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The apparent association of rheumatoid arthritis (RA) with the MHC region and, in particular, with the shared epitope present in the peptide-binding cleft of certain DR molecules has always amazed me. It is amazing because it suggests a narrow specificity of immune responses in RA whereas other observations suggest there should not be. Nevertheless, it is one of the few clear and unarguable findings that give us one end of a thread to unwind this complex disease. The MHC association was discovered decades ago and has been the subject of numerous investigations, but the mechanism is still not known. In fact, there is no indisputable evidence for which MHC gene or genes is responsible for the association. This is the time of unraveling the entire human genome sequence and, accordingly, there are expectations to find the genes that control our most common diseases. The MHC region was the first to be sequenced but this did not elucidate the mystery of its genes. Still, there are good candidates and, in fact, the shared epitope hypothesis gives strong arguments for a role of the DR molecule. It is under dispute whether other class II molecules are involved, such as DQ, or even other MHC molecules, such as tumor necrosis factor α, but let us say that the DR molecule (in particular, specific structures in its peptide binding pocket) does play an important role in the disease.

Association of MHC and rheumatoid arthritis. Why is rheumatoid arthritis associated with the MHC genetic region? An introduction.