Excitement—and Confusion—about HLA and Rheumatoid Arthritis

Rheumatoid arthritis has successfully resisted the efforts of many investigators to find a specific cause of the disease or a single genetic basis for risk. Vigorous debate continues about whether a retrovirus from the environment, an autoantigen from a patient's connective tissues or plasma, or a cross-reactive immune response between host tissues and a superantigen (for example, bacterial heat shock proteins) triggers this disease. Except for a person's recognized high risk for developing rheumatoid arthritis when she or he has an identical twin with the disease [1], there was little evidence for a genetic predisposition until Astorga and Williams [2] reported in 1969 that in 14 of 22 different patients with rheumatoid arthritis, lymphocytes mixed in cultures did not activate each other. These data, which in retrospect implied identical cell membrane antigens in the cells of different patients, attracted little attention until Stastny [3] found that in a cohort of white persons, 68% of patients with rheumatoid arthritis but only 12% of controls shared type Dw4 in the major histocompatibility complex (MHC).

The MHC is a cluster of genes that encode HLA molecules in humans on chromosome 6. A major function of these molecules is to enable macrophages and dendritic cells to present antigens to T cells in the periphery: Presentation of antigen by HLA to T cells is ineffective unless costimulatory molecules are present on both antigen-presenting cells (for example, B7.1 and B7.2) and lymphocytes (for example, CD28 and CTLA-4). CD8+ T cells are governed by MHC class I molecules (HLA A, B, and C); in CD4+ T cells, antigen is presented by MHC class II molecules (HLA D).

The following summary compresses many investigations in rheumatoid …