Study of plasma cell repertoire in systemic lupus erythematosus and rheumatoid arthritis

Autoimmune diseases are a class of diseases that result from the loss of tolerance to self-antigens. The B lymphocyte is a major player in humoral immune responses by secreting antibodies (also called immunoglobulins). During B cell development, immunoglobulins (lgs) undergo V(D)J recombination and somatic hypermutations to generate binding diversity. During these processes, antibodies against self-antigens (autoantibodies) may be generated as byproducts. Autoantibody-producing B cells are usually eliminated by immune tolerance mechanisms in the bone marrow and periphery. However, immune tolerance is broken in autoimmune diseases for unclear reasons and results in the overproduction of autoantibodies. This dissertation explores the potential mechanisms leading to a break B cell tolerance in two autoimmune diseases, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).;In patients with SLE, 60% of circulating plasmablasts produce auto- and poly-reactive antibodies with an enrichment of VH replacement products. A proportion of these auto-/poly-reactive antibodies cross-react with the viral-capsid antigens (VCA) from Epstein-Barr virus (EBV), and the VH replacement is further enriched in this group of antibodies. These results identify that EBV viral antigens are the potential cause for the enrichment of VH replacement products and production of pathogenic auto-/poly-reactive antibodies in SLE patients.;In patients with RA, 20% of circulating plasmablasts produce anticitrullinated protein antibodies (ACPAs). About 60% of these ACPAs cross-react with the outer membrane antigens and/or citrullinated enolase from Porphyromonas Gingivalis (P. Gingivalis). Germ-line reversions of some ACPAs completely eliminated their reactivity to citrullinated RA autoantigens but retained their reactivity to P. Gingivalis antigens. These results suggest that circulating plasmablasts in RA patients produce ACPAs and this process may be, in part, initiated by the anti-P. Gingivalis immune responses.;In summary, our study is the first to characterize the antibody repertoire of circulating plasmablasts in SLE and RA patients. Because circulating plasmablast repertoire closely represent the ongoing immune responses, our study suggests that the ongoing immune responses accelerate the production of autoantibodies. In addition, exogeneous microbial antigens may help the initial selection of the autoantibody-producing B cells in SLE and RA.