Peripheral deletion of rheumatoid factor B cells after abortive activation by IgG

Abstract

Rheumatoid factor (RF) B cells proliferate during secondary immune responses to immune complexed antigen and antigen specific T cells, but higher affinity RFs are not detected except in patients with rheumatoid arthritis and other autoimmune diseases. Consequently, there must exist highly efficient mechanisms for inactivation of these higher-affinity RF B cell clones under normal circumstances. Normal individuals express low affinity IgM rheumatoid factors (RFs) on peripheral B cells, but fail to express the higher affinity ''pathologic'' RFs that are associated with diseases such as rheumatoid arthritis (RA) (1). Evidence has shown that RF-expressing B cells are highly efficient antigenpresenting cells for multivalent, immune complexed antigen (2, 3) and may play a role in normal secondary immune responses (4, 5). Although T cells reactive to human IgG (hIgG) are lacking due to T cell tolerance, there are abundant T cells present during a secondary immune response able to recognize peptides derived from the antigen portion of an immune complex. Under normal circumstances, the provision of antigen together with T cell help results in clonal expansion, somatic mutation, and affinity maturation of B cells (6). The absence of higher-affinity RFs in normal individuals suggests that there exist very efficient mechanisms for the peripheral elimination of B cells expressing such higher affinity, somatically mutated RFs. However, the precise mechanisms of removal of these cells have not been established. Transgenic models of autoimmunity have supported and elaborated on previously proposed mechanisms for induction of B cell tolerance. These include physical elimination of self-reactive clones (deletion) and functional inactivation (anergy) followed by reduced life span (7-15). The current study shows that in vivo encounter of transgenic B cells which express a somatically mutated, monospecific, human IgM (hIgM) RF with soluble, deaggregated human IgG (DHGG) results in abortive activation of the RF B cells followed by cell death by a Fasindependent mechanism between 2 and 3 days after antigen encounter. RF B cells show no evidence of anergy after exposure to soluble hIgG, as they are unaffected in their ability to differentiate into antibody producing cells in the presence of antigen and T cell help. Indeed, the kinetics of abortive activation͞deletion and the lack of anergy provide an interval of opportunity for reactivation and survival of some RF B cells. This could potentially occur within the inflamed synovia of RA joints where the concentration of soluble IgG is lower than in plasma, and where both immune complexed antigen and antigen-specific T cells are present together with cytokines that promote B cell differentiation. We hypothesize that such stimulation within the inflammatory synovial environment may interfere with the normal process of activation induced deletion of higher affinity RF B cells in RA.

Inhibition of a vaccine-induced anti-tumor B cell response by soluble protein antigen in the absence of continuing T cell help

“…With regard to protein vaccines, there have been several hints of the vulnerability of germinalcenter B cells to soluble antigen, and it has been suggested that this vulnerability provides a mechanism for the elimination of autoreactive B cells (20,21). In a transgenic model, B cells expressing human IgM rheumatoid factor could be deleted by high doses (2 mg) of human IgG antigen (22). Ablation of the transgene was partial and slowly reversible, possibly because of the induction of CD4 ϩ T cell responses to the injected human IgG.…”

Genetic origin of IgG antibodies cloned by phage display and anti-idiotypic panning from three patients with autoimmune thrombocytopenia

“…They implicate a specific interaction of antibodies from IVIG (and therefore normal repertoires) especially with autoantibodies and B cell receptors derived from germ-line genes that are often used for the generation of autoantibodies. This interaction may control and down-regulate autoreactive B cells by one of several known mechanisms [46,47]. The anti-idiotypic interaction can now be further investigated at the molecular level by using the selected Fab for isolating the anti-idiotypic IVIG molecules from a phage display library from a healthy individual.…”

Rheumatoid Factors: Good or Bad for You?

“…Prior to the discovery of the role of TLRs in RF induction, studies using a murine model wherein transgenic mice express a human IgM RF to soluble human IgG demonstrated that in the absence of T-cell help RF B cells are deleted. RF B-cell activation in GCs only occurred in the presence of T-cell help [32]. Subsequently, CD40 signaling was identified as the minimal requirement to prevent deletion of RF B cells in this model [33].…”