It is now well accepted that plasma cells can become long-lived (memory) plasma cells and secrete antibodies for months, years or a lifetime. However, the mechanisms involved in this process of humoral memory, which is crucial for both protective immunity and autoimmunity, still are not fully understood. This article will address a number of open questions. For example: Is longevity of plasma cells due to their intrinsic competence, extrinsic factors, or a combination of both? Which internal signals are involved in this process? What factors provide external support? What survival factors play a part in inflammation and autoreactive disease? Internal and external factors that contribute to the maintenance of memory long-lived plasma cells will be discussed. The aim is to provide useful additional information about the maintenance of protective and autoreactive memory plasma cells that will help researchers design effective vaccines for the induction of life-long protection against infectious diseases and to efficiently target pathogenic memory plasma cells.

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

ObjectivesWe have previously shown that both short- and long-lived plasma cells (PCs) significantly contribute to autoantibody production in NZB/W mice as a model of lupus nephritis. The aim of this study was to determine the role of autoreactive long-lived (memory) PCs refractory to immunosuppression and B cell depletion in the pathogenesis of systemic lupus erythematosus.MethodsSplenic CD138+ antibody-secreting cells (ASCs) from >6-month-old NZB/W mice with high titres of anti-dsDNA autoantibodies or from Balb/c mice 5 days after secondary immunisation with ovalbumin (OVA) were adoptively transferred to immunodeficient Rag1−/− mice, in which the development of nephritis was investigated by measuring proteinuria. Total IgG and IgM as well as anti-dsDNA and anti-OVA antibody levels were followed up by ELISA. After 21 weeks the recipient mice were sacrificed so that PCs in spleen and bone marrow could be analysed using ELISPOT and flow cytometry and renal immunohistology performed.ResultsThe adoptive transfer of NZB/W and anti-OVA ASCs resulted in the continuous generation of anti-dsDNA antibodies and anti-OVA antibodies, respectively, exclusively by long-lived PCs that had homed to the spleen and bone marrow of recipient Rag1−/− mice. Rag1−/− mice generating autoantibodies including anti-dsDNA had reduced survival, proteinuria and immune complex nephritis with C1q, C3, IgG and IgM deposits 21 weeks after transfer.ConclusionsThese findings demonstrate that autoantibodies exclusively secreted by long-lived (memory) PCs contribute to autoimmune pathology and should be considered as candidate targets for future therapeutic strategies.

Long-lived plasma cells (PCs) not only provide protective humoral immunity, they are also an essential component of the autoreactive immunologic memory that may drive chronic immune responses in systemic autoimmunity, such as systemic lupus erythematosus (SLE). The therapeutic relevance of their targeting has been demonstrated in preclinical models and severe, treatment-refractory cases of autoimmune diseases using the proteasome inhibitor bortezomib. Herein, we describe in detail the dynamic serologic changes and effects on immune effector cells in eight SLE patients receiving a median two cycles of 1.3 mg/m intravenous bortezomib. Upon proteasome inhibition, immunoglobulin levels gradually declined by ∼30%, associated with a significant reduction of autoantibodies, and serum complement whereas B-cell activation factor levels increased. While proteasome inhibition was associated with a significant depletion of short- and long-lived PCs in peripheral blood and bone marrow by ∼50%, including those with a distinctly mature CD19 phenotype, their precursor B cells and T cells largely remained unaffected, resulting in a rapid repopulation of short-lived PCs after bortezomib withdrawal, accompanied by increasing autoantibody levels. Collectively, these findings identify proteasome inhibitors as a promising treatment option for refractory SLE, but also indicate that PC depletion needs to be combined with targeted B-cell therapies for sustained responses in systemic autoimmunity.