Article

Cracking the BAFF code

Department of Immunology, Monash University, Alfred Hospital, Melbourne, Victoria, Australia.
Nature Reviews Immunology (Impact Factor: 33.84). 08/2009; 9(7):491-502. DOI: 10.1038/nri2572
Source: PubMed

ABSTRACT 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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    • "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.
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    • "Addition of BAFF to cultured splenocytes leads to the specific survival of T2 B cells and BAFF overexpression in BAFF transgenic (Tg) mice leads to the expansion of the T2 B cell compartment [10]. In contrast, BAFF does not affect B cell development in the BM and this is explained by the lack of BAFFR expression on developing B cells prior to the immature B cell stage (reviewed in [11]). Hence, BAFF is required for the maturation and survival of mature B-2 B cells, but not B-1 B cells [12] "
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    • "BLyS signaling through BR3 governs transitional differentiation and mature B cell survival BLyS signaling via BR3 is indispensable for successful TR differentiation and for mature pre-immune B cell survival. Genetic deficiency in either BLyS or BR3 stalls B cell development at the late TR stages (reviewed in [1] [35]), and yields profound reductions in FO and MZ B cells. Similar effects are observed after treatment with BLyS neutralizing antibody or soluble decoy receptors [20] [21] [36] [37]. "
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