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Abstract
Rheumatoid arthritis (RA) is a disease characterized by a chronic and erosive inflammation of cartilaginous joints without evidence for persisting infectious agents. The association with HLA class II genes, autoimmune responses to cartilage proteins and the arthritogenicity of cartilage proteins in experimental animals suggest that cartilage autoimmunity plays an important role in the disease process. In the present review T cell recognition of type II collagen (CII) and its consequences for development of collagen-induced arthritis (CIA) is discussed. Susceptibility to disease is associated with major histocompatibility complex (MHC) genes; the important gene in the H-2q haplotype has been shown to be coding for the Aq molecule. An immunodominant peptide from CII located at position 256–270 has been defined and recognition of the Aq/CII256–270 peptide complex is essential for the development of arthritis. Interestingly, the structures recognized by T cells are mainly post-translational modifications of lysine at position 264 (K264). The majority of the CII-reactive T cells recognize a β-galactose O-linked to K264. In addition, it has recently been shown that the MHC class II molecules associated with RA, i.e. HLA-DR4 (DRB1*0401/DRA) and the HLA-DR1, possess peptide binding pockets with a very similar structures to the Aq molecule. Consequently DR1 and DR4 transgenic mice are highly susceptible to CIA and bind peptides derived from the same region of CII. The most interesting area for further investigation will be to understand how the recognition of this immunodominant CII peptide will normally induce tolerance in the immune system and how this tolerance is modulated or broken to allow the development of arthritis. Since the same structural interactions most likely occur also in humans, these questions have high relevance for solving the RA enigma.