Unexpected development of autoimmunity in BAFF‐R‐mutant MRL‐ lpr mice

Summary BAFF‐R is the predominant receptor that mediates B‐cell activating factor (BAFF)‐dependent B‐cell signalling and plays a critical role in late‐stage B‐cell maturation and survival. BAFF has been implicated in the development of autoimmunity and systemic lupus erythematosus (SLE). To define the role of BAFF‐R in autoimmunity and SLE, we crossed A/WySnJ mice with MRL‐ lpr mice and generated BAFF‐R‐mutant MRL‐ lpr mice. The BAFF‐R mutation markedly impaired the development of immature, mature and marginal zone B cells in the spleens of MRL‐ lpr mice. Unexpectedly, the BAFF‐R mutation in MRL‐ lpr mice did not result in decreased autoantibody production, hypergammaglobulinaemia or immune complex‐mediated glomerulonephritis. Rather, the ability of BAFF‐R‐mutant lpr splenic B cells to produce immunoglobulins in vitro was not decreased, although germinal centre formation, antibody response and B‐cell proliferation were impaired. Further studies found increased numbers of B cells in the bone marrow of BAFF‐R‐mutant MRL‐ lpr mice compared to the BAFF‐R‐intact lupus mice. ELISPOT analysis revealed that BAFF‐R‐mutant MRL‐ lpr mice had more antibody‐secreting cells in their bone marrow than the control mice. Thus, these findings could explain the development of autoimmunity and hypergammaglobulinaemia observed in BAFF‐R‐mutant MRL‐ lpr mice.