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

Antigens of pathogenic microbes that mimic autoantigens are thought to be r esponsible for the activation of autoreactive T cells. Viral infections hav e been associated with the development of the neuroendocrine autoimmune dis eases type 1 diabetes and stiff man syndrome, but the mechanism is unknown. These diseases share glutamic acid decarboxylase (GAD65) as a major autoan tigen. 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 sh ow that these GAD65-specific T cells crossreact with a peptide of the human cytomegalovirus (hCMV) major DMA-binding protein. This peptide was identif ied after database searching with a recognition pattern that had been deduc ed from the library studies. Furthermore, we showed that hCMV-derived epito pe can be naturally processed by dendritic cells and recognized by GAD65 re active 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 autoimm unity.