceptible haplotypes in this population. There were several hypothetical ways to produce susceptible HLA-DQ heterodimers to explain the susceptibility carried by DR3/DR4 and DR3/DR9 genotypes. Among all DR4 subtypes, only DRB1*0405 was associated with the increased risk of IDDM., Conclusions: These data strongly suggest that the HLA-DR-associated IDDM susceptibility is most likely explained by the formation of the susceptible DQ heterodimers encoded by the DQA1/DQB1 either in cis or in trans.

Immune mechanisms have been implicated in chronic viral hepatitis, and these may be influenced by genetic factors. To determine if disease severity in chronic viral hepatitis is associated with the human leukocyte antigens DR3 and/or DR4, 109 patients were evaluated prospectively. The frequencies of DR3 and DR4 in these patients were compared to those in 80 normal subjects. Patients with DR3 and/or DR4 had the same occurrence of severe disease as patients with other DR antigens (21% versus 30%, P = 0.3). Patients with DR3, however, had higher serum gamma globulin and immunoglobulin G levels than patients with DR4 and a greater frequency of severe disease (36% vs 12%, P = 0.046). Patients with DR4 had concurrent immunologic diseases more commonly than patients with DR3 (44% vs 9%, P = 0.005) and patients with other DR antigens (44% vs 9%, P = 0.0002). Patients with DR4 but not DR3 had severe disease less frequently than other patients (9% vs 31%, P = 0.02). The frequencies of DR3 in patients with severe disease (37% vs 18%, P = 0.06) and DR4 in patients without severe disease (44% vs 30%, P = 0.07) were different than those in normal subjects but not to a statistically significant level. We conclude that patients with DR3 and DR4 have different clinical and laboratory findings and disease severity. Patients with DR4 have milder disease than patients with other DR antigens. Disease severity, however, is not closely associated with DR3 or DR4.

We have undertaken a case referent study of the association between HLA allele frequency and specific IgE antibody to acid anhydride-human serum albumin (AA-HSA) conjugates among acid anhydride workers. Thirty cases with radio-allergosorbent test score versus AA-HSA conjugates > 2 were compared with 30 referents without specific IgE selected from the same factory sites as the cases and matched for age, sex, duration of exposure, atopic status, and smoking habit. We found a significant excess of HLA-DR3 in the cases with specific IgE to acid anhydrides when compared with the referents (50% versus 14%, Fisher's statistic = 8.4; odds ratio = 6, p = 0.05 corrected). The excess of HLA-DR3 was particularly associated with IgE versus trimellitic anhydride, with HLA-DR3 present in eight of 11 workers with and in two of 14 referents without IgE (Fisher's statistic = 8.5, odds ratio = 16, p = 0.004). The proportion of HLA-DR3 among the phthalic anhydride workers was not different in those with IgE (two of 12) from their referents (two of 14). These findings suggest MHC II proteins are an important determinant of the specificity of the IgE response to an inhaled hapten.

The objective of this study is to understand the metabolic and immunologic basis of diabetes in adult blacks with diabetic ketoacidosis (DKA). Twenty-one black adults presenting with DKA ([mean +/- SD] blood pH = 7.18 +/- 0.09, plasma glucose = 693 +/- 208 mg/dl, and positive serum ketones) had a subsequent clinical course of non-insulin-dependent diabetes mellitus (NIDDM). Human leukocyte antigens (HLAs) DR and DQ and antibodies to glutamic acid decarboxylase (GAD) and islet cell cytoplasmic proteins (ICP) were measured to assess autoimmunity. Insulin action was evaluated by the euglycemic insulin clamp, and insulin secretion was measured by C-peptide responses to oral glucose. Ketoacidosis was treated with insulin. Two subjects had a precipitating illness; four had a history of NIDDM. At the time of study, subjects' glycemic control was good (HbA1c = 5.7 +/- 1.6%). Nine subjects were treated with insulin, and 12 were on either sulfonylurea treatment or diet alone. Men (n = 12) were younger than women (n = 9) (40.8 +/- 9.8 and 51.1 +/- 6.3 years of age, respectively, P < 0.05) but similar in body mass index (27.8 +/- 2.7 and 29.98 +/- 4.1 kg/m2, respectively). Antibodies to GAD and ICP were absent. All but one subject was insulin resistant compared with normal subjects (glucose disposal 3.56 +/- 0.04 vs. 6.86 +/- 0.02 mg.kg-1.min-1), and insulin secretion was lower. HLA DR3 and DR4 frequency was higher than in nondiabetic black control subjects (65 vs. 30%, P < 0.012).(ABSTRACT TRUNCATED AT 250 WORDS)

The prevalence of circulating autoantibodies against thyroperoxidase (mic-TPO) was determined in 3,000 healthy blood donors (age range: 23 to 60 years) from the Hamburg area. Of the blood donors, 153 (5.1%) were found to have high titer of mic-TPO (> 350 IU/ml). Only two autoantibody positive subjects (0.06%) were chemically hyper- and hypothyroid, respectively. Analysis of HLA-DR specificities revealed that HLA-DR specificities DR3 and DR5 were significantly increased when compared to controls (n = 1,863). Comparison of the autoantibody-positive probands with a group of disease controls, i.e., Graves' patients and patients with lymphocytic thyroiditis, revealed a higher prevalence of HLA-DR3-positive HLA haplotypes in the disease controls when compared to autoantibody positives. Individuals with a mic-TPO level greater than 2,000 IU/ml were almost exclusively found to have one HLA-DR3 or HLA-DR5 positive HLA haplotype. We conclude that a high prevalence of high-titer mic-TPO can be found in healthy blood donors. Circulating signs of thyroid autoimmunity were associated with HLA specificities also found to be associated with autoimmune thyroid diseases.

HLA class I and class II antigens from 61 patients with posthepatitic cirrhosis and 29 HBsAg healthy carrier were examined by using the standard serum including 105 specificities in A, B, C, DQ and DR Loci of HLA provided by the 11th International Histocompatibility Workshop. The results showed the frequencies of HLA-B35 and DR3 were elevated in posthepatitic cirrhosis group as compared with the healthy control group (P < 0.001). The data showed that the frequencies of HLA-B8, C1 were significantly increased, while those of HLA--DR8 more significantly decreased in posthepatitic cirrhotic patients than in health virus carriers. Compared to the healthy controls, however, the frequencies of all 105 HLA specificities examined were identical to healthy carriers.

Distribution of HLA antigens, haptoglobin phenotypes (Hp), ABO blood groups and rhesus factor was investigated in 60 patients with fibrocavernous tuberculosis and 50 patients with tuberculomas. All the patients were Russian and had a history of surgery for tuberculosis. Carriers of antigens B27, DR2 of HLA system, HP 2-2 and blood group 0 (I) were encountered more often in the group of tuberculosis patients. Antigens A1, B12, DR3 and A2 occurred among tuberculoma patients more frequently and less frequently, respectively. Among those who developed postoperative complications carriers of blood group A (II) were found significantly less frequently. Antigens HLA and Hp types were unrelated to the incidence of pleuropulmonary and infectious postoperative complications. Tuberculosis reactivation in the postoperative period and postoperative recurrences occurred more often in carriers of HLA antigen DR2.

Objective: To identify risk factors for the development of cardiovascular autonomic neuropathy in patients with juvenile-onset type I diabetes mellitus., Design: Cross-sectional examination of an inception cohort 15 to 21 years after the onset of diabetes., Setting: Outpatient diabetes clinic., Patients: Seventy-nine patients with type I diabetes who experienced onset of disease before 21 years of age and who were followed for 15 to 21 years., Measurements: Autonomic nerve function was evaluated in all patients using deep breathing and tilt tests. On the basis of these tests, an index of cardiovascular autonomic neuropathy was derived and patients were classified as having intact, mildly impaired, or significantly impaired autonomic function., Results: The group with significantly impaired function had a higher mean hemoglobin A1 at the time of examination than the group without impairment, yet the groups did not differ regarding glycemic control during the first decade of diabetes. The HLA-DR3/4 phenotype was present in more than 50% of the patients with significant autonomic dysfunction and conferred relative odds of 6.2 (95% CI, 1.7 to 23.3) for the development of autonomic neuropathy when compared with other HLA-DR phenotypes. Sex, percent ideal body weight, and smoking did not have a statistically significant effect on the development of autonomic neuropathy., Conclusions: The development of cardiovascular autonomic neuropathy in type I diabetes mellitus is strongly associated with the HLA-DR3/4 phenotype. Thus, genetic predisposition may play an important role in the development of this complication.

Antiphospholipid antibodies (APA) are known to be associated with a number of seemingly heterogeneous pathological conditions that are part of the antiphospholipid syndrome, formerly called anticardiolipin syndrome. Recent studies on the mechanism of action of these autoantibodies suggest that we are dealing with a new autoimmune syndrome which may occur either in a primary form or in the context of other autoimmune diseases, mainly systemic lupus erythematosus (SLE). Moreover, increased levels of APA have been found in elderly subjects, who are known to display increased frequency of autoimmune phenomena. It is well known that many autoimmune diseases, including SLE, are associated with HLA antigens, particularly with HLA-B8,DR3 phenotype. In our study, APA serum levels were analyzed in 26 old subjects and in 56 young ones. The results demonstrate that HLA-B8,DR3-positive young females display significantly higher levels of APA than HLA-B8,DR3-negative ones. Interestingly, the same is true for elderly subjects on the whole with respect to young individuals. These data are consistent with previous findings demonstrating that HLA-B8,DR3-positive subjects (mainly female) as well as old subjects display (also in the absence of any clinical manifestation), multiple immune dysfunctions that may underlie the predisposition to autoimmunity.

The presence of HLA antigens B8 and DR3 in an individual is associated with his predisposition to developing Basedow's disease. A comparative study of a clinical course and immunological characterization of this disease in 208 patients, divided with relation to the presence or absence of the above antigens, showed that the disease developed in patients with HLA B8 and DR3 at a younger age and was accompanied twice as more frequently by ophthalmopathy. Thyrotoxicosis relapsed among these patients in conservative therapy much more frequently. A relapse after surgical intervention in the study group was noted thrice as more frequently compared to the control group. Focal infiltration of thyroid tissue with lymphoid cells was determined twice as less frequently in patients with HLA B8 and DR3. Any statistically significant difference was unnoticed in the severity of thyrotoxicosis and the frequency of detection of antibodies to thyroglobulin.