Autoantibodies are central to the pathogenesis of several autoimmune diseases including systemic lupus erythematosus. Plasma cells secrete these autoantibodies, but the anatomical sites of these cells are not well defined. Here, we found that although dsDNA-specific plasma cells in NZB/W mice were present in spleen and bone marrow, a large number were in the kidneys and their number correlated with the serum dsDNA-IgG titer. We observed renal plasma cells only in mice with nephritis, where they located mainly to the tubulointerstitium of the cortex and outer medulla. These cells had the phenotypic characteristics of fully differentiated plasma cells and, similar to long-lived bone marrow plasma cells, they were not in cell cycle. In patients with lupus nephritis, plasma cells were often present in the medulla in those with the most severe disease, especially combined proliferative and membranous lupus nephritis. The identification of the kidney as a major site of autoreactive plasma cells has implications for our understanding of the pathogenesis of lupus nephritis and for strategies to deplete autoreactive plasma cells, a long-standing therapeutic aim.
Expressing a wild mouse Fcgr2b promoter variant in C57BL/6 mice enhances germinal center responses and increases affinity maturation and autoantibody production.
Siglec-G is a member of the sialic acid–binding Ig-like lectin (Siglec) family expressed on all B cells. Siglec-G–deficient mice show a large expansion of the B1 cell compartment, demonstrating the crucial role of Siglec-G as an inhibitory receptor on this cellular subset. Although Siglec-G–deficient mice did not develop spontaneous autoimmunity, mice double-deficient for Siglec-G and the related Siglec protein CD22 did show autoimmunity at an older age. In this study, we addressed the question of whether loss of Siglec G on its own affects disease severity in animal models of rheumatoid arthritis and systemic lupus erythematosus. Siglec-G–deficient mice showed moderately increased clinical severity and higher inflammation of the knee joints following collagen-induced arthritis, when compared with control mice. The Siglec-G–deficient mouse was also backcrossed to the autoimmune prone MLR/lpr background. Although both Siglec-G–deficient and control MRL/lpr mice developed a lupus-like disease, Siglec-G–deficient MRL/lpr mice showed an earlier occurrence of autoantibodies; a higher lymphoproliferation of B and T cells; and an earlier onset of disease, as shown by proteinuria and glomerular damage in the kidney. Moreover, Siglec-G–deficient female mice showed a significantly reduced survival compared with female control MRL/lpr mice. Thus, the loss of the inhibitory receptor Siglec-G led to a moderate exacerbation of disease severity and early onset in both collagen-induced arthritis and spontaneous lupus nephritis in MRL/lpr mice.
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