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GAD65-specific autoantibodies enhance the presentation of an immunodominant T-cell epitope from GAD65

af Hällström-Reijonen, Charlotta; Daniels, Terri L; Lernmark, A. LU and Nepom, Gerald T (2000) In Diabetes 49(10). p.1621-1626
Abstract

GAD65 autoantibodies (GAD65Ab) are highly prevalent in type 1 diabetes, but their functional role in the pathogenesis of the disease and their relationship to T-cell reactivity to GAD65 is still unclear. We tested the hypothesis that GAD65Ab modulate presentation of GAD65 to T-cells. T-cell hybridoma T33.1, which recognizes the GAD65 274-286 epitope in the context of HLA-DRB1*0401, was incubated with antigen-presenting cells exposed to recombinant human GAD65 alone or complexed with GAD65Ab+ or GAD65Ab- sera. Stimulation of the T33.1 hybridoma was greatly enhanced by multiple GAD65Ab+ sera. The enhancement effect was most prominent with sera from patients with high GAD65 autoantibody levels. Sera from... (More)

GAD65 autoantibodies (GAD65Ab) are highly prevalent in type 1 diabetes, but their functional role in the pathogenesis of the disease and their relationship to T-cell reactivity to GAD65 is still unclear. We tested the hypothesis that GAD65Ab modulate presentation of GAD65 to T-cells. T-cell hybridoma T33.1, which recognizes the GAD65 274-286 epitope in the context of HLA-DRB1*0401, was incubated with antigen-presenting cells exposed to recombinant human GAD65 alone or complexed with GAD65Ab+ or GAD65Ab- sera. Stimulation of the T33.1 hybridoma was greatly enhanced by multiple GAD65Ab+ sera. The enhancement effect was most prominent with sera from patients with high GAD65 autoantibody levels. Sera from GAD65Ab- subjects had no effect. The correlation between T-cell stimulation and GAD65Ab levels was not absolute, suggesting that other variables such as autoantibody recognition of different regions of GAD65 and variable effects on processing of the 274-286 epitope may contribute. Uptake of antibody-complexed GAD65 was Fc receptor (FcR)-mediated because the enhancement of presentation was inhibited by monoclonal antibodies against FcR. Our results support the hypothesis that GAD65Ab modulate presentation of GAD65 to T-cells. Increased antigen uptake and heterogeneity in the autoantibody specificity may provide a mechanism for antibody-facilitated T-cell response influencing the progression of type 1 diabetes.

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author
publishing date
type
Contribution to journal
publication status
published
in
Diabetes
volume
49
issue
10
pages
6 pages
publisher
American Diabetes Association
external identifiers
  • scopus:0033815194
ISSN
0012-1797
language
English
LU publication?
no
id
96ce042e-9215-4796-9932-ed1b8ff5d5c6
date added to LUP
2017-09-06 15:15:15
date last changed
2017-09-06 15:15:15
@article{96ce042e-9215-4796-9932-ed1b8ff5d5c6,
  abstract     = {<p>GAD65 autoantibodies (GAD65Ab) are highly prevalent in type 1 diabetes, but their functional role in the pathogenesis of the disease and their relationship to T-cell reactivity to GAD65 is still unclear. We tested the hypothesis that GAD65Ab modulate presentation of GAD65 to T-cells. T-cell hybridoma T33.1, which recognizes the GAD65 274-286 epitope in the context of HLA-DRB1*0401, was incubated with antigen-presenting cells exposed to recombinant human GAD65 alone or complexed with GAD65Ab<sup>+</sup> or GAD65Ab<sup>-</sup> sera. Stimulation of the T33.1 hybridoma was greatly enhanced by multiple GAD65Ab<sup>+</sup> sera. The enhancement effect was most prominent with sera from patients with high GAD65 autoantibody levels. Sera from GAD65Ab<sup>-</sup> subjects had no effect. The correlation between T-cell stimulation and GAD65Ab levels was not absolute, suggesting that other variables such as autoantibody recognition of different regions of GAD65 and variable effects on processing of the 274-286 epitope may contribute. Uptake of antibody-complexed GAD65 was Fc receptor (FcR)-mediated because the enhancement of presentation was inhibited by monoclonal antibodies against FcR. Our results support the hypothesis that GAD65Ab modulate presentation of GAD65 to T-cells. Increased antigen uptake and heterogeneity in the autoantibody specificity may provide a mechanism for antibody-facilitated T-cell response influencing the progression of type 1 diabetes.</p>},
  author       = {af Hällström-Reijonen, Charlotta and Daniels, Terri L and Lernmark, A. and Nepom, Gerald T},
  issn         = {0012-1797},
  language     = {eng},
  number       = {10},
  pages        = {1621--1626},
  publisher    = {American Diabetes Association},
  series       = {Diabetes},
  title        = {GAD65-specific autoantibodies enhance the presentation of an immunodominant T-cell epitope from GAD65},
  volume       = {49},
  year         = {2000},
}