TYPE-II COLLAGEN IN CARTILAGE EVOKES PEPTIDE-SPECIFIC TOLERANCE AND SKEWS THE IMMUNE-RESPONSE

T cell recognition of type II collagen (CII) is a crucial event in the induction of collagen-induced arthritis in the mouse. Several CII pep tides have been shown to be of importance, dependent on which MHC hapl otype the mouse carries. By sequencing the rat CII and comparing the s equence with mouse, human, bovine and chicken CII, we have found that the immunodominant peptides all differ at critical positions compared with the autologous mouse sequence. Transgenic expression of the immun odominant Ag-restricted heterologous CII 256-270 epitope inserted into type I collagen (TSC mice) or type II collagen (MMC-1 mice) led to ep itope-specific tolerance. Immunization of TSC mice with chick CII led to arthritis and immune responses, dependent on the subdominant, A(q)- restricted and chick-specific CII 190-200 epitope. Immunization of F-1 mice, expressing both H-2(q) and H-2(r) as well as transgenic express ion of the A(q)-restricted CII 256-270 epitope in cartilage, with bovi ne CII, led to arthritis, dependent on the A(r)-restricted, bovine-spe cific epitope CII 607-621. These data show that the immunodominance of CII recognition is directed towards heterologous determinants, and th at T cells directed towards the corresponding autologous epitopes are tolerated without evidence of active suppression. (C) 1998 Academic Pr ess.