Regulation of inherently autoreactive VH4-34B cells in the maintenance of human B cell tolerance

The study of human B cell tolerance has been hampered by difficulties in id entifying a sizable population of autoreactive B lymphocytes whose fate cou ld be readily determined. Hypothesizing that B cells expressing intrinsical ly autoreactive antibodies encoded by the VH4-34 heavy chain gene (VH4-34 c ells) represent such a population, we tracked VH4-34 cells in healthy indiv iduals. Here, we show that naive VH4-34 cells are positively selected and m ostly restricted to the follicular mantle zone. Subsequently, these cells a re largely excluded from the germinal centers and underrepresented in the m emory compartment. In healthy donors but not in patients with systemic lupu s erythematosus (SLE), these cells are prevented from differentiating into antibody-producing plasma cells. This blockade can be overcome ex vivo usin g cultures of naive and memory VH4-34 cells in the presence of CD70, IL-2, and IL-10. VH4-34 cells may therefore represent an experimentally useful su rrogate for autoantibody transgenes and should prove valuable in studying h uman B cell tolerance in a physiological, polyclonal environment. Our initi al results suggest that both positive and negative selection processes part icipate in the maintenance of tolerance in autoreactive human B cells at mu ltiple checkpoints throughout B cell differentiation and that at least some censoring mechanisms are faulty in SLE.