Recent investigations from this laboratory have documented the presence of suppressor T cells of the mixed lymphocyte reaction (MLR) ~ in two unrelated individuals (1). 2 That is, when T cells from these individuals were cocultured in an MLR with the responder cells of human leukocyte antigen (HLA) identical persons, the responses of such persons to allogeneic cells were inhibited. One of these suppressor cell donors, an HLA-Dw4 homozygous male, failed to respond in the MLR to almost all allogeneic cells and, therefore, his cells could be cocultured in MLR's with responder cells of varied haplotype to determine if they were suppressible. 2 Only those responders who were heterozygous or homozygous for the Dw4 antigen were inhibited, regardless of their associated HLA-A or B antigens, indicating that identity between suppresser and responder at HLA-D was required for suppression. Another individual, J.H., failed to respond in an MLR to her husband, W.H., and when J.H.'s T cells were added to the responder lymphocytes of HLA identical persons, their responses to W.H. were suppressed (1). Unlike the other suppressor cell donor, J.H. responded vigorously when challenged by stimulator cells other than W.H. It was not possible, therefore, to map the restriction between the J.H. suppressor T cell and responder cells to a specific locus within HLA due to allogeneic stimulation of J.H.'s lymphocytes which occurred when responder cells other than those homozygous for HLA-Dw2 were tested.The present studies are an effort to clarify the nature of determinants recognized by the antigen-specific MLR suppressor T cell from J.H.

In independent studies, 51% and 36% of patients with rheumatoid arthritis have been shown to possess HLA-Dw4 compared to 7% and 13% of controls. In one study Dw4 positive patients more frequently had rheumatoid factor in their sera than did Dw4 negative patients. In order to determine if the Dw4 specificity is associated with the disease or with the presence of rheumatoid factor, the frequency of this HLA antigen has been determined in 24 healthy women known to have rheumatoid factor (median titer 1 :160). Only 3 were found to have the Dw4 specificity, suggesting that this specificity is not associated with rheumatoid factor in the absence of rheumatoid arthritis. The number of documented associations between HLA and disease has risen steadily over the past several years. One of the most intriguing of these associations for rheumatologists is the association between rheumatoid arthritis and HLA-Dw4. As initially described by Stastny (1) and confirmed by McMichael et al. (2), either 5 1% or 36% of patients with rheumatoid arthritis possessed the Dw4 specificity, compared to 7% or 13% of controls, respectively. The explanation for this association is unknown, as is the explanation for every other HLA and disease association. Nonetheless, because it is anticipated that immune response genes will be found in the HLA-D region (3) and because such genes have been shown to quantitatively control antibody responses to specific proteins in several species (4). the possibility that such genes or their products play a pathogenetic role in rheumatoid arthritis must be considered.I n this regard, when rheumatoid arthritis patients who were Dw4 positive were compared with those who were Dw4 negative, a higher percentage of patients with Dw4 had rheumatoid factor (2). This correlation between rheumatoid factor positivity and the presence of HLA-Dw4, although tentative, suggests a possible explanation for the association between rheumatoid arthritis and HLA-Dw4: the presence of an immune response gene, in linkage disequilibrium with HLA-Dw4, could code for an antibody response to immunoglobulin. By definition, such a gene would be found more frequently in persons with HLA-Dw4 than in a control population.