Background Autoantibodies contribute significantly to the pathogenesis of systemic lupus erythematosus (SLE). The long-lived plasma cells (LLPC) secreting such autoantibodies are refractory to conventional immunosuppressive treatments. Although they are generated long before the disease becomes clinically apparent, it is unknown whether their generation continues in the established disease.
Objectives Here, we analyze the generation of autoreactive LLPCs in lupus-prone NZB/W F1 mice over their lifetime, and LLPC regeneration after depletion.
Methods BrdU pulse-chase experiments were used to follow the establishment of the LLPS compartment. Bortezomib and cyclophosphamide therapy was used to deplete the LLPCs.
Results Autoreactive LLPCs are established in the spleen and bone marrow of lupus-prone mice very early in ontogeny, before week 8 and before the onset of symptoms. The generation of LLPCs then continues throughout life. LLPC counts in the spleen plateaued by week 10, but continued to increase in the bone marrow. When LLPCs are depleted by the proteasome inhibitor bortezomib, their numbers regenerate within two weeks. Persistent depletion of LLPCs was achieved only by combining a shot of bortezomib with maintenance therapy, e.g., cyclophosphamide, depleting the precursors of LLPCs or preventing their differentiation into LLPCs.
Conclusions In lupus-prone NZB/W F1 mice, autoreactive LLPCs are generated throughout life. Their sustained therapeutic elimination requires both the depletion of LLPCs and the inhibition of their regeneration.
Disclosure of Interest : None declared
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.