Autoantibodies from long-lived ‘memory’ plasma cells of NZB/W mice drive immune complex nephritis

Abstract

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.

Bone marrow analysis of immune cells and apoptosis in patients with systemic lupus erythematosus

“…24,25 Recently, Cheng et al demonstrated that bone marrow plasma cells continuously secreted anti-dsDNA antibodies and caused immune complex nephritis after they were transferred from NZB/W mice to Rag1À/À mice. 26 This result is consistent with the results of the present study, which showed that the increased percentage of plasma cells in the bone marrow of SLE patients correlated with increased antidsDNA antibody and serum complement levels, which are significantly associated with lupus nephritis. This indicates that increased numbers of plasma cells in the bone marrow may trigger lupus by secreting anti-dsDNA antibodies; this increases the formation of anti-dsDNA-containing immune complexes, which then activate the complement system.…”

Ligation of CD180 inhibits IFN-α signaling in a Lyn-PI3K-BTK-dependent manner in B cells

“…Because the terminal differentiation of GC B cells results in plasma cells, 43 and memory B cells are CD180-positive, we deduced that the downregulation of CD180 may participate in the differentiation of B cells into plasma cells but not to memory B cells. Recently, Cheng et al 44 showed that the adoptive transfer of CD138 1 anti- body-secreting cells (ASCs) from the spleen of NZB/W mice into Rag1-deficient mice could result in elevated serum autoantibody levels, immune complex nephritis, and a reduced survival rate. Moreover, transplantation of lipogranulomas, which are rich in anti-RNP auto-ASCs, leads to auto-antibody production in recipients.…”

Autoreactive CD19+CD20− Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis

“…Residual autoreactive PCs after anti-CD20 depletion could continuously secrete pathogenic autoantibodies and either contribute to the chronic condition or lead to reactivation of the disease (15,(36)(37)(38). To assess the impact of CD19 and CD20 mAbs on humoral immune responses, we measured the serum and CNS Ab levels after a single injection of the mAbs at day 7 after EAE induction (Fig.…”