Matrix Metalloproteinases as Targets for the Immune System during Experimental Arthritis

Novel therapies for rheumatoid arthritis aiming at intervention in the inflammatory process by manipulation of autoreactive T and B lymphocytes receive major interest. However, the development of such therapies is largely hampered by the lack of knowledge of self-Ags recognized during the disease process. Recently, we predicted putative T cell self-epitopes based on a computer search profile. In the present study, the predicted self-epitopes were tested for T cell recognition in two experimental arthritis models, and their arthritogenic capacity was analyzed. Fourteen of n = 51 predicted self-epitopes were recognized during experimental arthritis of which six were able to actively induce arthritis. Interestingly, three of these six peptides were derived from matrix metalloproteinases (MMP), and only T cells responsive to MMP-derived epitopes were able to passively transfer arthritis to naive rats. Moreover, we demonstrate the presence of Abs to MMP-3 during the course of adjuvant arthritis. Together these data indicate that MMPs play a pivotal role as target for T and B cells during the development of inflammatory arthritis. This finding sheds new light on the pathophysiological role of MMPs during arthritis and opens novel possibilities for Ag-specific immunotherapy.