Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren’s syndrome

Abstract

BAFF (BLyS, TALL-1, THANK, zTNF4) is a member of the TNF superfamily that specifically regulates B lymphocyte proliferation and survival. Mice transgenic (Tg) for BAFF develop an autoimmune condition similar to systemic lupus erythematosus. We now demonstrate that BAFF Tg mice, as they age, develop a secondary pathology reminiscent of Sjögren’s syndrome (SS), which is manifested by severe sialadenitis, decreased saliva production, and destruction of submaxillary glands. In humans, SS also correlates with elevated levels of circulating BAFF, as well as a dramatic upregulation of BAFF expression in inflamed salivary glands. A likely explanation for disease in BAFF Tg mice is excessive survival signals to autoreactive B cells, possibly as they pass through a critical tolerance checkpoint while maturing in the spleen. The marginal zone (MZ) B cell compartment, one of the enlarged B cell subsets in the spleen of BAFF Tg mice, is a potential reservoir of autoreactive B cells. Interestingly, B cells with an MZ-like phenotype infiltrate the salivary glands of BAFF Tg mice, suggesting that cells of this compartment potentially participate in tissue damage in SS and possibly other autoimmune diseases. We conclude that altered B cell differentiation and tolerance induced by excess BAFF may be central to SS pathogenesis

B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: Longitudinal observations

“…Cross-sectional studies have documented elevated circulating levels of BLyS in variable percentages of patients with SLE, rheumatoid arthritis, Sjögren's syndrome, or human immunodeficiency virus infection (23,24,(33)(34)(35). The entry of at least 1 BLyS antagonist (anti-BLyS mAb) into clinical trials in SLE (26) underscores the need to fully delineate the "normal" fluctuations in BLyS expression among both healthy individuals and patients with SLE.…”

Clonality analysis of lymphoproliferative disorders in patients with Sjögren's syndrome

“…BAFF is a member of the tumour necrosis factor (TNF) superfamily, also called B lymphocyte stimulator (BLys), which specifically regulates B lymphocyte proliferation and survival, and has emerged as a potential survival factor for B cell lymphomas. Continuous B cell activation resulting from increased BAFF may lead to the development of B cell lymphoma in SS [20]. Furthermore, it has been considered that gradual progression from polyclonal to monoclonal in lacrimal or minor salivary glands may lead to lymphoma development in SS patients.…”

Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications

“…Excessive levels of the TNF family ligand B-lymphocyte stimulator (BLyS) have been demonstrated in RA synovial fluid. Approaches targeting the BLyS and other systems (like APRIL) to selectively eliminate the activated autoimmune lymphocytes in RA are under development [162] . Belimumab is a human recombinant IgG mAb which acts by binding BLyS protein and prevents the interaction with the B cell activating factor receptor.…”