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.