Multiple cross-reactive self-ligands for Borrelia burgdorferi-specific HLA-DR4-restricted T cells

T cell recognition of self antigens is a key event in the pathogenesis of a utoimmune diseases. To date, the initial events that trigger autoreactive T cells are unknown. The "molecular mimicry" hypothesis predicts that during an infection T cells that recognize both a microbial antigen and a related self peptide become activated and cause autoimmune disease. We have system atically examined the recognition of self antigens by HLA-DR4-restricted ce lls specific for peptides of the outer surface protein A (OspA) of Borrelia burgdorferi, the etiological agent of Lyme disease. We used the peptide sp ot synthesis technique for complete peptide substitution analyses of two im munodominant OspA epitopes. Each amino acid residue of the epitopes was sub stituted with all 20 naturally occurring amino acids and the altered peptid es were tested for recognition by a panel of OspA-specific T cells. The bin ding motifs (supertopes) revealed by these analyses were used to screen pub lic data- bases for matching human or murine peptides. Several hundred pept ides were identified by this search and synthesized. Of these, 28 were reco gnized by OspA-specific T cells. Thus, T cell cross-reactivity is a common phenomenon and the existence of cross-reactive epitopes alone does not impl y molecular mimicry-mediated pathology and autoimmunity.