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. 2001 Mar 27;98(7):3988-91.
doi: 10.1073/pnas.071050898.

Cytomegalovirus in autoimmunity: T cell crossreactivity to viral antigen and autoantigen glutamic acid decarboxylase

H S Hiemstra  1 , N C Schloot, P A van Veelen, S J Willemen, K L Franken, J J van Rood, R R de Vries, A Chaudhuri, P O Behan, J W Drijfhout, B O Roep
Affiliations

Cytomegalovirus in autoimmunity: T cell crossreactivity to viral antigen and autoantigen glutamic acid decarboxylase

H S Hiemstra et al. Proc Natl Acad Sci U S A. .

Abstract

Antigens of pathogenic microbes that mimic autoantigens are thought to be responsible for the activation of autoreactive T cells. Viral infections have been associated with the development of the neuroendocrine autoimmune diseases type 1 diabetes and stiff-man syndrome, but the mechanism is unknown. These diseases share glutamic acid decarboxylase (GAD65) as a major autoantigen. We screened synthetic peptide libraries dedicated to bind to HLA-DR3, which predisposes to both diseases, using clonal CD4(+) T cells reactive to GAD65 isolated from a prediabetic stiff-man syndrome patient. Here we show that these GAD65-specific T cells crossreact with a peptide of the human cytomegalovirus (hCMV) major DNA-binding protein. This peptide was identified after database searching with a recognition pattern that had been deduced from the library studies. Furthermore, we showed that hCMV-derived epitope can be naturally processed by dendritic cells and recognized by GAD65 reactive T cells. Thus, hCMV may be involved in the loss of T cell tolerance to autoantigen GAD65 by a mechanism of molecular mimicry leading to autoimmunity.

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Figures

Figure 1
Figure 1
Recognition of hCMV 674–687 and GAD65 339–352. HCMV 674–687 = PYAVAFQPLLAYAY and GAD65 339–352 = TVYGAFDPLLAVAD. Proliferative responses of clone PM1#11 to a range of peptide concentrations are indicated (means ± SD of triplicate tests).
Figure 2
Figure 2
Clonality of PM1#11 crossreacting response to GAD65 and hCMV. T cells were prepulsed overnight with either GAD65 339–352 or hCMV major DNA-binding protein 674–687 (10 μM). After washing the T cells, cells were stimulated with DR3-matched irradiated peripheral blood mononuclear cells and either GAD65 339–352 or hCMV major DNA-binding protein 675–687 (1 μM) and cultured as described. As a control for the ability to proliferate, prepulsed cells were stimulated with IL-2. In a negative control experiment (data not shown), PM1#11 was mixed with a coxsackie B4 virus-specific T cell clone and prepulsed with either the coxsackie B4 virus-derived epitope or GAD65 339–352. The response of the T cell mixture, after washing, to GAD65 339–352 was completely abrogated after prepulsing with GAD65 339–352, but not after prepulsing with coxsackie B4A virus-derived epitope. In all experiments, responses are the means ± SD of triplicate tests. Mean background of triplicates after prepulsing never exceeded 500 cpm.
Figure 3
Figure 3
Recognition of hCMV and GAD65 protein. Crossreactivity of T cell clone PM1#11 with recombinant protein of GAD65 (filled bars) and hCMV (hatched bars) compared with medium alone (i.e., T cells and dendritic cells without antigen; open bars) was tested by proliferation and cytokine production (ELISPOT analysis). IL-4 production was undetectable (data not shown).
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