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Suppressive-B-cell factor (SBF) is an autoregulatory B-cell lymphokine produced by heat-aggregated-IgG stimulated B-lymphocytes which suppresses polyclonal immunoglobulin production. SBF production by rheumatoid arthritis (RA) patients' peripheral blood B-lymphocytes inversely correlates with disease activity and in vitro rheumatoid factor production. To further define the role of SBF in the pathogenesis of RA, the present study measured SBF production by surgically-obtained synovial membrane mononuclear leukocytes. SBF production by RA synovial leukocytes was similar to the levels previously described for RA peripheral blood leukocytes. Both RA and osteoarthritis (OA) synovial leukocytes produced significantly less SBF than leukocytes obtained from otherwise healthy patients with plica. OA patients produced less SBF than RA patients, but the difference was not statistically significant. SBF values for combined RA patients and controls with OA or plica correlated with the degree of histological plasma cell infiltration providing further evidence for SBF production by cells of the B-lymphocyte lineage. Depletion studies also demonstrated that synovial SBF was produced by B-lymphocytes. The molecular weight (34,000) of synovial SBF was similar to the molecular weight of peripheral blood SBF. Decreased SBF production by RA synovial B-lymphocytes is a functional abnormality in RA which may contribute to the perpetuation of synovial rheumatoid factor production and chronic synovial inflammation.

The mechanisms whereby formed immune complexes (IC) or immunoglobulin aggregates can suppress further antibody production were explored by culturing normal human peripheral blood mononuclear leukocytes (PBL) with heat-aggregated IgG (HAIgG) and collecting the culture supernatants at 24 hr. These supernatants were found to suppress a pokeweed mitogen (PWM)-induced rheumatoid factor plaque-forming cell (RF-PFC) response in normal individuals. PWM-induced anti-trinitrophenylated sheep red blood cell (TNP-SRBC) PFC were also inhibited by suppressor supernatants from HAIgG-stimulated PBL, suggesting that the polyclonal PFC response was inhibited by a suppressor factor. The suppressor factor inhibited PWM stimulated RF-PFC throughout the culture period, but suppression was maximal at the peak of the RF-PFC response. Suppressor factor was only effective at the initiation of cultures, suggesting that it inhibited early events in the PWM-stimulated RF-PFC response. Molecular weight determination of the suppressor factor by differential membrane fractionation suggested a m.w. range of 30,000 to 50,000, and chromatography on Sephadex G-100 showed a peak activity at an approximate m.w. of 32,000. Studies suggested the factor was not an interferon. Depletion of T lymphocytes by E rosetting and macrophages/monocytes by G-10 adherence did not affect the generation of suppressor factor. Depletion of T lymphocytes (OKT4, OKT8) and NK cells (Leu-11b) by antibody-dependent, complement-mediated cytotoxicity also did not affect the generation of suppressor factor. Depletion of B lymphocytes with OKB7 resulted in the generation of significantly less suppressor factor. Suppression produced by unstimulated purified B lymphocytes was approximately one-half that seen when B lymphocytes were stimulated with HAIgG. Differential membrane fractionation studies suggested that only HAIgG-stimulated B cell cultures contained peak activity in the 30,000 to 50,000 m.w. fraction. Supernatants from unstimulated purified T cells also generated suppression, which was approximately one-half of that seen with HAIgG-stimulated B cells, but no increase in suppressor activity was seen in T cell cultures after incubation with HAIgG. These studies demonstrate that HAIgG is capable of stimulating B lymphocytes to produce a lymphokine, suppressive B cell factor (SBF), which is capable of suppressing a polyclonal PFC response. SBF may be important in feedback control of human immunoglobulin production.

Rheumatoid arthritis (RA) is a disorder characterized by defective immunoregulation. Hypergammaglobulinemia, circulating immune complexes (IC), and autoantibodies such as rheumatoid factor (RF) are common serum abnormalities. To assess IC-mediated feedback suppression in RA, we evaluated the ability of a suppressive B cell factor (SBF) generated by culturing heat-aggregated IgG (HAIgG) with peripheral blood mononuclear leukocytes (PBL) from patients with RA and normal controls to suppress the pokeweed mitogen (PWM)-induced RF plaque-forming cell (PFC) response of normal PBL. RA patients generated less SBF than age-matched controls. Background suppression (supernatants obtained from PBL cultured without HAIgG) was similar in the RA patients and age-matched controls. To determine the effects of nonsteroidal antiinflammatory drug (NSAID) therapy on suppression, RA patients and age-matched controls were studied before and after NSAID therapy. NSAID therapy significantly reduced background suppression in RA patients who were not on immunosuppressive drugs and in age-matched controls, but there was no effect on SBF in RA patients or controls. There was a small increase in background suppression when NSAID were administered to RA patients on immunosuppressives, suggesting an ameliorative effect of NSAID in this group of patients, which tended to increase their level of suppression when compared with RA patients only on NSAID. Spontaneous RF-PFC were measured in normal controls and RA patients and were compared with suppressor activity. There were increased numbers of spontaneous RF-PFC in RA patients. Total suppressor activity was greatest in young adult controls, who also had the least RF-PFC. The percentage of suppression correlated inversely with the number of RF-PFC in patients and controls. Additionally, disease activity in RA as measured by total joint count and erythrocyte sedimentation rate (ESR) was shown to correlate inversely with total suppressor activity. We conclude that the PBL from patients with RA produce decreased SBF after HAIgG stimulation and that loss of suppression is also associated with aging. This study suggests a defect in IC-stimulated B cell suppressor activity in RA leading to decreased ability to suppress antibody and further IC formation. The combination of increased RF-PFC and decreased SBF suggests that there is defective B cell autoregulation in RA, which may be involved in the pathogenesis and chronicity of this disease.