Background/Purpose: Autoantibodies contribute significantly to the pathogenesis of systemic lupus erythematosus (SLE). The long-lived plasma cells (LLPC) secreting such autoantibodies are unfortunately refractory to conventional immunosuppressive treatments. Although generated long before the disease becomes clinically apparent, the kinetic of their generation in established disease is unclear. 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 over two weeks in mice of different age were used to analyze the generation of LLPC. Treatments were performed using Bortezomib, cyclophosphamide and a combination of both for very short (36h), short (5 days) and “longterm” treatment (15 and 30 days). Plasma cell numbers were quantified using flowcytometry. Autoreactive plasma cells were analyzed using ELIspot.

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. After depletion of LLPCs by the proteasome inhibitor bortezomib, their numbers regenerate within two weeks. A persistent, therapeutic depletion of LLPCs was achieved only by combining a short treatment with bortezomib with a longterm depletion of plasma cell precursors.

Conclusion: In lupus-prone NZB/W F1 mice, autoreactive LLPCs are generated throughout life. Their sustained therapeutic elimination requires both, depletion of LLPCs and the inhibition of their regeneration by specific depletion of their precursors.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/successfull-long-term-depletion-of-memory-plasma-cells-requires-a-combined-depletion-of-plasma-cells-and-their-precurors-in-nzbw-mice/