Immunoglobulin production by cultured lymphocytes of patients with rheumatoid arthritis : association with disease severity

Abstract

The synthesis of immunoglobulin (Ig) in cultures of mononuclear cells from the blood of patients with recent onset rheumatoid arthritis (RA) was studied. B lymphocytes were activated with mitogenic activators, pokeweed mitogen and Staphylococcus aureus Cowan I, and with Epstein-Barr virus (EBV). Ig production was assayed by counting the number of Ig-secreting cells and by determining the concentration of secreted Ig in the culture medium. The patients were followed by medical examinations, radiography, and clinical laboratory tests at six month intervals for two years. Mitogen-induced Ig synthesis by the cells of patients was significantly decreased compared to healthy subjects. The decreased responses were evident already at diagnosis before any disease-modifying anti-rheumatic medication was started. The mechanism of decreased responses were then studied by supplementing the cultures with modifying agents to examine the contribution of B cells, T cells and monocytes to the impaired Ig synthesis. Phytohaemagglutinin-induced interleukin-2 (IL-2) production was also studied. The low responses of rheumatoid lymphocytes to mitogens is, according to these experiments, due to poor helper function, possibly mediated by reduced production of IL-2. Further, the association of the in vitro responses with disease outcome was studied. Impaired mitogen-induced IgM production, as well as decreased PHA-induced IL-2 release, at the onset of disease, associated with joint destructions two years later. EBY -induced Ig response was associated with the disease: cultured mononuclear cells of patients with severe disease were not able to down-regulate excessive Ig synthesis in long term cultures. When used as a test high EBY-induced Ig synthesis predicted with a high probability the development of joint erosions and a poor outcome of disease. The in vitro assessment of immune functions may make it possible to develop tests which identify already in the early phase of disease the patients in risk to have destructive disease.