MICHAEL PAUL CANCRO

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..2008) show that BAFF, a tumor necrosis factor (TNF) family member, promotes B cell survival by hindering interactions between TNF-receptor-associated factors, blocking their negative regulation of nonclassical NF-kappaB activity...

..This review discusses the mechanism of BLyS action on B cells, its role in SLE, and specific targeting of BLyS in the treatment of SLE...

..Together, these findings set the stage for integrated analyses of how age-related changes at the molecular, cellular and population levels interact to yield the overall aging phenotype...

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..Volcanic ash clouds disrupted the 2010 ESF/EMBO meeting on B cells and protection. Nevertheless, the delegates who did make it to Catalonia put together their own programme of talks covering a range of themes from mutualism to epigenetics...

..Differential expression of the three BLyS receptors during differentiation and activation provides related yet distinct homeostatic niches for follicular, marginal zone, and memory B-cell subsets...

..Together, these observations suggest that positive selection is a critical feature in the establishment and maintenance of all lymphocyte pools, prompting re-evaluation of the underlying biological rationale for this process...

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..Our results indicate that the size and dynamics of most B cell subsets shift with age, suggesting age-associated alterations in both intrinsic and microenvironmental factors that govern these processes...

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..BLyS responsiveness thus balances peripheral selection against cell numbers, providing an elastic system that varies selective stringency based on homeostatic demands...

..These findings suggest that compromised TR B cell generation in NOD mice yields relaxed TR selection, affording autoreactive specificities access to mature pools...

..Together, these findings establish the coupling of BcR signaling with Bcmd/BR3 expression as a fundamental aspect of follicular B cell selection, survival, and activation...

..Our rapidly expanding understanding of BLyS and its receptors may eventually afford novel pharmacologic strategies aimed at the direct manipulation of peripheral B cell selection and homeostasis...

..As our understanding of this system advances, molecular targets for manipulating humoral immunity in both health and disease should be revealed...

..These data suggest a novel role for TACI in anti-chromatin B cell homeostasis and differentiation...

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..Further, within each niche, relative fitness to compete for available cytokine is determined by exogenous inputs via adaptive and innate receptor systems, affording intramural hierarchies that determine clonotype composition...

..We propose a model whereby these "distal" homeostatic adjustments relax the stringency of specificity based selection, affording a potential explanation for the increased frequency of autoreactive specificities with age...

..Two recent Immunity papers link peripheral tolerance with the ability of developing B cells to capture BAFF. These findings suggest that an increase in effective BAFF levels leads to autoreactive B cell maturation...

..These observations suggest a model whereby the regulation of BLyS receptors by differentiative and stimulatory cues yield characteristic BLyS receptor signatures, thus specifying homeostatic niche and competitive advantage...

..Two recent Immunity articles (Enzler et al., 2006; Sasaki et al., 2006) probe the roles of Nuclear Factor kappa-B (NF-kappaB) pathways in survival and differentiation mediated by B cell activation factor of the TNF family (BAFF)...

..Interestingly, these autoantibody-inducing CD4+ T-cell responses are also present in the thymus. Therefore, an elevated frequency of autoantibody-inducing CD4+ T cells predisposes lupus-prone mice to the development of autoantibodies...

..Our findings identify a molecular mechanism for the reliance of primary B cells on continuous BR3 and BCR signaling, as well as for the gradual resistance to negative selection that is acquired during B cell maturation...

..Overall, this study demonstrates the efficacy of B lymphocyte-directed therapy via in vivo BLyS neutralization for the prevention of autoimmune diabetes...

..Together, these findings show that memory B cells and natural antibody-secreting cells are BLyS-independent and suggest that these pools can be separately manipulated...

..These findings link the negative regulatory functions of FcgammaRIIB with BLyS-mediated B-cell survival...

..A refined understanding of these relationships should yield insight into the selection and maintenance of B cell subsets, as well as an appreciation of how homeostatic mechanisms may contribute to immunosenescence...

..BLyS family ligands and receptors also play a role in activated and memory B cell pools, suggesting they might likewise be targeted to promote or delete particular antigen-experienced subpopulations in a similar way...

..Thus, IL-27p28, as a natural antagonist of gp130-mediated signaling, may be useful as a therapeutic for managing inflammation mediated by cytokines that signal through gp130...

..However, although BLyS enhances viability among TLR stimulated B cells, APRIL does not, suggesting that TACI but not BLyS receptor 3 may share survival promoting pathways with TLRs...

..Instead, an optimal translational research model supports a bidirectional flow of information from animal models to clinical research...

..Consequently, these results have wide implications for understanding the mechanisms regulating immune tolerance to nucleic acids and pathogen-associated molecules...

..Moreover, it implies a developmentally regulated coupling of BCR and BAFF receptors at the transitional stages and beyond...

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..The resulting antisera will be assessed for broadly neutralizing activity in vitro using a well-established virus pseudotype assay. ..

..We will assess whether reduced available BLyS levels will restore normal selective stringency by in vivo treatment with soluble TACI Ig or neutralizing anti-BLyS antibody in normal and autoimmune models. ..

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..In this regard, the ISDR will foster research and research training that bears directly on control and manipulation of the immune system in health and disease. ..

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..In the fourth aim, the life span, homing characteristics, and repertoire diversity of recirculating mature B-cells in aged marrow will be determined, to assess the identity and functional significance of this population. ..

..A/WySnJ mice. ..

..We will assess whether reduced available BLyS levels will restore normal selective stringency by in vivo treatment with soluble TACI Ig or neutralizing anti-BLyS antibody in normal and autoimmune models. ..