HLA Class II Antigen Processing and Presentation Pathway Components Demonstrated by Transcriptome and Protein Analyses of islet β-Cells from Donors with Type 1 Diabetes (original) (raw)
Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes
Diabetologia, 2016
Human pancreatic beta cells may be complicit in their own demise in type 1 diabetes, but how this occurs remains unclear. One potentially contributing factor is hyperexpression of HLA class I antigens. This was first described approximately 30 years ago, but has never been fully characterised and was recently challenged as artefactual. Therefore, we investigated HLA class I expression at the protein and RNA levels in pancreases from three cohorts of patients with type 1 diabetes. The principal aims were to consider whether HLA class I hyperexpression is artefactual and, if not, to determine the factors driving it. Pancreas samples from type 1 diabetes patients with residual insulin-containing islets (n = 26) from the Network for Pancreatic Organ donors with Diabetes (nPOD), Diabetes Virus Detection study (DiViD) and UK recent-onset type 1 diabetes collections were immunostained for HLA class I isoforms, signal transducer and activator of transcription 1 (STAT1), NLR family CARD doma...
Recognition of HLA Class I–Restricted β-Cell Epitopes in Type 1 Diabetes
Diabetes, 2006
Type 1 diabetes results from the autoimmune destruction of insulin-producing pancreatic β-cells by cytotoxic T-lymphocytes (CTLs). In humans, few β-cell epitopes have been reported, thereby limiting the study of β-cell–specific CTLs in type 1 diabetes. To identify additional epitopes, HLA class I peptide affinity algorithms were used to identify a panel of peptides derived from the β-cell proteins islet amyloid polypeptide (IAPP), islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP), insulin, insulinoma-associated antigen 2 (IA-2), and phogrin that were predicted to bind HLA-A*0201. Peripheral blood mononuclear cells from 24 HLA-A*0201 recent-onset type 1 diabetic patients and 11 nondiabetic control subjects were evaluated for γ-interferon secretion in response to peptide stimulation in enzyme-linked immunospot assays. We identified peptides IAPP9-17, IGRP215-223, IGRP152-160, islet IA-2(172-180), and IA-2(482-490) as novel HLA-A*0201–restricted T-cell epito...
Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus
Diabetologia, 2005
Unfortunately there were miscalculations in Tables and of this paper. The corrected tables are reproduced below (with the amended values in colour), along with the corrected paragraph from the Results. The authors believe that these miscalculations are minimal and do not change the conclusion of the paper. The allele frequency of HLA-DR4 was 44.7% in fulminant diabetic patients, 29.1% in autoimmune diabetic patients, and 21.8% in healthy control subjects. HLA-DR4 occurred at a significantly greater frequency in fulminant diabetic patients than in healthy controls (p=2.85E-09, pc=2.57E-08, [OR 2.90]), but there was no significant difference in the frequency of HLA-DR4 between autoimmune type 1 diabetic patients and healthy controls. The HLA-DR2 allele was observed in only 1.0% of autoimmune type 1 diabetes, but in 10.1% of fulminant diabetic patients, with
Diabetes, 2006
Cytotoxic T-lymphocytes (CTLs) are considered to be essential for β-cell destruction in type 1 diabetes. However, few islet-associated peptides have been demonstrated to activate autoreactive CTLs from type 1 diabetic subjects. In an effort to identify novel epitopes, we used matrix-assisted algorithms to predict peptides of glial fibrillary acidic protein (GFAP), prepro-islet amyloid polypeptide (ppIAPP), and islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP) that likely bind to HLA-A*0201 with a strong affinity and contain a COOH-terminal proteasomal cleavage site. Seven peptides stabilized HLA-A*0201 expression in binding assays and were used to stimulate peripheral blood mononuclear cells and were evaluated for granzyme B secretion. We found that 5 of 13 type 1 diabetic subjects and 4 of 6 antibody-positive relatives exhibited greater numbers of granzyme B–secreting cells in response to at least one putative epitope compared with healthy control subjec...
Immunogenetics of HLA class II in Israeli patients with adult-onset Type 1 diabetes mellitus
Human Immunology, 2007
The distribution of HLA class II alleles and genotypes in Israelis of different ethnic origin with adult-onset type 1 diabetes (T1D) was examined. The results were compared with published findings in healthy Israelis and childhood-onset T1D Israelis. An additional comparison was made between subgroups of patients with rapidly and slowly progressive adult-onset T1D (LADA). A DNA-based low-resolution analysis was performed for DRB1* and DQB1* alleles and a high-resolution analysis for DRB1*04 and DQB1*1 alleles. In all, 87% of the study group was positive for DRB1*03 or DRB1*04 compared with 36% of the healthy controls. The main alleles accounting for susceptibility to T1D were DRB1*0402, found in 77.9% of carriers of DRB1*04 and DQB1*0302, found in 74.6% of carriers of DQB1*03.
Diabetologia, 2008
Aims/hypothesis To further our understanding of antigen presentation by HLA class II molecules, we have examined the influence of HLA class II genotype on expression of autoantibodies to islet antigen-2 (IA-2A). Methods HLA class II genotype and IA-2A were determined within 3 months of diagnosis in 618 patients with type 1 diabetes (median age 11 years [range 0.7-20.9]). Antibodies to the juxtamembrane region of IA-2 were measured by a radiobinding assay in 481 of 484 IA-2A-positive patients. Results IA-2A prevalence was highest in patients carrying at least one HLA-DRB1*04-DQA1*0301 (385 of 450; 86%), DRB1*07-DQA1*(0201 or 0301) (58 of 64; 91%) or DRB1*09-DQA1*0301 haplotype (18 of 19; 95%). Multiple regression showed that IA-2A were strongly associated with the number of these haplotypes carried; only 69 of 132 (52%) patients carrying none of these haplotypes had IA-2A, compared with 322 of 391 (82%) patients with one and 93 of 95 (98%) with two of these haplotypes (p<0.001). IA-2 juxtamembrane antibodies were less frequent in IA-2A-positive patients with one (35%) or two (36%) DRB1*03-DQB1*02 or DRB1*07-DQB1*02 haplotypes than in those negative for these haplotypes (52%) (p=0.002), but showed an independent positive association with IA-2A level (p<0.001). Conclusions/interpretation HLA class II alleles strongly influence the prevalence of IA-2A. The high IA-2A prevalence in patients carrying DRB1*04, DRB1*07 and DRB1*09 alleles in linkage disequilibrium with DQA1*0301 or the closely related DQA1*0201 suggests the humoral response to IA-2 may be driven by HLA-DQA1 genes.
The Journal of clinical endocrinology and metabolism, 2017
A declining first phase insulin response (FPIR) is characteristic of the disease process leading to clinical type 1 diabetes (T1D). It is not known whether reduced FPIR depends on class II HLA type, islet autoimmunity, or both. To dissect the role of class II HLA genotypes and biochemical islet autoantibodies in the compromised FPIR. A total of 438 HLA DR-DQ genotyped children in the prospective Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study were analyzed for FPIR in a total of 1149 intravenous glucose tolerance tests (IVGTT) and categorized by their class II HLA genotype and the number of biochemical islet autoantibodies at the time of the first FPIR. Age-adjusted hierarchical linear mixed models were used to analyze repeated measurements of FPIR. The associations between class II HLA genotype, islet autoantibody status and FPIR. A strong association between the degree of risk conferred by class II HLA genotype and positivity for islet autoantibodies existed (P<0...