The Molecular Basis of Susceptibility to Rheumatoid Arthritis

Abstract

This chapter discusses the development, current understanding, and some of the implications of the molecular basis of susceptibility to rheumatoid arthritis as it relates to the inheritance of particular polymorphic conformations of the major histocompatibility complex (MHC) class II molecules. The way the interpretation of these susceptibility structures as peptide-binding pockets alters the paradigm underlying the study of histocompatibility leukocyte antigens (HLA)-disease associations to one based on rational structural hypotheses is discussed. Disease susceptibility genes, rather than being “disease genes,” are MHC class II alleles that are positively selected and physiologic. The penetrance of rheumatoid arthritis is accordingly low, but in the heterozygous state, the gene encoding the shared epitope confers susceptibility indicating it has a dominant mode of action. However, when two susceptibility alleles are inherited together this greatly increase the penetrance and severity of the ensuing disease and raises questions about the way these structures act cooperatively to provide the molecular basis of susceptibility. From the perspective of the person with rheumatoid arthritis, the illness usually appears to be a sporadic event that often makes its appearance only well into adulthood.