SELECTION OF SELF-REACTIVE PEPTIDES WITHIN HUMAN AGGRECAN BY USE OF AHLA-DRB1-ASTERISK-0401 PEPTIDE BINDING MOTIF

The pathogenesis of joint destruction in rheumatoid arthritis remains ill-defined. Joint destruction is thought to be the result of tissue d amage mediated by T cells. The mere presence of articular cartilage ap pears responsible for sustaining chronic synovitis and thereby forward s a role for cartilage-responsive T cells in RA Taking advantage of th e positive DRB10401 association with RA susceptibility, we reasoned t hat T-cell recognition of autoantigens in RA would be restricted by DR B10401-encoded molecules. A DR4 (B1*0401) peptide binding motif was u sed for the identification of putative T-cell epitopes within human ag grecan, a candidate autoantigen. Thirteen peptides were synthesized an d tested for binding DRB10401 or 0404-encoded molecules. Selected bin ders were tested for induction of proliferative responses in periphera l blood mononuclear cells from donors carrying the DR4 or DR1 specific ity. Both healthy and RA donors responded to human aggrecan-derived pe ptides, thereby identifying these sequences as T-cell epitopes. intere stingly, responses to aggrecan-derived epitopes were significantly dec reased in RA patients compared to controls. This was not due to an ove rall hyporesponsiveness of RA patients since responses to a recall ant igen or mitogen did not differ from controls. The data suggest that in RA, aggrecan-specific T cells may exist in a different stage of activ ation or may have left the periphery to home to the joint. (C) 1997 Ac ademic Press Limited.