Differential requirements for induction of total immunoglobulin and physiological rheumatoid factor production by human peripheral blood B cells

Rheumatoid factors (RFs) are autoantibodies directed against the Fc part of IgG. Considerable evidence exists that there are two classes of RFs, patho logical and physiological. Whereas pathological RFs are associated with dis ease, physiological RFs are considered to be a normal component of the immu ne response. RF+ precursor B cells present as part of the B cell repertoire of healthy individuals are held responsible for the production of physiolo gical RFs, which is a transient phenomenon with a clear correlation with an initiating stimulus such as immunization or exposure to an infection. Here we demonstrate a difference in the regulatory control of total Ig and RF p roduction by peripheral blood (PB) B cells of both healthy controls (HC) an d patients with rheumatoid arthritis (RA). Highly purified B cells from HC and patients with RA were cocultured with T cells stimulated with immobiliz ed anti-CD3 mAb. Similar to IgM production, IgM-RF production was shown to be dependent on CD40 cross-linking. However, activation of PB B cells in th e CD40 system in the presence of IL-2, IL-4, IL-10, combinations of these c ytokines or supernatant of anti-CD3-stimulated T cells failed to induce det ectable IgM-RF, whereas total IgM production was considerable. From these r esults we conclude that conditions to activate physiological RF+ B cells re quire additional contact besides CD40-CD40L interactions between T and B ce lls. Since the requirements for RF production were similar using PB B cells from HC and patients with RA it is suggested that the regulatory propertie s of RF+ precursors in the PB B cell compartment is equal among these group s. Together, these results indicate that conditions for the induction of to tal Ig and physiological RFs are different.