High levels of in vitro IgM rheumatoid factor synthesis correlate with HLA-DR4 in normal individuals

The association between the HLA-DR4 histocompatibility antigen and in vitro synthesis of IgM and IgM rheumatoid factor (IgM-RF) by blood mononuclear cells was investigated in 35 normal subjects. In vitro cultures of T and B cells were stimulated with pokeweed mitogen, and the secreted IgM-RF, tetanus antibody, and total IgM protein were measured by solid-phase radioimmunoassay. In cultures containing unseparated T cells, IgM-RF production in the DR4+ and DR4- subgroups was not significantly different. However, depletion of OKT8+ cells containing T suppressor cells resulted in significantly higher IgM and IgM-RF synthesis in the DR4+ subgroup. Moreover, 6 of the 8 highest levels of IgM-RF were produced by DR4+ individuals, while only 7 of the remaining 27 individuals were DR4+ (P = 0.035). Ratios of secreted IgM-RF:IgM indicated that there was a relative enrichment for IgM-RF- specific B cell precursors in DR4+ high responders, although total numbers of circulating B cells were not increased. High responder B cells had high levels of responsiveness when mixed with T helper cells from low responders, whereas low responder B cells consistently produced low responses, even when cocultured with T helper cells from high responder donors. The data suggest that a subset of normal individuals has a pokeweed mitogen-responsive lymphocyte population that contains a B cell subpopulation specific for IgM-RF synthesis and that this condition is associated with HLA-DR4. In certain individuals who have the DR4 type, there may be a component of a susceptible genetic background, upon which other factors act to induce IgM-RF synthesis and which may produce clinical manifestations of rheumatoid arthritis.