Detection of GAD65-Specific T-Cells by Major Histocompatibility Complex Class II Tetramers in Type 1 Diabetic Patients and At-Risk Subjects

Reijonen, Helena; Novak, Erik J.; Kochik, Sharon A.; Heninger, Anne-Kristin; Liu, Andrew W.; Kwok, William W.; Nepom, Gerald T.

doi:10.2337/diabetes.51.5.1375

Cited by 185 publications

(183 citation statements)

References 33 publications

Supporting

Mentioning

169

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

Section: T-cell Assay Standardizationmentioning

confidence: 61%

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

2003

View full text Add to dashboard Cite

“…Thus, low-avidity T cells are present in both populations, independent of genotype, whereas the presence of CD4 T cells with higher avidity, capable of recognizing the native proinsulin peptide, is under INS genetic control. Parallel tetramer assays were performed using either another T1D autoantigen, GAD65, 24 or an antigen from the hemagglutinin of influenza virus. 25 As shown in Figures 1c and d, no differences in tetramer positivity for these antigens were found among subjects classified by INS-VNTR genotype, indicating specificity for the proinsulin immune response.…”

Section: Resultsmentioning

confidence: 99%

Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin

Durinovic‐Belló

Gersuk

et al. 2010

Genes Immun

View full text Add to dashboard Cite

Immune responses to autoantigens are in part controlled by deletion of autoreactive cells through genetically regulated selection mechanisms. We have directly analyzed peripheral CD4 þ proinsulin (PI) 76-90 (SLQPLALEGSLQKRG)-specific T cells using soluble fluorescent major histocompatibility complex class II tetramers. Subjects with type I diabetes and healthy controls with high levels of peripheral proinsulin-specific T cells were characterized by the presence of a disease-susceptible polymorphism in the insulin variable number of tandem repeats (INS-VNTR) gene. Conversely, subjects with a 'protective' polymorphism in the INS-VNTR gene had nearly undetectable levels of proinsulin tetramer-positive T cells. These results strongly imply a direct relationship between genetic control of autoantigen expression and peripheral autoreactivity, in which proinsulin genotype restricts the quantity and quality of the potential T-cell response. Using a modified tetramer to isolate low-avidity proinsulin-specific T cells from subjects with the susceptible genotype, transcript arrays identified several induced pro-apoptotic genes in the control, but not diabetic subjects, likely representing a second peripheral mechanism for maintenance of tolerance to self antigens.

show abstract

“…MHC tetramers have been used to detect autoreactive antigen-specific CD4+ T cells in human subjects associated with T1D, MS, pemphigus vulgaris, and celiac disease [2,4,6,11,[16][17][18][19]. Because construction of appropriate MHC tetramers requires knowledge both of the HLA restriction element and of a suitable peptide epitope, diseases that have dominant HLA gene associations and dominant autoantigen targets are well suited for application of this technology, whereas other autoimmune disorders with more heterogeneous genetics or antigen targets are less optimal.…”

Section: Discussionmentioning

confidence: 99%

Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation

Laughlin

Burke

Pugliese

et al. 2008

Clinical Immunology

View full text Add to dashboard Cite

CD4+ T cells specific for the diabetes-associated autoantigen GAD65 were analyzed using peripheral blood samples after pancreas transplantation in subjects with T1D with clinical evidence of recurrent autoimmune diabetes. MHC class II tetramers facilitated the identification and cloning of antigenspecific autoreactive cells, which were found at several time points over a multiyear span, in spite of chronic immunosuppression of the subjects. Comparisons of TCR clonotypes by cDNA sequencing revealed that identical T cells were present in the circulation, separated by long time intervals, consistent with a persistent memory response associated with recurrent autoimmunity.

show abstract

Detection of GAD65-Specific T-Cells by Major Histocompatibility Complex Class II Tetramers in Type 1 Diabetic Patients and At-Risk Subjects

Cited by 185 publications

References 33 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

Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin

Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation

Contact Info

Product

Resources

About