Background
It has been suggested that rheumatoid arthritis (RA) is initiated or perpetuated by CD4 T cells activated by presentation of joint antigens by susceptible MHC class II molecules including HLA-DR4 and DR1. A number of candidate antigens have been investigated including cartilage-derived type II collagen and aggrecan. Immunisation of susceptible strains of mice with aggrecan, including BALB/c (H-2d), induces autoimmune arthritis, providing an animal model of human RA [1]. Immunisation with peptides predicted to bind to HLA-DR4 also induces T-cell responses in HLA-DR4 transgenic mice [2]. The auto-immune T-cell response focuses on only a few epitopes within restricted regions of aggrecan such as the G1 globular domain, for reasons that are poorly understood. One explanation is a failure of self-tolerance due to poor presentation of these aggrecan epitopes in the thymus, and presentation of the same epitopes in joints following release and processing of the normally sequestered aggrecan induced by early inflammatory events. T-cell responses have also been observed in RA patients mapping epitopes within the G1 domain.