Mature B Cells Preferentially Lose Tolerance in the Chronic Graft-versus-Host Disease Model of Systemic Lupus Erythematosus

Abstract

Chronic graft-vs-host (cGVH) disease is a well-characterized systemic lupus erythematosus (SLE) model. Induction of cGVH in anti-DNA H chain knockin (3H9KI) transgenic mice results in specific activation of anti-dsDNA B cells. In this study, we show that B cells from 3H9KI mice were activated by cGVH even when adoptively transferred into irradiated JHT−/− recipients that lack endogenous B cells. This process of activation was reflected by high autoantibody titers and changes in phenotypic markers. We have used this system to characterize the particular B cell subsets that were responsible for secreting autoantibodies during cGVH response. We isolated splenic B cell subsets based on their expression of specific cell surface markers and used them in our adoptive transfer studies. We found that mature B cells were the most vulnerable to the allostimulus and were the major source of autoantibodies compared with immature B cells. The greater susceptibility of mature B cells to become activated and thereby lose tolerance was unanticipated and has implications for maintenance of peripheral tolerance and for the development of autoimmunity. Furthermore, of the mature B cells, marginal zone B cells were particularly responsible for mounting the initial response to the cGVH stimulus. This observation underscores the critical role of marginal zone B cells in activation and production of autoantibodies.