Transgenic mouse models of rheumatoid arthritis.

A combined analysis of data available in the literature has demonstrated that the strongest association in rheumatoid arthritis (RA) is with DR genes rather than DQ or DP genes. Functional and structural data of RA-associated DR molecules suggest that selective binding of peptides is the molecular basis for this association. The establishment of functional transgenic mice expressing RA-associated HLA class II molecules has proven to be useful in the delineation of the role of these molecules in immune responses possibly related to RA and in the development of humanized models for this disease. Such humanized mice develop arthritis upon immunization with type II collagen (CII), which shows similarities with RA. Interestingly, the immunodominant T-cell determinant in CII is derived from positions 261-273, which overlap with a previously identified CII T-cell epitope restricted by the mouse Aq molecule, which is associated with collagen-induced arthritis. Studies in collagen transgenic mice have shown that recognition of this peptide may lead either to T-cell tolerance or to an arthritogenic response. It is therefore proposed that the T-cell recognition of the CII peptide bound by DR molecules is one of the molecular interactions of critical importance in the development of RA and accordingly also an important target for prevention and treatment of this disease.