A link between B cell receptor expression and autoantibody production in rheumatoid arthritis
By now, it is a well known fact, that B cells play an important role in the development of autoimmunity. On the one hand, they are the precursors of the antibody-secreting plasmablasts and memory cells; on the other hand they also act as antigen-presenting cells.
Various cells of the immune system express a plethora of receptors that bind to the
Fc-portion of immune complexes containing IgG (Fc-gamma-receptors, FcγR), but
B cells and plasma cells only express the low affinity FcγRIIb. This receptor has repressive functions and mediates the deletion of autoreactive B cells and the inhibition of IgG secretion, thereby helping to preserve B cell tolerance.
Human autoimmune diseases that are characterized by an abnormal production of autoreactive antibodies have been suspected to come along with impaired FcγRIIb function. Alterations of the expression of FcγRIIb on B cells have been shown for Lupus erythematosus and several other autoimmune diseases, but until now, data have been lacking for rheumatoid arthritis.
In a recently published paper in the journal Arthritis Research and Therapy (1) a group of scientists from the University of Chile has now made an attempt to close this gap. They studied the activation of B cells and the expression of B cell receptors in healthy people and in rheumatoid arthritis patients before and after onset of anti-tumor necrosis factor (anti-TNF) therapy. They correlated these data to the autoantibody profile of the patients by determining their ACPA status (ACPA is the abbreviation for autoantibodies to citrullinated protein antigens). For this purpose they used an ELISA test for autoantibodies against modified and citrullinated vimentin (anti-MCV). These antibodies have been described to be highly specific for rheumatoid arthritis. (2)
Diego Catalan and his coworkers observed a higher frequency of activated B cells as defined by increased expression of the costimulatory molecule CD 86 in rheumatoid arthritis patients than in healthy controls.
Simulataneously, memory B cells and plasmablasts from rheumatoid arthritis patients exhibited reduced FcγRIIb expression. This down regulation of FcγRIIb expression was associated with elevated levels of MCV autoantibodies.
After six months of treatment with an anti-TNF biological drug the proportion of B cells expressing CD 86 had decreased, paralleled by normalized FcγRIIb expression in naïve B cells from patients who responded to the therapy. However, this effect of TNF alpha was not sufficient to prevent the down regulation of FcγRIIb in memory B cells of the patients. This was reflected in stably raised MCV titres during that period of time.
Other studies e.g. by Pascale Nicaise-Roland et al., (3) have demonstrated that changes of antibody levels only become significant after 18 months of TNF-alpha treatment. A complete restoration of the physiological B cell phenotype and considerably lower antibody titres may possibly occur during a longer time span.
The results of this study will certainly add to a better understanding of the molecular mechanisms that are involved in the regulation of B cell function and their contribution to the autoimmune processes that are effective in rheumatoid arthritis.
