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Development of autoimmune nephritis in genetically asplenic and splenectomized BAFF transgenic mice

Abstract

B cell activating factor belonging to the TNF family (BAFF or BLyS) is a critical B cell survival factor essential for B cell maturation. BAFF transgenic (Tg) mice develop autoimmunity resembling Systemic Lupus Erythematosus (SLE) in a T cell-independent but toll-like receptor (TLR) signalling-dependent manner, requiring TLR-induced innate B cell-derived pro-inflammatory autoantibody deposition in the kidneys. Importantly, neutralizing BAFF in the clinic shows efficacy in patients with SLE, confirming its critical role in the progression of this disease in both humans and mouse models. The specific B cell types that produce autoantibodies in BAFF Tg mice are TLR-activated innate marginal zone (MZ) B cells and B1 cells, but not follicular B cells. Interestingly, in BAFF Tg mice MZ-like B cells infiltrate salivary glands whereas B1 B cells infiltrate the kidneys. To ascertain the relevance of B1 and MZ-like B cells in the development of nephritis in BAFF Tg mice, we generated genetically asplenic as well as splenectomized BAFF Tg animals. BAFF Tg mice born without a spleen lack MZ B cells, have very reduced B1a B cell numbers but a normal B1b B cell compartment. Loss of these B cell subsets failed to protect BAFF Tg mice against nephritis indicating that B1b B cells are an important subset for the development of autoimmune nephritis in BAFF Tg mice. Thus the spleen is dispensable for the development of autoimmune nephritis in BAFF Tg mice and points toward a pathogenic role for innate B1 B cells. Identifying similar innate B cells in humans may offer the possibility of more targeted B cell therapies.

Type Journal
Authors Fletcher, C. A.; Groom, J. R.; Woehl, B.; Leung, H.; Mackay, C.; Mackay, F.:
Publisher Name J AUTOIMMUN
Published Date 2011-01-01 00:00:00
Published Volume 36
Published Issue 2
Published Pages 125-34
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?10957_11371/11 Fletcher JA_.pdf