Cracking the BAFF code.
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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ABSTRACT: The interaction between Receptor Activator of NF-κB Ligand (RANKL) and its receptor RANK is essential for the differentiation and bone resorbing capacity of the osteoclast. Osteoprotegerin (OPG), a soluble homodimer, acts as a decoy receptor for RANKL and thus inhibits osteoclastogenesis. An imbalance in the RANKL/RANK/OPG axis, with decreased OPG and/or increased RANKL, is associated with diseases that favor bone loss, including osteoporosis. Recently, we established a yeast surface display system and screened libraries of randomly mutated RANKL proteins to identify mutations that abolish binding to OPG while preserving recognition of RANK. These efforts yielded several RANKL variants possessing substantially higher affinity for RANK compared to their wild-type (WT) counterpart. Using recombinant RANKL mutant proteins, we find those with increased affinity for RANK produce more robust signaling in osteoclast lineage cells and have greater osteoclastogenic potential. Our results are the first to document gain of function RANKL mutations. They indicate that the physiological RANKL/RANK interaction is not optimized for maximal signaling and function, perhaps reflecting the need to maintain receptor specificity within the tumor necrosis factor superfamily (TNFSF). Instead, we find, a biphasic relationship exists between RANKL/RANK affinity and osteoclastogenic capacity. In our panel of RANKL variants, this relationship is driven entirely by manipulation of the kinetic off-rate. Our structure-based and yeast surface display-derived insights into manipulating this critical signaling axis may aid in the design of novel anti-resorptive therapies as well as provide a paradigm for design of other receptor-specific TNF superfamily ligand variants. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.Journal of Cellular Biochemistry 04/2015; DOI:10.1002/jcb.25191 · 3.37 Impact Factor
Retrovirology 01/2014; 11(Suppl 1):O45. DOI:10.1186/1742-4690-11-S1-O45 · 4.77 Impact Factor
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ABSTRACT: The therapeutic benefit of depleting B cells in rheumatoid arthritis (RA) has refocused attention on B cells with increasing awareness on their role in autoimmunity and their function beyond autoantibody production. The rapid increase in our comprehension of B-cell pathobiology is progressively opening novel perspectives in the area of B cell-targeted therapies with the expectation to define more specific approaches able to preserve the homeostasis of the humoral response while disrupting the pathogenic components. In parallel, B-cell activity in RA is starting to be explored in its clinical value, in search of novel biomarkers embedded in the pathogenic process that could help classifying the disease and predicting its heterogeneous outcome beyond inflammation dynamics. In this review, we summarize current knowledge on the multiple roles that B cells play in several aspects of RA. We also analyze their distribution and potential function in different anatomic compartments with specific reference to the main sites in which the disease may be sustained and exert its detrimental effects: the systemic circulation, synovium, bone marrow, and draining lymph nodes. We also highlight novel data encouraging further research in the field of biomarkers related to B cells and their regulatory factors.04/2014; 2014:1-14. DOI:10.1155/2014/681678