BAFF: a local and systemic target in autoimmune diseases - PubMed (original) (raw)

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BAFF: a local and systemic target in autoimmune diseases

I Moisini et al. Clin Exp Immunol. 2009 Nov.

Abstract

BAFF (B lymphocyte activating factor of the tumour necrosis factor family) is a vital homeostatic cytokine for B cells that helps regulate both innate and adaptive immune responses. Increased serum levels of BAFF are found in a number of different autoimmune diseases, and BAFF is found in inflammatory sites in which there is lymphoid neogenesis. BAFF antagonism has been used in several autoimmune disease models, resulting in B cell depletion, decreased activation of T cells and dendritic cells (DC) and a reduction in the overall inflammatory burden. BAFF, through its interaction with BAFF-R, is required for survival of late transitional, marginal zone and mature naive B cells, all of which are depleted by BAFF blockade. Through their interactions with TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BCMA (B cell maturation protein), BAFF and its homologue APRIL (a proliferation-inducing ligand), support the survival of at least some subsets of plasma cells; blockade of both cytokines results in a decrease in serum levels of immunoglobulin (Ig)G. In contrast, neither BAFF nor APRIL is required for the survival or reactivation of memory B cells or B1 cells. BAFF also helps DC maturation and interleukin (IL)-6 release and is required for proper formation of a follicular dendritic cell (FDC) network within germinal centres, although not for B cell affinity maturation. The clinical efficacy of BAFF blockade in animal models of autoimmunity may be caused both by the decline in the number of inflammatory cells and by the inhibition of DC maturation within target organs. Blockade of BAFF and its homologue APRIL are being explored for human use; several Phase I and II clinical trials of BAFF inhibitors for autoimmunity have been completed and Phase III trials are in progress.

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Figures

Fig. 1

Fig. 1

The interaction of BAFF (a B lymphocyte activating factor of the tumour necrosis factor family) and its homologue APRIL (a proliferation-inducing ligand) with the three BAFF receptors and with proteoglycans (PG) on B cells. BAFF binds to BAFF-R and TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) with high avidity and to BCMA (B cell maturation protein) with lower (human) or no (mouse) avidity, whereas APRIL binds only to TACI and BCMA. TACI-immunoglobulin (Atacicept) blocks both BAFF and APRIL, whereas anti-BAFF-R (anti-BLyS/Belimumab) blocks selectively only soluble BAFF.

Fig. 2

Fig. 2

Opsonized apoptotic particles and immune complexes containing nucleic acids are taken up into plasmacytoid dendritic cells (pDC) and B cells via Fc receptors and the B cell receptor (BCR), respectively. Activation of intracellular Toll-like receptors (TLRs) in pDC results in release of interferon (IFN)-α that stimulates myeloid dendritic cells (mDC) to up-regulate co-stimulatory molecules, and to make BAFF and other proinflammatory cytokines including interkeukin (IL)-6. Activation of TLRs in B cells up-regulates expression of BAFF (a B lymphocyte activating factor of the tumour necrosis factor family) receptors and increases BCR-mediated signalling. BAFF further up-regulates TLR expression, promotes B cell survival and, together with IL-6, promotes immunoglobulin class-switching and plasma cell differentiation, thus further increasing autoantibody titres. The activated myeloid dendritic cells (mDC) also act as antigen-presenting cells for T cells that help B cell responses. In BAFF transgenic mice, however, excess BAFF levels can drive the autoimmune response without the need for T cell help.

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