Cracking the BAFF code

Department of Immunology, Monash University, Alfred Hospital, Melbourne, Victoria, Australia.
Nature Reviews Immunology (Impact Factor: 34.99). 08/2009; 9(7):491-502. DOI: 10.1038/nri2572
Source: PubMed


The tumour necrosis factor (TNF) family members B cell activating factor (BAFF) and APRIL (a proliferation-inducing ligand) are crucial survival factors for peripheral B cells. An excess of BAFF leads to the development of autoimmune disorders in animal models, and high levels of BAFF have been detected in the serum of patients with various autoimmune conditions. In this Review, we consider the possibility that in mice autoimmunity induced by BAFF is linked to T cell-independent B cell activation rather than to a severe breakdown of B cell tolerance. We also outline the mechanisms of BAFF signalling, the impact of ligand oligomerization on receptor activation and the progress of BAFF-depleting agents in the clinical setting.

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    • "B-cell activating factor (BAFF)-transgenic mice develop a lupus-like illness with the production of anti-DNA antibodies and development of glomerulonephritis suggesting a pathogenic role for BAFF in SLE [14] [20] [27]. Moreover, compared with normal subjects, BAFF concentrations are higher in patients with various autoimmune conditions [26]. On March 9, 2011, the US Food and Drug Administration approved belimumab, a fully human anti-BAFF monoclonal antibody, as a new B-cell-specific treatment for SLE. "
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    ABSTRACT: Recently B-cell activating factor (BAFF) was identified by our group and others as a novel therapeutic target for the treatment of autoimmune diseases. To expand upon this, we utilized microarrays to screen for molecules upregulated in B cells from BAFF-inhibited mice with lupus-like disease and identified metabotropic glutamate receptor 3 (Grm3). In addition to confirming the expression of this receptor in B cells, a synthetic agonist of Grm3 was found to downregulate B cells and ameliorate autoimmune symptoms in mice. Conversely, a Grm3 antagonist increased B-cell numbers and further aggravated disease. Thus, these results suggest that activation of Grm3 ameliorates lupus-like disease in mice by reducing B cell numbers. Not only do the findings presented in this study increase our understanding of the inhibitory signals initiated on the surface of B cells, but they also identity a novel potential target for the treatment of autoimmune diseases. Copyright © 2015. Published by Elsevier Inc.
    Clinical Immunology 06/2015; 160(2). DOI:10.1016/j.clim.2015.05.016 · 3.67 Impact Factor
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    • "BAFF and APRIL are produced by innate immune cells [22] such as neutrophils [23], macrophages, monocytes, dendritic cells (DCs) or follicular DCs [24], but also T cells [25], B cells [26] or non-hematopoietic cells such as fibroblastlike synoviocytes from patients with rheumatoid arthritis [27] or salivary gland and conjunctival epithelial cells from patients with Sj€ ogren's syndrome [28] [29]. Receptors for BAFF and APRIL are mainly expressed by B cells but also by T cells, monocytes or DCs, indicating that the role of BAFF and APRIL extends beyond that of B cell biology [22]. An excess of BAFF may lead to development of autoimmune disorders in mice and humans [30e32]. "
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin. We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1+ neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β and IL-17A dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3+ T cells from murine fibrotic lungs ex vivo. Finally we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Our data therefore support a role for BAFF in the establishment of pulmonary fibrosis and a crosstalk between IL-1β, BAFF and IL-17A.
    Journal of Autoimmunity 10/2014; 56. DOI:10.1016/j.jaut.2014.08.003 · 8.41 Impact Factor
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    • "Besides, IgD-activated basophils have been shown to upregulate the production of IL-4 and IL-13 as well as of B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL; Chen et al., 2009). The last two factors are crucial for B cell survival and proliferation and together with IL-4 and IL-13 can promote IgG and IgA class switch other than IgM secretion (Mackay and Schneider, 2009). The importance of IL-6 was underlined for both MC-induced B cell proliferation and IgA switching and for the survival and antibody production of plasma cells driven by basophils. "
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    ABSTRACT: It has been proven that both resting and activated mast cells (MCs) and basophils are able to induce a significant increase in proliferation and survival of naïve and activated B cells, and their differentiation into antibody-producing cells. The immunological context in which this regulation occurs is of particular interest and the idea that these innate cells induce antibody class switching and production is increasingly gaining ground. This direct role of MCs and basophils in acquired immunity requires cell to cell contact as well as soluble factors and exosomes. Here, we review our current understanding of the interaction between B cells and MCs or basophils as well as the evidence supporting B lymphocyte-MC/basophil crosstalk in pathological settings. Furthermore, we underline the obscure aspects of this interaction that could serve as important starting points for future research in the field of MC and basophil biology in the peculiar context of the connection between innate and adaptive immunity.
    Molecular Immunology 10/2014; 63(1). DOI:10.1016/j.molimm.2014.02.016 · 2.97 Impact Factor
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