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Celiac disease (CD) is an autoimmune disease characterized by gluten intolerance. The main cause of this immune - mediated enteropathy is gluten, a protein mainly present in wheat, rye, barley and spelt. The predisposition to celiac disease is determined by HLA class II genes encoding MHC II heterodimer molecules, more specifically HLA-DQ2 and HLA-DQ8. Up to date the exact number of people suffering from celiac disease in Bosnia and Herzegovina is still not known because there is no public registry for this disease. The aim of this study was to evaluate the HLA-DQ2 and HLA-DQ8/DR4 presence in tested group of patients (n = 23) referred to Polyclinic Atrijum in Sarajevo in period from August 2022. to August 2023. HLA-DQ2 and DQ8/DR4 allele identification was performed using Real-time PCR technique. According to the obtained results a total of 26% (n=6) of tested patients were positive for HLA-DQ2 and HLA-DQ8/DR4 alleles. Two of the patients were positive for HLADQ2 alleles and four patients were positive for HLA-DQ8/DR4 alleles. To our knowledge this is the first study evaluating the presence of HLADQ2 and HLA-DQ8 genotypes in tested population in Bosnia and Herzegovina. [ABSTRACT FROM AUTHOR]

Summary: Background: In solid organ transplantation, HLA matching between donor and recipient is associated with superior outcomes. In islet transplantation, an intervention for Type 1 diabetes, HLA matching between donor and recipient is not performed as part of allocation. Susceptibility to Type 1 diabetes is associated with the presence of certain HLA types. This study was conducted to determine the impact of these susceptibility antigens on islet allograft survival. Methods: This is a single-centre retrospective cohort study. This cohort of transplant recipients (n = 268) received islets from 661 donor pancreases between March 11th, 1999 and August 29th, 2018 at the University of Alberta Hospital (Edmonton, AB, Canada). The frequency of the Type 1 diabetes susceptibility HLA antigens (HLA-A24, -B39, -DQ8, -DQ2 and–DQ2-DQA1∗05) in recipients and donors were determined. Recipient and donor HLA antigens were examined in relation to time to first C-peptide negative status/graft failure or last observation point. Taking into account multiple transplants per patient, we fitted a Gaussian frailty survival analysis model with baseline hazard function stratified by transplant number, adjusted for cumulative islet dose and other confounders. Findings: Across all transplants recipients of donors positive for HLA-DQ8 had significantly better graft survival (adjusted HRs 0.33 95% CI 0.17–0.66; p = 0.002). At first transplant only, donors positive for HLA-DQ2-DQA1∗05 had inferior graft survival (adjusted HR 1.96 95% CI 1.10–3.46); p = 0.02), although this was not significant in the frailty analysis taking multiple transplants into account (adjusted HR 1.46 95% CI 0.77–2.78; p = 0.25). Other HLA antigens were not associated with graft survival after adjustment for confounders. Interpretation: Our findings suggest islet transplantation from HLA-DQ8 donors is associated with superior graft outcomes. A donor positive for HLA-DQ2-DQA1∗05 at first transplant was associated with inferior graft survival but not when taking into account multiple transplants per recipient. The relevance of HLA-antigens on organ allocation needs further evaluation and inclusion in islet transplant registries and additional observational and interventional studies to evaluate the role of HLA-DQ8 in islet graft survival are required. Funding: None.

Celiac disease (CD) is an autoimmune disease characterized by gluten intolerance. The main cause of this immune - mediated enteropathy is gluten, a protein mainly present in wheat, rye, barley and spelt. The predisposition to celiac disease is determined by HLA class II genes encoding MHC II heterodimer molecules, more specifically HLA-DQ2 and HLA-DQ8. Up to date the exact number of people suffering from celiac disease in Bosnia and Herzegovina is still not known because there is no public registry for this disease. The aim of this study was to evaluate the HLA-DQ2 and HLA-DQ8/DR4 presence in tested group of patients (n = 23) referred to Polyclinic Atrijum in Sarajevo in period from August 2022. to August 2023. HLA-DQ2 and DQ8/DR4 allele identification was performed using Real-time PCR technique. According to the obtained results a total of 26% (n=6) of tested patients were positive for HLA-DQ2 and HLA-DQ8/DR4 alleles. Two of the patients were positive for HLA-DQ2 alleles and four patients were positive for HLA-DQ8/DR4 alleles. To our knowledge this is the first study evaluating the presence of HLA-DQ2 and HLA-DQ8 genotypes in tested population in Bosnia and Herzegovina.

Celiac peptide-generating α- and γ-gliadins consist of a disordered N-terminal domain extended by an α-helical-folded C-terminal domain. Celiac peptides, primarily located along the disordered part of α- and γ-gliadin molecules, are nicely exposed and directly accessible to proteolytic enzymes occurring in the gastric (pepsin) and intestinal (trypsin, chymotrypsin) fluids. More than half of the potential celiac peptides identified so far in gliadins exhibit cleavage sites for pepsin. However, celiac peptides proteolytically truncated by one or two amino acid residues could apparently retain some activity toward HLA-DQ2 and HLA-DQ8 receptors in docking experiments. Together with the uncleaved peptides, these still active partially degraded CD peptides account for the incapacity of the digestion process to inactivate CD peptides from gluten proteins. In contrast, sourdough fermentation processes involve other proteolytic enzymes susceptible to the deep degradation of celiac peptides. In particular, sourdough supplemented by fungal prolyl endoproteases enhances the degrading capacities of the sourdough fermentation process toward celiac peptides. Nevertheless, since tiny amounts of celiac peptides sufficient to trigger deleterious effects on CD people can persist in sourdough-treated bread and food products, it is advisable to avoid consumption of sourdough-treated food products for people suffering from celiac disease. As an alternative, applying the supplemented sourdough process to genetically modified low gluten or celiac-safe wheat lines should result in food products that are safer for susceptible and CD people.

Copyright of Meandros Medical & Dental Journal is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Celiac disease (CD), despite its high morbidity, is an often-underdiagnosed autoimmune enteropathy. Using a modified version of the Brazilian questionnaire of the 2013 National Health Survey, we interviewed 604 Mennonites of Frisian/Flemish origin that have been isolated for 25 generations. A subgroup of 576 participants were screened for IgA autoantibodies in serum, and 391 participants were screened for HLA-DQ2.5/DQ8 subtypes. CD seroprevalence was 1:29 (3.48%, 95% CI = 2.16–5.27%) and biopsy-confirmed CD was 1:75 (1.32%, 95% CI = 0.57–2.59%), which is superior to the highest reported global prevalence (1:100). Half (10/21) of the patients did not suspect the disease. HLA-DQ2.5/DQ8 increased CD susceptibility (OR = 12.13 [95% CI = 1.56–94.20], p = 0.003). The HLA-DQ2.5 carrier frequency was higher in Mennonites than in Brazilians (p = 7 × 10−6). HLA-DQ8 but not HLA-DQ2.5 carrier frequency differed among settlements (p = 0.007) and was higher than in Belgians, a Mennonite ancestral population (p = 1.8 × 10−6), and higher than in Euro-Brazilians (p = 6.5 × 10−6). The glutathione pathway, which prevents reactive oxygen species-causing bowel damage, was altered within the metabolic profiles of untreated CD patients. Those with lower serological positivity clustered with controls presenting close relatives with CD or rheumatoid arthritis. In conclusion, Mennonites have a high CD prevalence with a strong genetic component and altered glutathione metabolism that calls for urgent action to alleviate the burden of comorbidities due to late diagnosis. [ABSTRACT FROM AUTHOR]

To circumvent the limitations of available preclinical models for the study of type 1 diabetes (T1D), we developed a new humanized model, the YES-RIP-hB7.1 mouse. This mouse is deficient of murine major histocompatibility complex class I and class II, the murine insulin genes, and expresses as transgenes the HLA-A*02:01 allele, the diabetes high-susceptibility HLA-DQ8A and B alleles, the human insulin gene, and the human co-stimulatory molecule B7.1 in insulin-secreting cells. It develops spontaneous T1D along with CD4+ and CD8+ T-cell responses to human preproinsulin epitopes. Most of the responses identified in these mice were validated in T1D patients. This model is amenable to characterization of hPPI-specific epitopes involved in T1D and to the identification of factors that may trigger autoimmune response to insulin-secreting cells in human T1D. It will allow evaluating peptide-based immunotherapy that may directly apply to T1D in human and complete preclinical model availability to address the issue of clinical heterogeneity of human disease.

To circumvent the limitations of available preclinical models for the study of type 1 diabetes (T1D), we developed a new humanized model, the YES-RIP-hB7.1 mouse. This mouse is deficient of murine major histocompatibility complex class I and class II, the murine insulin genes, and expresses as transgenes the HLA-A*02:01 allele, the diabetes high-susceptibility HLA-DQ8A and B alleles, the human insulin gene, and the human co-stimulatory molecule B7.1 in insulin-secreting cells. It develops spontaneous T1D along with CD4+ and CD8+ T-cell responses to human preproinsulin epitopes. Most of the responses identified in these mice were validated in T1D patients. This model is amenable to characterization of hPPI-specific epitopes involved in T1D and to the identification of factors that may trigger autoimmune response to insulin-secreting cells in human T1D. It will allow evaluating peptide-based immunotherapy that may directly apply to T1D in human and complete preclinical model availability to address the issue of clinical heterogeneity of human disease. [ABSTRACT FROM AUTHOR]

Aim: We evaluated the frequency of human leukocyte antigen (HLA) DQ2/DQ8 haplotypes as well as celiac disease (CD) among the first-degree relatives (FDRs) of CD patients, compared with healthy controls, and compared the HLA typing with serologic tests in this population. Background: Until now, no study has examined the frequency of HLA-DQ2/DQ8 haplotypes among the FDRs of Iranian patients with CD. Methods: In the current case-control study, 100 FDRs of CD patients and 151 healthy controls were included. Demographic characteristics were assessed using a research-made questionnaire. A blood sample was collected from each participant for HLA-DQ typing and measuring serum levels of anti-gliadin and anti-transglutaminase (anti-tTG) antibodies. Results: The mean age of the FDRs of CD patients and controls was 30 and 35 years, respectively. Also, 51% (n=51) of the FDRs and 51.7% (n=78) of controls were female. CD was diagnosed among 3% (n=3) of the FDRs of CD patients. No significant difference was found in terms of the frequency of HLA-DQ alleles between the FDRs of CD patients and controls. Out of 100 FDRs of CD patients, 40% had HLA-DQ2 allele, 16% carried HLA-DQ8 allele, and 4% had both alleles. Surprisingly, the CD was diagnosed in three subjects among 60 FDRs of CD patients with HLA-DQ2 allele (3% of the whole population). This diagnosis was based on the results of serological tests as well as endoscopy and intestinal biopsy. Conclusion: CD was confirmed among 3% (n=3) of the FDRs of CD patients. We found that HLA typing is not effective in predicting CD among FDRs of CD patients. Other methods such as serological tests have a higher priority compared with HLA-DQ typing. [ABSTRACT FROM AUTHOR]

Background/Aim: To determine the frequency of celiac disease (CD)-predisposing human leukocyte antigen (HLA)-DQ genotypes in the Saudi population, where the prevalence of CD is 1.5% as recently reported in a mass screening study. Patients and Methods: In a cross-sectional population-based study, a total of 192 randomly selected healthy school children (97 females, mean age 10.5 ± 2.2 years, all negative for tissue transglutaminase-IgA) were typed for D QA1 and D QB1 genes by polymerase chain reaction sequence–specific oligonucleotide probes. Results: Of the 192 children, 52.7% carried the high-risk CD-associated HLA-DQ molecules: homozygous DQ2.5 ( 2.6%), DQ2.5/DQ2.2 ( 4.7%), heterozygous DQ2.5 ( 28.15%), homozygous DQ8 ( 4.2%), DQ8/DQ2.2 ( 3.6%), and double dose DQ2.2 ( 9.4%). Low-risk CD-associated HLA-DQ molecules (single dose DQ2.2 and heterozygous DQ8) constituted 3.6% and 9.4%, respectively. Among the very low–risk groups, individuals lacking alleles that contribute to DQ2/DQ8 variants (33.5%), 13.5% carried only one of the alleles of the high-risk HLA-DQ2.5 heterodimer called “half-heterodimer” (HLA-DQA1*05 in 12% and HLA-DQB1* 02 in 1.5%), and 20.8% lacked all the susceptible alleles (DQX.x). Gender distribution was not significantly different among the CD-risk groups. Conclusion: We report one of the highest frequencies of CD-predisposing HLA-DQ genotypes among healthy general populations (52.7%) worldwide, which might partly explain the high prevalence of CD in the Saudi community.

ABSTRACT Nonmenstrual toxic shock syndrome (nmTSS), linked to TSST-1-producing CC30 Staphylococcus aureus, is the leading manifestation of toxic shock syndrome (TSS). Due to case rarity and a lack of tractable animal models, TSS pathogenesis is poorly understood. We developed an S. aureus abscess model in HLA class II transgenic mice to investigate pathogenesis and treatment. TSST-1 sensitivity was established using murine spleen cell proliferation assays and cytokine assays following TSST-1 injection in vivo. HLA-DQ8 mice were infected subcutaneously with a tst-positive CC30 methicillin-sensitive S. aureus clinical TSS-associated isolate. Mice received intraperitoneal flucloxacillin, clindamycin, flucloxacillin and clindamycin, or a control reagent. Abscess size, bacterial counts, TSST-1 expression, and TSST-1 bioactivity were measured in tissues. Antibiotic effects were compared with the effects of control reagent. Purified TSST-1 expanded HLA-DQ8 T-cell Vβ subsets 3 and 13 in vitro and instigated cytokine release in vivo, confirming TSST-1 sensitivity. TSST-1 was detected in abscesses (0 to 8.0 μg/ml) and draining lymph nodes (0 to 0.2 μg/ml) of infected mice. Interleukin 6 (IL-6), gamma interferon (IFN-γ), KC (CXCL1), and MCP-1 were consistent markers of inflammation during infection. Clindamycin-containing antibiotic regimens reduced abscess size and TSST-1 production. Infection led to detectable TSST-1 in soft tissues, and TSST-1 was detected in draining lymph nodes, events which may be pivotal to TSS pathogenesis. The reduction in TSST-1 production and lesion size after a single dose of clindamycin underscores a potential role for adjunctive clindamycin at the start of treatment of patients suspected of having TSS to alter disease progression. IMPORTANCE Staphylococcal toxic shock syndrome (TSS) is a life-threatening illness causing fever, rash, and shock, attributed to toxins produced by the bacterium Staphylococcus aureus, mainly toxic shock syndrome toxin 1 (TSST-1). TSS was in the past commonly linked with menstruation and high-absorbency tampons; now, TSS is more frequently triggered by other staphylococcal infections, particularly of skin and soft tissue. Investigating the progress and treatment of TSS in patients is challenging, as TSS is rare; animal models do not mimic TSS adequately, as toxins interact best with human immune cells. We developed a new model of staphylococcal soft tissue infection in mice producing human immune cell proteins, rendering them TSST-1 sensitive, to investigate TSS. The significance of our research was that TSST-1 was found in soft tissues and immune organs of mice and that early treatment of mice with the antibiotic clindamycin altered TSST-1 production. Therefore, the early treatment of patients suspected of having TSS with clindamycin may influence their response to treatment.

Background ― Rheumatoid arthritis (RA) is an inflammatory, autoimmune disease induced by certain auto-antigens. HLA-DRB1*0401 allele has a significant relationship with RA incident. Additionally, DQβ1*0301, *302(DQ8), *303, and *304 can increase RA risk especially in DQA1*0301 and *302 coincident. Recent studies suggest that distribution of this allele is different in various populations Material and Methods ― 70 patients and 70 healthy controls were analyzed for human leukocyte antigen (HLA) allele by specific primer-polymerase chain reaction (SSP-PCR) method. Patients were evaluated in terms of ESR and CRP. Data analysis was performed in SPSS V.17. Results ― HLA-DQ8 allele was significantly more frequent in RA patients compared to control (P

Celiac disease is caused by an abnormal intestinal T cell response to cereal gluten proteins. The disease has a strong human leukocyte antigen (HLA) association, and CD4+ T cells recognizing gluten epitopes presented by disease-associated HLA-DQ allotypes are considered to be drivers of the disease. This paper provides an update of the currently known HLA-DQ restricted gluten T cell epitopes with their names and sequences. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Type 1 diabetes is an autoimmune disorder characterised by loss of insulin-producing beta cells of the pancreas. Progress in understanding the cellular and molecular mechanisms underlying the human disease has been hampered by a dearth of appropriate human experimental models. We previously reported the characterisation of islet-infiltrating CD4+ T cells from a deceased organ donor who had type 1 diabetes. Methods: Induced pluripotent stem cell (iPSC) lines derived from the above donor were differentiated into CD14+ macrophages and tested for their capacity to present antigen to T cell receptors (TCRs) derived from islet-infiltrating CD4+ T cells from the same donor. Results: The iPSC macrophages displayed typical macrophage morphology, surface markers (CD14, CD86, CD16 and CD11b) and were phagocytic. In response to IFNγ treatment, iPSC macrophages upregulated expression of HLA class II, a characteristic that correlated with their capacity to present epitopes derived from proinsulin C-peptide to a T cell line expressing TCRs derived from islet-infiltrating CD4+ T cells of the original donor. T cell activation was specifically blocked by anti-HLA-DQ antibodies but not by antibodies directed against HLA-DR. Conclusions/interpretation: This study provides a proof of principle for the use of iPSC-derived immune cells for modelling key cellular interactions in human type 1 diabetes. [ABSTRACT FROM AUTHOR]

Objectives: It remains unknown what degree of risk is conferred by celiac disease (CD)‐predisposing human leukocyte antigen (HLA)‐DQ genotypes in Saudi Arabia compared with in Western countries. In this study, we aimed to determine the CD risk gradient associated with the HLA‐DQ genotypes and to compare HLA‐DQ genotypes between symptomatic patients with CD and screening‐identified asymptomatic CD patients. Methods: We enrolled three groups of subjects, including 46 CD children diagnosed consecutively over the past 10 years, 54 CD children diagnosed during a mass screening of schoolchildren, and 192 healthy controls. All the participants were typed for the HLA‐DQA1 and HLA‐DQB1 genes by polymerase chain reaction sequence‐specific oligonucleotide probes. Results: Comparing the patients with CD to controls, we identified 5 groups in the CD risk gradient: (i) very high risk associated with the DQ2.5/DQ8 genotype (odds ratio [OR] 46.93); (ii) high risk (homozygous DQ2.5, DQ2.5/DQ2.2; OR 4.12‐5.04); (iii) intermediate risk (heterozygous DQ2.5, DQ8/DQ2.2; OR 1.61 and 1.67); (iv) low risk (DQ8, DQ2.2); and (v) very low risk (DQ2.x, DQX.5, DQX.x). Heterozygous DQ8 was more common in screening‐identified group compared to symptomatic patients (13.0% vs 2.2%); however, other genotypes were very similar between the two groups. Conclusion: The highest risk of developing CD in our Saudi Arabia population is associated with the DQ2.5/DQ8 genotype. [ABSTRACT FROM AUTHOR]

Background: Type 1 diabetes (T1D) and celiac disease (CD) are the two most common autoimmune childhood diseases that share their HLA-DQ2 and DQ8 genetic origin. There has been a current increase in both diseases worldwide. In children from the low-population State of Sonora (15 inhabitants/km2) in northwestern Mexico, there is no information on their genetic risk or the distribution of the related alleles in the general population. Aims: To compare the HLA-DQ allele frequency in a representative sample of newborns from Sonora with that of T1D and CD patients to determine the risk gradient and identify the presence of celiac autoimmunity in the T1D group. Methods: The study included 397 Sonoran newborns, 44 cases of T1D, and 25 CD cases. The CD and T1D cases were clinically diagnosed by specialists at the Hospital Infantil del Estado de Sonora and the autoantibodies were determined by ELISA. Whole blood was collected, gDNA was extracted, and HLA-DQ2 and DQ8 were typed by PCR-SSP. The risk gradient was calculated by comparing the allele frequencies of the cases with those of the newborns. Results: The Sonoran HLA-DQ risk heterodimer proportion was 16.1% for HLA-DQ2 and 13.6% for HLA-DQ8 with an HLA-DQ2: HLA-DQ8 ratio of 1.2:1. The DQ8/DQ2 genotype represented a 1:14 risk for T1D, whereas the DQ8/DQB1*0201 combination resulted in a 1:6 risk for CD. The prevalence of CD autoimmunity in T1D children was 7%. Conclusion: The Sonoran population has a distinctive HLA-DQ allele distribution due to its ancestry. The HLA-DQ8 combinations with DQ2 or one of its alleles conferred the highest risk for both diseases and T1D and CD frequently appear together.

Antecedentes: La diabetes tipo 1 (DT1) y la enfermedad celíaca (EC) son 2 enfermedades autoinmunes frecuentes en la infancia y comparten su predisposición genética (HLA-DQ2 y DQ8). La prevalencia de ambas se ha incrementado en el mundo. En el estado de Sonora (15 habitantes/km2), se desconoce información sobre su riesgo genético o la distribución de los alelos asociados en la población general. Objetivo: Comparar la frecuencia alélica HLA-DQ de una muestra representativa de recién nacidos sonorenses con la de pacientes DT1 y EC para determinar el gradiente de riesgo e identificar la presencia de autoinmunidad celíaca en el grupo de DT1. Métodos: Se incluyeron 397 recién nacidos sonorenses, 44 casos DT1 y 25 EC, diagnosticados clínicamente y con autoanticuerpos por ELISA. Se colectó una muestra de sangre, se extrajo ADNg y tipificaron HLA-DQ2 y DQ8 por PCR. El gradiente de riesgo se calculó comparando las frecuencias alélicas de los casos con respecto a los recién nacidos. Resultados: La proporción de heterodímeros de riesgo en sonorenses fue de 16.1% para HLA-DQ2 y de 13.6% para HLA-DQ8 con una proporción HLA-DQ2:DQ8 de 1.2:1. El genotipo DQ8/DQ2 representó un riesgo de 1:14 para DT1, mientras que para EC el DQ8/DQB1*0201 generó un riesgo de 1:6. La prevalencia de autoinmunidad asociada a EC fue del 7% en los niños DT1. Conclusión: Los sonorenses tienen una distribución de alelos HLA-DQ distintiva debido a su ascendencia. Las combinaciones del HLA-DQ8 con DQ2 o uno de sus alelos confirieron el máximo riesgo para ambas enfermedades. La DT1 y EC frecuentemente se presentan juntas.

Copyright of Revue Francaise d'Allergologie is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Paediatrics & Family Medicine / Pediatria i Medycyna Rodzinna is the property of Medical Communications Sp. z o.o. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract: Background: The frequency of HLA‐DQ2 and DQ8 predisposing genotypes for celiac disease (CD) has shown significant variation among different world regions and has not been previously determined among the highly interbred Brazilian population. The aim of this study was to investigate the frequency of these genotypes among Brazilian newborns (NB). Methods: We typed DQA1*05 ‐ DQB1*02 (DQ2.5) and DQA1*03 ‐ DQB1*03:02 (DQ8) alleles in 329 NB using qPCR technique. Subsequently we confirmed our results by PCR‐SSP using a reference kit which further identified DQ2.2 (DQA1*02:01 ‐ DQB1*02). Results: Among the 329 NB, using qPCR technique: 5 (1.52%) carried both DQ2.5 and DQ8 variants; 58 (17.63%) carried only DQ2.5 (DQA1*05 and DQB1*02) and 47 (14.29%) carried only the DQ8 (DQA1*03 and DQB1*03:02) variant. The use of the PCR‐SSP method yielded further information; among the 329 samples: 34 (10.34%) tested positive for DQ2.2 and among the 47 previously DQ8 positives samples, we found 10 (3.04%) that also tested positives for DQ2.2. Conclusion: 43.7% of the analyzed individual tested positive for at least one of the CD predisposing HLA‐DQ genotypes in our group of Brazilian NB. The highest frequency was found for DQ2.5 positive subjects (17.6%) followed by DQ8 (11.3%); DQ2.2 (10.3%); DQ8 and DQ2.2 (3.0%); DQ2.5 and DQ8 (1.5%). We found no positive sample for DQ2.5 associated with DQ2.2. [ABSTRACT FROM AUTHOR]

Background/Aim: To determine the frequency of celiac disease (CD)-predisposing human leukocyte antigen (HLA)-DQ genotypes in the Saudi population, where the prevalence of CD is 1.5% as recently reported in a mass screening study. Patients and Methods: In a cross-sectional population-based study, a total of 192 randomly selected healthy school children (97 females, mean age 10.5 ± 2.2 years, all negative for tissue transglutaminase-IgA) were typed for DQA1 and DQB1 genes by polymerase chain reaction sequence--specific oligonucleotide probes. Results: Of the 192 children, 52.7% carried the high-risk CD-associated HLA-DQ molecules: homozygous DQ2.5 (2.6%), DQ2.5/DQ2.2 (4.7%), heterozygous DQ2.5 (28.15%), homozygous DQ8 (4.2%), DQ8/DQ2.2 (3.6%), and double dose DQ2.2 (9.4%). Low-risk CD-associated HLA-DQ molecules (single dose DQ2.2 and heterozygous DQ8) constituted 3.6% and 9.4%, respectively. Among the very low--risk groups, individuals lacking alleles that contribute to DQ2/DQ8 variants (33.5%), 13.5% carried only one of the alleles of the high-risk HLA-DQ2.5 heterodimer called "half-heterodimer" (HLA-DQA1*05 in 12% and HLA-DQB1*02 in 1.5%), and 20.8% lacked all the susceptible alleles (DQX.x). Gender distribution was not significantly different among the CD-risk groups. Conclusion: We report one of the highest frequencies of CD-predisposing HLA-DQ genotypes among healthy general populations (52.7%) worldwide, which might partly explain the high prevalence of CD in the Saudi community. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is an autoimmune disease characterized by gluten intolerance. The main cause of this immune - mediated enteropathy is gliadin, a protein mainly present in wheat, rye, barley and spelt. The predisposition to celiac disease is determined by HLA class II genes encoding MHC II heterodimer molecules, more specifically HLA-DQ2 and HLA-DQ8. Up to date the exact number of people suffering from celiac disease in Bosnia and Herzegovina is still not known because there is no public registry for this disease. The aim of this study was to evaluate the HLA-DQ2 and HLA-DQ8/DR4 presence in tested group of patients referred to Polyclinic Atrijum in Sarajevo in period from August 2022. to August 2023. HLA-DQ2 and DQ8/DR4 allele identification was performed using Real-time PCR technique. According to our preliminary results, approximately 20% of tested patients were positive for HLA-DQ2 and/or HLA-DQ8/DR4 haplotype. To our knowledge this is the first study evaluating the presence of HLA-DQ2 and HLA-DQ8 genotypes in tested population in Bosnia and Herzegovina. However, for better understanding of HLA-DQ2 and HLA-DQ8 genotype association with celiac disease and their distribution in Bosnian and Herzegovinian population, a larger study with higher number of tested patients with clinical data should be conducted. [ABSTRACT FROM AUTHOR]

Background: Studies have reported the controversial association between multiple sclerosis (MS) and celiac disease (CD). Thus, we aimed to conduct a case control study on patients with MS, CD, and controls to investigate CD in patients with MS by means of comparing CD genetic markers in patients with MS and controls. We also evaluated serological markers in patients with MS. Materials and Methods: This is a case control study conducted on 60 patients with MS, 140 patients with CD, and 151 healthy controls in 2015 in Tehran, Iran. HLA typing was done to identify the carriers of the DQB1*02, DQB1*0301, DQA1*05, or DQA1*0201 alleles for HLA-DQ2, DQB1*0302, or DQA1*03 for HLA-DQ8. All data were analyzed using SPSS software (version 23, IBM Corp). Serological markers including anti-gliadin antibodies (AGA) (IgA, IgG), anti-tissue trans glutaminase antibodies (Anti tTG) (IgA, IgG), anti-endomysial antibody (EMA) (IgA, IgG), and total IgA were assessed in MS group by enzyme immunoassays. Results: The data of 60 patients with MS (26.7% male, mean age = 34.83 years), 140 patients with CD (33.6% male, mean age = 38.37 years) and 151 controls (48.3% male, mean age = 40.43 years) were analyzed. The results of serological markers were not positive in any of the patients with MS. The prevalence of IgA deficiency (IgA ≤ 0.7) was 13.3% in patients with MS. 34 (56.7%) patients with MS, 90 (59.6%) controls, and 135 (96.4%) patients with CD had positive results in either or both HLA DQ2 and DQ8. There was a significant difference in the HLA typing results between the patients with MS and controls with CD group (P < 0.001), while comparing the MS group with the controls there was not a significant difference in the result of HLA typing (P = 0.69). Four (50%) patients with MS and IgA deficiency had positive DQ2 and/or DQ8. Conclusion: Our results did not show any correlation between MS and CD, which was similar to other studies. [ABSTRACT FROM AUTHOR]

Purpose: Celiac disease (CD) diagnosis can be established by serological and small bowel biopsy (SBB), while absence of HLA-DQ2 and -DQ8 haplotypes excludes the disease. The present study aims at evaluating the diagnosis of a representative sample of pediatric and adult CD patients of Gaza strip in light of DQ2 and DQ8 haplotypes expression. Methods: Unrelated CD patients ( n = 101) and matched healthy controls ( n = 97) were genotyped for DQA1*05, DQB1*02 and DQB1*03:02 alleles by allele-specific real-time PCR. The diagnosis was re-evaluated according to the patient laboratory tests and HLA-DQ genotype. Results: The diagnosis of 35 patients who have been managed for CD could not be confirmed. Twenty-five of them were diagnosed upon their clinical presentation only. The remaining were either negative for serological and SBB tests or negative for HLA-DQ haplotypes. The HLA-DQ alleles were negative in 4 SBB and one Anti-EMA positive patients. The frequency of DQ2 and DQ8 haplotypes among the remaining 65 confirmed cases was 70.8 and 15.4%, respectively, compared to 17.5 and 27.8% in the controls. The DQB1*02 allele was the most common in the cases (84.6%) followed by DQA1*05 allele (80%) and DQB1*03:02 allele (20%). The DQA1*05 allele was commonest in the control group (54.6%) followed by DQB1*02 allele (42.3%) and DQB1*03:02 allele (28.9%). Conclusions: Absence of HLA-DQ2 and HLA-DQ8 genotyping in the workup of patients may result in CD misdiagnosis, particularly in a setting with poor histopathological diagnostic capacity. [ABSTRACT FROM AUTHOR]

Résumé Considéré comme un substitut fiable des céréales à gluten, le maïs fait encore l’objet de réserves concernant sa consommation par les patients souffrant d’intolérance sévère au gluten ou de maladie cœliaque. Les protéines de réserve des grains de maïs correspondent à des zéines, différentes des protéines du gluten de blé, gliadines et gluténines. Malgré tout, les alignements de séquence de certaines zéines montrent des homologies importantes avec les protéines du gluten de blé. Une recherche bio-informatique systématique des protéines de réserve du maïs disponibles, n’a cependant pas permis d’identifier dans ces protéines, des peptides immunotoxiques capables de provoquer l’érosion de la muqueuse intestinale. Ces peptides sont incapables de s’ancrer correctement dans la corbeille des groupes HLA-DQ2 et HLA-DQ8, comme le montrent les expériences d’ancrage moléculaire in silico. Ces peptides ne présentent donc aucun danger pour les patients souffrant d’intolérance sévère au gluten ou de maladie cœliaque. Le maïs est bien une céréale sans gluten qui peut être consommée sans danger par les patients souffrant de maladie cœliaque. Maize has long been recognized as a safe substitute for gluten-containing cereals for patients with severe gluten intolerance or celiac disease. Maize storage proteins consist primarily of zeins, which substantially differ from wheat gluten proteins, gliadins and glutenins. Yet sequence alignments reveal consistent identities and homologies between certain zeins and wheat gluten proteins. Systematic bioinfomatic searching for potential immunotoxic epitopes in all available amino acid sequences from maize storage proteins failed to identify any immunotoxic epitopes likely to provoke the intestinal mucosa erosion currently seen in celiac disease patients. The absence of immunotoxic epitopes in maize storage proteins was further confirmed by an in silico molecular docking approach, using HLA-DQ2 and HLA-DQ8 as templates. None of the suspected maize immunotoxic epitopes could be fully accommodated in the HCM-II basket of HLA-DQ2 and HLA-DQ8 during docking experiments. The results of the in silico approach confirm the absence of immunotoxic epitopes in maize storage proteins and help reinforce its status as a safe food for celiac disease patients. Maize thus deserves to be recognized as a gluten-free cereal with no harmful impact on celiac disease patients. [ABSTRACT FROM AUTHOR]

Background: no systematic studies on the prevalence of coeliac disease (CD) have been reported from China. In western populations CD is more common in patients with insulin dependent diabetes mellitus (IDDM) and in diarrhoea-predominant irritable bowel syndrome (D-IBS). We have screened patients with these conditions presenting to the outpatient department of a large hospital of "Traditional Chinese Medicine" (TCM) in Nanjing, Jiangsu province, P.R. China. Methods: we tested sera of 78 unrelated Han Chinese patients (5 IDDM and 73 D-IBS), using ELISA serological tests for IgG anti-gliadin antibodies (IgG-AGA) and IgA anti-tissue transglutaminase antibodies (IgA-tTG). Results: six out of 78 patients (7.7%) were positive for IgG-AGA (two men and four women) and two (2.6%) were positive for IgA-tTGs. One of the latter patients was negative for IgG-AGA. Besides, one patient had a dubious IgA-tTG antibody and a positive IgG-AGA. None of the six patients agreed to undergo duodenal biopsy. Two out of these six patients followed a gluten-free diet for one year. In one patient the diarrhoea ceased and his body weight increased. Another stopped losing weight. Conclusions: this study previously published as a letter in GUT (Wu J, Xia B, von Blomberg BME, Zhao C, Yang XW, Crusius JBA, Peña AS. Coeliac disease: emerging in China? Gut 2010; 59(3): 418-9) demonstrated that CD may exist in the Jiangsu province of P.R. China. The present article draws attention to the difficulties of following a standard protocol in China such as established in western countries and highlights important factors less well known in the west in relation to the development of CD in China. Wheat production became significant in China between 1600 and 1300 B.C. After the Han dynasty (500-200 B.C.), wheat was one of the main cereals in China. One the major wheat fields in China is located in the Jiangsu province where the research for this article was performed. A review of Chinese literature shows that the predominant HLA-DQ CD risk alleles and haplotypes are present in the Jiangsu province. Genetic background, food consumption, and the results of our study suggest that CD should actively be investigated in P.R. China.

Objective The aim of this study is to assess the prevalence of HLA-DQ2 and HLA-DQ8 in women diagnosed with lipedema. Methods Leukocyte histocompatibility antigen (HLA) tests of 95 women diagnosed with lipedema were analyzed using non-probabilistic sampling for convenience. The prevalence of HLA-DQ2 and HLA-DQ8 was compared to the general population. Results The prevalence of HLA-DQ2+ was 47.4%, that of HLA-DQ8+ was 22.2%, the presence of any celiac disease associated HLA (HLA-DQ2+ or HLA-DQ8+) was 61.1%, both HLA (HLA-DQ2+ and HLA-DQ8+) was 7.4%, and the absence of celiac disease associated HLA was 39%. Compared to the general population, there was a significantly higher prevalence of HLA-DQ2, HLA-DQ8, any HLA, and both HLAs in lipedema patients. The mean weight of patients with HLA-DQ2+ was significantly lower than the overall study population, and their mean BMI significantly differed from the overall mean BMI. Conclusion Lipedema patients seeking medical assistance have a higher prevalence of HLA-DQ2 and HLA-DQ8. Considering the role of gluten in inflammation, further research is needed to establish if this association supports the benefit of gluten withdrawal from the diet in managing lipedema symptoms., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Amato et al.)

Purpose: Irritable bowel syndrome (IBS) is common but therapies are unsatisfactory. Food is often suspected as cause by patients, but diagnostic procedures, apart from allergy testing, are limited. Based on the hypothesis of non-celiac wheat sensitivity (WS) in a subgroup of IBS patients, we tested the long-term response to a gluten-free diet (GFD) and investigated HLA-DQ2 or -DQ8 expression as a diagnostic marker for WS in diarrhea-dominant (IBS-D) and mixed-type IBS (IBS-M). Methods: The response to a GFD served as reference test for WS and HLA-DQ2/8 expression was determined as index test. Patients were classified as responders if they reported complete or considerable relief of IBS symptoms on at least 75 % of weeks over a 4-month period of gluten-free diet. Established questionnaires (IBS-Quality of Life (IBS-QoL), IBS Symptom Severity Scale (IBS-SSS), European Quality of Life-5 Dimensions (EQ-5D)) were used for secondary outcome measures. Results: Thirty-five patients finished the study. Of these, 12 (34 %) were responders and classified as having WS (95 % CI 21-51 %). HLA-DQ2/8 expression had a specificity of 52 % (95 % CI 33-71 %) and sensitivity of 25 % (95 % CI 8-54 %) for WS. Responders showed improvement in quality of life and symptom scores. At 1-year follow-up, all responders and 55 % of non-responders were still on GFD and reported symptom relief. Conclusion: Using strict criteria as recommended for IBS studies, about one third of patients with IBS-D or IBS-M are wheat sensitive, with a similar proportion in both IBS types. Expression of HLA-DQ2/8 is not useful as diagnostic marker for WS. Long-term adherence to a GFD is high and can sustain symptomatic improvement. [ABSTRACT FROM AUTHOR]

Objective: To determine the frequency of alleles and genotypes of HLA-DQA1 and HLA-DQB1 genes in patients with celiac disease and their impact on the clinical expression of the disease. Subjects and Methods: The study involved 110 patients (60 women and 50 men) with celiac disease diagnosed according to the revised ESPGHAN (The European Society for Pediatric Gastroenterology Hepatology and Nutrition) criteria at the Clinic of Internal Medicine and Pediatric Clinic, University Hospital Centre Rijeka. The genotyping of HLA class II alleles was performed by polymerase chain reaction method (PCR) with allele-specific primers (Sequence Specific Primer-SSA) using commercial kits of low and medium resolution GenoVision SSP. Results: All patients had at least one risk HLA-DQA1 or HLA-DQB1 allele. Homozygotes for the HLA-DQB1 alleles were 36.3 %, and for HLA-DQA1 34.5 %. Genotypes for the HLA-DQ2 and/or HLA-DQ8 heterodimers were present in 92.7 % of patients. HLA-DQ2 was present in 79.1 % of patients while HLA-DQ8 in 20.9 %. There are no significant difference (P > 0.05) in the frequency of the HLA-DQ2 and/or HLA-DQ8 carriers depending on the type of celiac disease. An earlier diagnosis and greater incidence of other autoimmune diseases in homozygotes, compared to other genotypes, was observed. Conclusions: The results have shown that the presence of HLA-DQ2/DQ8 heterodimers in Croatian celiac patients is in range with the existing north-south gradient in European populations. HLA genotyping in celiac patients has explicit effects in clinical practice when setting up the diagnosis. [ABSTRACT FROM AUTHOR]

Background: Recent studies have shown a critical role for HLA-DQ2 and HLA-DQ8 in the pathogenesis of celiac disease. No study has been performed on the prevalence of these two HLA types in Iranian celiac patients. Materials and Methods: - logic tests. HLA typing for HLA-DQ2 (DQB1*02), HLA-DQ8 (DQB1*03), HLA-DQ B1*05 and HLA-DQ B1*06 was performed using polymerase chain (PCR) reaction. Results: Twenty two (91.7%) celiac patients and twenty seven (73%) controls were positive for the HLA-DQ2 and/or HLA-p=0.068). However, celiac patients were statistically more positive for homozygote HLA-DQ2, whereas non-celiac participants were more positive for homozygote HLA-DQ8 (p<0.05). Conclusion: other hand, the higher prevalence of homozygote HLA-DQ2 in celiac patients shows its stronger role in disease pathogenesis. Further studies on larger populations are needed in Iran. [ABSTRACT FROM AUTHOR]

Coeliac disease (CD) is an immune-mediated systemic condition elicited by gluten and related prolamines in genetically predisposed individuals and characterised by gluten-induced symptoms and signs, specific antibodies, a specific human leukocyte antigen (HLA) type and enteropathy. The risk of coeliac disease is increased in first-degree relatives, certain syndromes including Down syndrome and autoimmune disorders. It is thought to occur in 1 in 100-200 individuals, but still only one in four cases is diagnosed. Small-bowel biopsy is no longer deemed necessary in a subgroup of patients, i.e. when all of the following are present: typical symptoms or signs, high titres of and transglutaminase antibodies, endomysial antibodies, and HLA-type DQ2 or DQ8. In all other cases, small-bowel biopsy remains mandatory for a correct diagnosis. Therapy consists of a strictly gluten-free diet. This should result in complete disappearance of symptoms and of serological markers. Adequate follow-up is considered essential. Conclusion: Although small-bowel biopsy may be omitted in a minority of patients, small-bowel biopsy is essential for a correct diagnosis of CD in all other cases. Diagnostic work-up should be completed before treatment with gluten-free diet instituted. [ABSTRACT FROM AUTHOR]

Celiac disease is caused by an abnormal intestinal T-cell response to gluten proteins of wheat, barley and rye. Over the last few years, a number of gluten T-cell epitopes restricted by celiac disease associated HLA-DQ molecules have been characterized. In this work, we give an overview of these epitopes and suggest a comprehensive, new nomenclature. [ABSTRACT FROM AUTHOR]

The basis of proper recognition of pathogens and tumours is provided by adaptive immunity. This immunological reaction of the recognition function of T-cell receptors on T lymphocytes detects antigenic peptides bound to major histocompatibility complex (MHC) molecules. Structural insight into this process has few grown considerably in the last years. In some of the cases, antigens are self-protein fragments causing autoimmunity diseases. Type 1 diabetes is such a disease connected with the human leukocyte antigen-DQ8 molecule, a class II MHC glycoprotein. Its crystal structure, complexed with LVEALYLVCGERGG peptide (insulin B peptide), has been solved, and important information about the significance of P1, P4 and P9 binding pockets has been discovered. The complex structure also revealed an unusual large number of intermolecular hydrogen bonds between insulin B peptide and MHC molecule. To further investigate the dynamics of peptide/MHC interactions, we perform molecular dynamic simulations in explicit water. Analysis of the results provided useful information of the binding of the peptide antigen to MHC molecule, which is supported by numerous hydrogen bonds besides the electrostatic (P1 and P9 pockets) or hydrophobic interactions (P4). Results also allowed some implications to be drawn for the role of residues located outside of the binding groove. [ABSTRACT FROM PUBLISHER]

Abstract: HLA-DR0401, 0403 and 0405 are associated with variable T1D susceptibilities when linked with a common HLA-DQ8 (DQA1∗0301/DQB1∗0302). It is unknown how the modest differences within the peptide binding regions of DR4 subtypes lead to distinct autoimmune risks. Since all Class II HLA molecules share the same intracellular compartments during biosynthesis, it is possible that DQ and DR compete with one another to bind and present antigenic peptides. As such, it is reasonable to hypothesize that a strong DR4 self-peptide binder down-modulates DQ8 epitope presentation more than a weak one. In this study, we first examined the binding of the peptides derived from two putative beta-cell autoantigens – GAD65 and insulin. Protective DR0403 bound similar number of self-peptides as susceptible DR0401 while highly susceptible DR0405 bound substantially less self-peptides than rest two molecules. Kinetic assays were used to further compare the stability of peptide:DR complexes formed between DR0401, 0403 and selected GAD65 peptides, which also bound DQ8. Two peptides with naturally processed DQ8 epitopes bound protective DR0403 with longer half-life and lower dissociation rate than susceptible DR0401, confirming DR0403 as a better peptide competitor than DR0401. The distinguishing peptide binding features of DR0401, DR0403, and DR0405 highlighted in this study help to explain the hierarchy of genetic associations between T1D and these DR4 subtypes. The enhanced peptide competition of DR0403 leads to a down-modulation of DQ8 epitope presentation, as compared to weak competitors such as DR0401 and DR0405, and therefore contributes to disease protection. [Copyright &y& Elsevier]

The strong MHC class II association in human as well as murine Type 1 diabetes (T1D) suggests a central role for CD4+ T cells in the disease pathogenesis. Nonetheless, CD8+ T cells also play a role in the pathogenic process. We describe how CD4+ or CD8+ T cells can contribute differentially to the pathogenesis of T1D using the HLA-DQ8 transgenic mouse models. HLA-DQ8 transgenic mice expressing the costimulatory molecule, B7.1 (RIP.B7.1), or the proinflammatory cytokine, TNF-α (RIP.TNF) or both (RIP.B7.RIP.TNF) under the control of rat insulin promoter (RIP) were used. Our observations indicate that in the RIP-B7 model, CD4+ T cells were absolutely required for diabetes to occur. However, when CD8+ T cells were also present, the incidence of diabetes increased. On the other hand, in the RIP-TNF model, CD8+ T cells were absolutely required for diabetes to occur. Interestingly, when CD4+ T cells were also present, the incidence of diabetes decreased. In the RIP-B7.RIP-TNF double transgenic mouse model, either CD4+ or CD8+ T cells were sufficient to precipitate diabetes in 100% of the animals. Thus, the relative roles of CD4+ or CD8+ T cells in the pathogenesis of T1D are possibly determined by the local inflammatory stimuli. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a polygenic autoimmune disease with a strong HLA association particularly, HLA-DQ8. We investigated whether islet-specific expression of granulocyte/macrophage colony-stimulating factor (Ins.GM-CSF) in Aß°.NOD.DQ8 mice (HLA-DQ8 transgenic mice on a NOD background lacking endogenous mouse MHC class II molecules) would predispose to development of spontaneous autoimmune diabetes. Aß°.NOD.DQ8 mice expressing GM-CSF in the pancreatic ß cells (8+ G+) as well as litter mates lacking either HLA-DQ8 (8 - G+) or GM-CSF (8+ G - ) or both (8 - G - ) exhibited insulitis and sialadenitis of varying degrees. But none of the mice progressed to develop T1D. Other than the marked mononuclear cell infiltration in livers of mice expressing GM-CSF irrespective of HLA-DQ8 expression (8+ G+ or 8 - G+), no other changes were observed in the animals. Thus, we have shown for the first time that expression of HLA-DQ8 in the diabetes-predisposing mileu of NOD genetic background is not sufficient to predispose to development of autoimmune diabetes even when the potent immunostimulatory cytokine, GM-CSF is expressed in the pancreatic islets. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of our study was to test the hypothesis that HLA genotypes conferring risk of diabetes, cord blood autoantibodies, or both are associated with increased birthweight. Methods: HLA genotypes were determined in dried blood spots of cord blood from a total of 16,709 children born to healthy mothers in the Diabetes Prediction in Skåne (DiPiS) study, a population-based observational clinical investigation of newborn children. Children born to mothers with diabetes or gestational diabetes were excluded. Autoantibodies to glutamic acid decarboxylase (GAD65Ab) and insulinoma-associated protein 2 were determined in standard radioligand binding assays. Birthweight was adjusted for gestational age and divided into quartiles. The upper quartile was defined as high relative birthweight (HrBW) and the lower quartile as low relative birthweight (LrBW). Results: Genotypes conferring risk of type 1 diabetes were strongly associated with relative birthweight (rBW) (p=0.01). The high-risk HLA-DQ2/8, DQ8/0604 and DQ8/X genotypes were associated with HrBW (odds ratio [OR] [95% CI]=1.20 [1.08–1.33], p=0.0006). The HLA-DQB1∗0603 allele, which is negatively associated with type 1 diabetes, was also associated with HrBW (p=0.025), confirming a previous report on DQB1∗0603-linked HLA-DR13. GAD65Ab were negatively associated with HrBW (OR [95% CI]=0.72 [0.56–0.93], p=0.01). Regression analysis showed that the HLA-associated increase in rBW was independent of confounding factors. Conclusions/interpretation: HLA genotypes may be associated with intrauterine growth independent of type 1 diabetes risk. The epidemiological observation that high birthweight is a risk factor for type 1 diabetes could possibly result from a moderating effect on intrauterine growth of HLA genotypes conferring a high risk of diabetes. [ABSTRACT FROM AUTHOR]

Abstract: In the last decade, CD4+CD25+ T regulatory cells have been implicated in the protection against autoimmune diseases. The human DQ8 major histocompatibility complex (MHC) class II molecule is associated with rheumatoid arthritis (RA) and various other autoimmune diseases in humans. The human leukocyte antigen (HLA)-DQ8 transgenic mouse, containing the human DQ8 MHC class II molecule, is predisposed toward collagen-induced arthritis. However, the biologic pathways responsible for DQ8-associated autoimmunity have yet to be defined, including possible defects in the CD4+CD25+ T regulatory cell compartment. To explore this concept, we examined the suppressive capacity of CD4+CD25+ T regulatory cells from DQ8 transgenic mice in vitro and, using CD25-specific depleting antibodies, investigated their influence on collagen-induced arthritis in vivo. CD4+CD25+ T regulatory cells isolated from DQ8 transgenic mice were found to be sufficient suppressors of splenocyte proliferation and interferon (INF)-γ production. Furthermore, depletion of these cells before immunization led to significant increases in arthritis severity, collagen-specific antibodies, and INF-γ production. These results indicate that HLA-DQ8 mice contain naturally occurring CD25+ regulatory cells that modulate collagen-induced arthritis and imply that DQ8 expression does not hinder the development of CD25+ T regulatory cells. [Copyright &y& Elsevier]

To evaluate the contributions of DR3 and DQ8 to the etiopathogenesis of type 1 diabetes in a diabetes-predisposing milieu, we developed human leukocyte antigen (HLA) transgenic mice on the nonobese diabetic (NOD) background in the absence of the endogenous class II molecule, I-Ag7 and studied the incidence of both spontaneous and experimental (induced) autoimmune diabetes. Transgenic expression of HLA-DR3 and -DQ8 (either alone or in combination) did not confer susceptibility to spontaneous or cyclophosphamide-induced type 1 diabetes. Expression of I-Ag7 was mandatory for development of spontaneous or cyclophosphamide-induced diabetes. However, multiple low doses of streptozotocin could induce diabetes in all groups of mice independent of the class II molecules expressed. In unmanipulated mice, only islets from I-Ag7+/+ mice revealed significant intra-islet infiltration. Although a characteristic peri-insulitis/peri-ductulitis was present in Aβ0/NOD mice, islets from DR3, DQ8 and DR3.DQ8 double transgenic mice demonstrated significantly less infiltration. In conclusion, transgenic expression of HLA-DR3 and -DQ8 associated with predisposition to type 1 diabetes alone is not sufficient to induce spontaneous diabetes in NOD mice lacking endogenous class II molecules. [Copyright &y& Elsevier]