Pathogenesis of Rheumatoid Arthritis

Like other autoimmune diseases, RA is a complex disorder in which genetic and environmental factors contribute to the breakdown of tolerance to self antigens. The specificity of the pathogenic T and B cells remains unknown, because of which the understanding of the pathogenesis is incomplete. Susceptibility to RA is linked to the HLA-DR4 haplotype. Recent linkage and genome-wide association studies have revealed a large number of genes in which polymorphisms are associated with RA. There is an association with the gene encoding a tyrosine phosphatase, PTPN22, but the role of this enzyme in lymphocyte regulation is poorly understood (see Chapter 14).

The identification of anti-CCP immune responses has led to new ideas about the pathogenesis of RA (Fig. 18-10). According to one model, environmental insults, such as smoking and some infections, induce the citrul-lination of self proteins, leading to the creation of new antigenic epitopes. In genetically susceptible individuals, tolerance to these epitopes fails, resulting in T cell and antibody responses against the proteins. If these modified

Susceptibility genes (HLA, other)

Environmental factors (e.g., infection, smoking)

Failure of tolerance, unregulated lymphocyte activation

Enzymatic modification (e.g., citrullination) of self protein

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