GAIL BISHOP

..We have thus identified a novel genetic variant of hCD40 with a gain-of-function immune phenotype...

..This suggests that LMP1 utilizes a modified CD40 signaling pathway. Failure to regulate TRAFs may contribute to the enhanced capacity of LMP1 to activate B cells as well as promote B cell transformation...

..This review seeks to summarize these components, and to highlight recent advances in each area that contribute to a greater understanding of the complex processes involved in B-cell activation...

..Additionally, TRAF3(-/-) B cells displayed enhanced TLR-mediated expression of AID and Ig isotype switching. Thus, TRAF3 plays varied and cell type-specific, biological roles in TLR responses...

..This review summarizes current understanding of the nature of these interactions, and how they induce and regulate CD40 functions...

..TRAF3 is also important for signaling via innate immune receptors, as well as an oncogenic mimic of a normal receptor that is implicated in promoting both malignancies and autoimmunity...

..These include activation of kinases and transcription factors, and interactions with other signalling proteins, culminating in the induction or inhibition of biological functions...

..CD40-mediated B cell activation is mimicked by several biological response modifiers, as well as by a viral oncoprotein encoded by the Epstein-Barr virus (EBV)...

..Recently, advances have been made both in understanding how these various signals regulate B cell effector functions and in identifying many new receptor-ligand pairs that contribute to the regulation of B cell function by T lymphocytes...

..This review will summarize the known important biological roles of CD40, and discuss what is currently known about how CD40 signals...

..In addition, it shows synergy with signals delivered by the B cell antigen receptor and heightens CD40-mediated B cell activation, demonstrating that resiquimod can enhance antigen-specific responses in B lymphocytes...

..Both signals were partially dependent upon induction of TNF-alpha and IL-6, and the cytoplasmic adaptor molecule TNF receptor-associated factor 2 is involved in both R-848- and CD40-mediated differentiation...

..This review provides a brief overview of the EBV-encoded proteins involved in B-cell transformation, and the current state of knowledge about their roles in this process...

..Understanding both the biological effects of this receptor-ligand interaction, as well as how CD40 signaling pathways are controlled, adds to our detailed picture of the complex interplay between B and T cells...

..For each of these receptors, multiple mechanisms of TRAF regulation contribute to signal transduction and the ultimate effect on the B cell. Recent findings concerning these regulatory mechanisms are summarized in this overview...

..Furthermore, we find that the function of CTAR1, but not CTAR2, correlates with TRAF binding and present evidence that as yet unidentified cytoplasmic proteins may associate with LMP1 to mediate some of its signaling activities...

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..In contrast, TRAF2 appears to play a positive role in B cell differentiation, and this activity is apparent even when its binding site on CD40 is disrupted...

..MHC class II ligation thus blocks proximal signaling events in the CD95-mediated apoptotic pathway...

..Comparison of the amino acid sequence with other A beta chains that have been tested in signal transduction experiments suggests that amino acid 9 may be important to the signaling ability of class II A molecules...

..Interestingly, the role of PKD was dependent upon the association of CD40 with TRAF2, and was inhibited by the binding of TRAF3, revealing a novel functional link between these two classes of signaling molecules...

..In contrast, CD40 rescue was completely abrogated in TRAF6-deficient B cells, which showed reduced activation of Akt in response to CD40 engagement. These results reveal a new rapid mechanism to balance B cell activation and apoptosis...

..Several approaches show that ubiquitination and proteasomal activity are integral to TRAF2 degradation, and inhibition of this process potentiates CD40 signaling...

..Our results indicate a potentially important role for CD120b in the activation of IgM secretion and that TRAF2 is used by CD40 and CD120b in distinct ways...

..Further investigation into the potential usefulness of F. tularensis LPS as an adjuvant component of a more optimal subunit vaccine is warranted, as it is now clear that it is not biologically inactive, as assumed previously...

..These findings indicate that TRAF3 is a critical regulator of peripheral B cell homeostasis and may be implicated in the regulation of peripheral self-tolerance induction...

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..In addition, the dual stimulation increased cFos/AP-1 species in stimulated cells, effectively expanding the repertoire of AP-1 dimers as compared to singly stimulated B cells...

..Our findings argue against such a possibility and rather suggest that GABPbeta1S has a critical role in maintaining the transcriptional activity of the GABPalpha/beta complex...

..In this brief review, we highlight the current state of knowledge of the diverse roles of TRAF molecules in the functions of B lymphocytes...

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..These findings reveal potent biologic functions for T cell CD40 and suggest an additional means for amplification of autoimmune responses...

..Furthermore, CD40 stimulation led to phosphorylation of c-Jun on its activation domain, implicating CD40-mediated Jun kinase activation in the transcriptional regulation of IL-6 production...

..Furthermore, data suggest an indirect role for TNFR-associated factor-2 in the cooperative signaling...

..CD40 and CD120b used primarily divergent mechanisms to activate NF-kappaB, exemplifying how TNFR family members can use diverse mechanisms to mediate similar downstream events...

..Together, our findings highlight the central importance of TRAF3 in LMP1-mediated signaling, which is critical for EBV persistent infection and EBV-associated pathogenesis...

..Our data reveal that CD40 and LMP1 unexpectedly use TRAF3 in different ways, and that TRAF3 is required for LMP1-mediated activation of B cells...

..These effects were dependent upon TRAF2 and PKD activity. These findings suggest a model in which Btk contributes to the enhancement of the CD40 response by TRAF2 in a PKD-dependent manner...

..These findings demonstrate previously unappreciated roles for TRAF2 in signaling by TNF receptor family members, using an approach that facilitates the analysis of genes critical to the viability of whole organisms...

..Our data indicate that TRAF2 serves as the master regulator of TRAF degradation in response to CD40 signaling, and this function is dependent upon both the TRAF Zn domains and receptor binding position...

..Thus, signaling through the LMP1 cytoplasmic tail results in amplified and abnormal mimicry of CD40 functions in vivo, indicating possible ways in which LMP1 contributes to the pathogenesis of EBV-associated human disease...

..This suggests that Pim-1 could regulate the survival and proliferation of B cells...

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..These promising findings suggest that the nontoxic anti-inflammatory properties of HNK could be valuable for blocking the autoimmune response...

..These data demonstrate that TRAF6 acts as a critical adapter of both the Src/ERK1/2 and IKK/NF-kappaB proinflammatory signaling pathways in monocytes and macrophages...

..Together, our data indicate an important role of the TM domain of the MHC class II molecules in the intracellular trafficking and, consequently, antigen processing and presentation...

..These results support a paradigm where TNFR-associated factor 6 signaling downstream of CD40 alters the pattern of response of macrophages to TNF-alpha leading to induction of antimicrobial activity...

..The information to be gained can be used for small molecule drug design and other therapies that manipulate immunity in for vaccines, and treatment of autoimmune and malignant disease. ..

..What is the relationship between LMP 1 signals and autoantibody production? B. How does LMP1 expression affect the development and progression of autoimmune disease? ..

..This grant is critical to support our continuing efforts in training pre-doctoral students from diverse backgrounds for independent careers as immunologists, and also to providing geographic diversity in graduate training in immunology. ..

..To explore the role of TRAF5 in B cell activation. ..

..This project seeks to examine the mechanisms by which LMP1 affects B lymphocyte function, and how it mediates effects that contribute to pathogenesis of autoimmunity and B cell cancers. ..

..The information to be gained can be used for small molecule drug design and other therapies that manipulate immunity in for vaccines, and treatment of autoimmune and malignant disease. ..

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..abstract_text> ..

..This project seeks to examine the mechanisms by which LMP1 affects B lymphocyte function, and how it mediates effects that contribute to pathogenesis of autoimmunity and B cell cancers. ..