A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin

Alleva, David G.; Crowe, Paul D.; Jin, Liping; Kwok, William W.; Ling, Nicholas; Conlon, Paul; Gottlieb, Peter A.; Putnam, Amy; Gaur, Amitabh

doi:10.1172/jci8525

Cited by 194 publications

(180 citation statements)

References 37 publications

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“…Remarkably, activated endothelium that presented autoantigenic epitopes caused autoreactive T-cells to selectively transmigrate through the endothelial cell layer, and provides an in vitro model resembling extravasation of T-cells into the intra-islet milieu. This study provides evidence for a role of islet endothelium in both antigen processing and presentation, [122,128] and migration of autoreactive T-cells to insulitic lesions. Autoreactive T-cell clones also proved useful to test the popular hypothesis that molecular mimicry, i.e.…”

Section: T-cell Assay Standardizationmentioning

confidence: 61%

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

2003

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Section: T-cell Assay Standardizationmentioning

confidence: 61%

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

2003

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“…Indeed, T-cell autoreactivity has been described against DR4-(0401), DR16-and DQ8-restricted insulin B-chain epitopes. 18,22,38,39 Recent studies in NOD mice showed that the InsB12-20 and InsB13-21 peptides are the core nonamers for IA g7 binding and induced T-cell reactivity in the NOD mouse. 40,41 Within InsB12-23 four binding registers exist capable of binding this molecule.…”

Section: Discussionmentioning

confidence: 99%

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

et al. 2011

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Human leukocyte antigen (HLA) class II haplotypes are established risk factors in type 1 diabetes (T1D). The heterozygous DQ2/8 genotype confers the highest risk, whereas the DQ6/8 genotype is protective. We hypothesized that DQ2/8 transmolecules composed of a and b chains from DQ2 and DQ8 express unique b-cell epitopes, whereas DQ6 may interfere with peptide binding to DQ8. Here we show that a single insulin epitope (InsB13-21) within the T1D prototype antigenic InsB6-22 peptide can bind to both cis-and trans-dimers, although these molecules display different peptide binding patterns. DQ6 binds a distinct insulin epitope (InsB6-14). The phenotype of DQ8-restricted T cells from a T1D patient changed from proinflammatory to anti-inflammatory in the presence of DQ6. Our data provide new insights into both susceptible and protective mechanism of DQ, where protecting HLA molecules bind autoantigens in a different (competing) binding register leading to 'epitope stealing', thereby inducing a regulatory, rather than a pathogenic immune response.

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“…Although recognition of B:9-23 has long been suspected, direct evidence for the presence and importance of DQ8-restricted B:9-23-specific CD4 + T cells in human subjects with T1D is limited and no study has definitively established the immunogenic register of B:9-23 as presented by DQ8. Alleva et al showed that T cells from the peripheral blood of DR4-DQ8 T1D subjects had measurable proliferative and IFN responses to the B:9-23 peptide (19). In addition, the proliferation of a B:9-23-specific T-cell line could be blocked through addition of an anti-DQ Ab (19).…”

Section: Significancementioning

confidence: 99%

“…Alleva et al showed that T cells from the peripheral blood of DR4-DQ8 T1D subjects had measurable proliferative and IFN responses to the B:9-23 peptide (19). In addition, the proliferation of a B:9-23-specific T-cell line could be blocked through addition of an anti-DQ Ab (19). Eerligh et al also reported the isolation of a DQ8 restricted Ins B:6-22 T-cell clone from a T1D subject (20).…”

Section: Significancementioning

confidence: 99%

Autoreactive T cells specific for insulin B:11-23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes

Yang¹,

Chow²,

Sosinowski

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Previous studies in type 1 diabetes (T1D) in the nonobese diabetic mouse demonstrated that a crucial insulin epitope (B:9-23) is presented to diabetogenic CD4 T cells by IA g7 in a weakly bound register. The importance of antigenic peptides with low-affinity HLA binding in human autoimmune disease remains less clear. The objective of this study was to investigate T-cell responses to a lowaffinity self-epitope in subjects with T1D. HLA-DQ8 tetramers loaded with a modified insulin peptide designed to improve binding the lowaffinity register were used to visualize T-cell responses following in vitro stimulation. Positive responses were only detectable in T1D patients. Because the immunogenic register of B:9-23 presented by DQ8 has not been conclusively demonstrated, T-cell assays using substituted peptides and DQ8 constructs engineered to express and present B:9-23 in fixed binding registers were used to determine the immunogenic register of this peptide. Tetramer-positive T-cell clones isolated from T1D subjects that responded to stimulation by B:11-23 peptide and denatured insulin protein were conclusively shown to recognize B:11-23 bound to HLA-DQ8 in the low-affinity register 3. These T cells also responded to homologous peptides derived from microbial antigens, suggesting that their initial priming could occur via molecular mimicry. These results are in accord with prior observations from the nonobese diabetic mouse model, suggesting a mechanism shared by mouse and man through which T cells that recognize a weakly bound peptide can circumvent tolerance mechanisms and play a role in the initiation of autoimmune diseases, such as T1D.antigen presentation | self-antigen | MHCII tetramers T ype 1 diabetes (T1D) is a polygenic T-cell-mediated autoimmune disease with strong genetic linkages to the MHC class II and insulin promoter regions (1). Class II molecules are fundamental for CD4 + T-cell activation, whereas the insulin promoter polymorphism can modulate insulin levels in the thymus thereby influencing the threshold of selection for insulinspecific autoreactive T cells (2, 3). In the nonobese diabetic (NOD) mouse model of autoimmune mediated diabetes, insulinspecific IA g7 -restricted CD4 + T cells have been strongly implicated in β-cell destruction. In prediabetic NOD mice, 50% of the T-cell clones established from islet-infiltrating lymphocytes were insulin-specific and the majority of these clones recognized the insulin B:9-23 (B:9-23 SHLVEALYLVCGERG) epitope (4, 5). Moreover, substitution of a single residue in the B:9-23 region abrogated development of diabetes in a transgenic mouse model (6, 7). Thus, in the murine NOD model, the IA g7 -restricted B:9-23 epitope is considered to be pivotal in the development of diabetes.The position or "register" that B:9-23 occupies within the IA g7 binding groove has been a controversial but important question. At least three binding registers (R) have been considered, defined here by which B:9-23 amino acid occupies the first binding pocket (p1) position in the IA g7 ...

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A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin

Cited by 194 publications

References 37 publications

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

The role of T-cells in the pathogenesis of Type 1 diabetes: From cause to cure

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

Autoreactive T cells specific for insulin B:11-23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes

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