T-CELL RESPONSE OF I-A(Q) MICE TO SELF TYPE-II COLLAGEN - MESHING OF THE BINDING MOTIF OF THE I-A(Q) MOLECULE WITH REPETITIVE SEQUENCES RESULTS IN AUTOREACTIVITY TO MULTIPLE EPITOPES

Type II collagen (CII) is of immunological interest because of its rep etitive structure and properties as an autoantigen. The mouse gene has recently been cloned, thus enabling T cell-defined epitopes to be ide ntified. Multiple novel epitopes on mouse CII are here detested in the autoreactive T cell response. The major response is directed to an ep itope with residues 707-721 located on the CB10 fragment, Some 25 othe r epitopes are also recognized, including the autologous homologue of the 256-270 epitope which dominates in the response to foreign collage n, The cells reactive with mouse collagen peptides were of T(h)1 type, as judged by release of IFN-gamma. NO significant reactivity was dete cted to mouse CII peptides during ongoing disease. Alignment of the mo use epitopes revealed a sequence motif with characteristic side chains at residues P1, P4 and P7, and to a lesser extent at P5, within a non amer core sequence. Binding of these epitopes was simulated in a compu ter model of the I-A(q) molecule, where peptides with anchor residues at P1, P4 and P7 were indeed found to fit the binding groove best, The spacing of pockets and the fine structure of the binding surface of t he I-A(q) molecule meshes with the repetitive structure of the collage n (X-Y-Gly), thus providing a likely explanation for the occurrence of multiple epitopes, Comparison with human DR binding motifs showed tha t the I-A(q) motif resembles most closely that of the DR4 subtypes whi ch predispose for rheumatoid arthritis.