mannose binding lectins

..Thus, human Sec24 isoforms expand the repertoire of cargo for signal-mediated ER export, but are in part functionally redundant...

..Here, we will discuss the molecular mechanisms involved in HIV-1 transmission and viral clearance. A better understanding of these processes is crucial to understand and develop strategies to combat transmission...

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..Our data also suggest that engagement of the MR by ManLAMs delivers a negative signal that interferes with the LPS-induced positive signals delivered by the Toll-like receptors...

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..Thus Langerin is a natural barrier to HIV-1 infection, and strategies to combat infection must enhance, preserve or, at the very least, not interfere with Langerin expression and function...

..In conclusion, MR-dependent phagocytosis is coupled neither to the activation of NADPH oxidase nor to the maturation of phagosomes until fusion with the Hck compartment and therefore constitutes a safe portal of entry for microorganisms...

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..New studies have also demonstrated that different ligand binding and/or sensing receptors collaborate for full and effective immune responses...

..Transient ablation of this DC subset by cytochrome c injection resulted in a failure of tolerance induction to cell-associated Ags, indicating that this DC subset is essential for tolerance induction by apoptotic cell clearance...

..This suggests that dermal LCs can mediate CHS and provides an explanation for previous differences observed in the two-model systems...

..Therefore, the crystal structure of LangA should be helpful for the development of new marker reagents selective for LCs and also of therapeutic compounds that may enhance the inhibitory role of Langerin towards HIV infection...

..Finally, we have shown that langerin ECD triggering with a specific mAb promotes global rearrangements of LC morphology. Our results open the way to the definition of a new membrane deformation mechanism...

..We propose that this is an important and previously unappreciated element of immunosurveillance that needs to be taken into account in the design of novel vaccine strategies...

..Collectively, these data identify a previously unrecognized role for AAMac-derived RELM-alpha in limiting the pathogenesis of Th2 cytokine-mediated pulmonary inflammation, in part through the regulation of CD4(+) T cell responses...

..Like its human counterpart, Mrc1 contains 30 exons and 29 introns. A protein module that resembles a subdomain of the B chain of the plant lectin Ricin has been found within the N-terminal cysteine-rich domain of the mannose receptor...

..Endocytosis of these ligands by MR may have implications for tissue homeostasis and immunity, including antigen presentation, in secretory organs...

..We use the structures to rationalize the carbohydrate binding specificities of Cys-MR and compare the recognition properties of Cys-MR with other beta-trefoil proteins...

..But there is a close relationship between dextran recognition and mannose/fucose recognition, with dextran- and mannose-conjugates co-localizing in intracellular compartments...

..The results are consistent with a role for langerin in internalization of both self and nonself glycoprotein antigens...

..Therefore, anti-Langerin antibodies localize a majority of CD8(+) DCs to non-T cell regions of mouse spleen, where they are distinct from adjacent macrophages...

..In this Review we describe new developments in the understanding of the biology of LCs and other langerin(+) DCs and discuss the challenges that remain in identifying the role of different DC subsets in tissue immunity...

..They are highly specialized leukocytes that serve immunogenic and tolerogenic purposes. Here, we review some aspects of LC biology, emphasizing those areas where LC are or may turn out to be special...

..The diversity of CLRs able to bind HIV-1 in skin DCs may reflect their ability to bind a range of microbial glycoproteins...

..Our results suggest an unexpected contribution of MR to splenic function through the recognition of sulphated ligands that could influence the filtering capability of this organ...

..We propose a structural model for the mannose receptor family where at least two conformations exist that may serve to regulate differences in ligand selectivity...

..Furthermore, the Q-rich domain with the preceding 18 amino acids of Gts1p bound mediators for RNA polymerase II...

..The intensity of Langerin expression reaches adult levels by 3 wk after birth. Early Langerin expression appears to correlate at least in part with the physical presence of Birbeck granules...

..Knowledge of which APC subsets express MR will assist the design of experiments to address its immunological functions. Here the expression of MR by MHC class II positive APC in non-lymphoid organs of the mouse is described...

..These data point to a novel function of the adhesion receptor DC-SIGN as an efficient DC-specific Ag receptor that can be used as a target to induce viral and antitumor immunity...

..It opens the possibility for a delivery pathway for MR carbohydrate recognition domains (CRDs) ligands that needs to be investigated further...

..In conclusion, inflammatory dendritic epidermal cells but not Langerhans cells are expressing CD206 in situ and use it for receptor-mediated endocytosis...

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..SFI1/GNA and similar fusion proteins offer a novel and effective approach for delivering haemolymph active toxins by oral administration, which could be used in crop protection by expression in transgenic plants...

..These data suggest a role for both the MR and CLEVER-1 in directing the traffic of cancer cells within the lymphatic system...

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..The results suggest an ER-export mechanism in which transmembrane and luminal determinants mediate oligomerization required for efficient recruitment of ERGIC-53 into budding vesicles via the C-terminal COPII-binding phenylalanine motif...

..These data support a role for the MR in T helper cell type 2 cytokine-driven, immune responses and suggest a non-M(phi) contribution to sMR production in vivo...

..However, further studies are needed to define the in vivo contribution of MBL to clearance and destruction of HIV, the reasons for low neutralization by MBL and ways that MBL anti-viral effects can be augmented...

..Langerin is a potent LC-specific regulator of membrane superimposition and zippering, representing a key molecule to trace LCs and to probe BG function...

..In conclusion, we have evidenced a novel regulatory role of MPs that promotes their candidacy as a vaccine against fungi...

..The study extends the application of PCA to carbohydrate-mediated protein-protein interactions of low affinity...

..These studies have identified SIGNR1 as a major MR for fungal and other pathogens present on specific subsets of Mphi...

..The presence of an ER retention motif in a protein of the ER-Golgi intermediate compartment has important implications for the retention mechanism mediated by this signal...

..Therefore, DEC-205 may have a different specificity as an antigen uptake receptor or contribute to an alternative DC function...

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..Like most lectins, MBPs display weak intrinsic affinity for monovalent sugar ligands, but bind avidly to multivalent ligands...

..Thus DEC-205 is a novel endocytic receptor that can be used by dendritic cells and thymic epithelial cells to direct captured antigens from the extracellular space to a specialized antigen-processing compartment...

..In addition to yeast studies, insights have also come from investigations into several inherited disorders that have recently been attributed to defects in the secretory pathway...

..Our data suggest that induction of BG is a consequence of the antigen-capture function of Langerin, allowing routing into these organelles and providing access to a nonclassical antigen-processing pathway...

..Understanding these fundamental processes of cell biology will be crucial for the elucidation and treatment of many inherited and acquired diseases, such as cystic fibrosis, Alzheimer's disease and viral infections...

..These findings suggest that ERGIC-53 may function as a molecular chaperone for the transport from ER to Golgi of a specific subset of secreted proteins, including coagulation factors V and VIII...

..This study demonstrates that the mannose receptor is expressed on tissue macrophages and on subsets of vascular and lymphatic endothelial cells. Thus, the mannose receptor maybe a marker of the so-called reticuloendothelial system...

..A role for sMR in the immune response is proposed based on its binding properties, regulation by cytokines, and the previous discovery of putative ligands for the cysteine-rich domain of the mannose receptor in lymph nodes and spleen...

..The new IgG anti-CD207 mAbs should be useful for further research on LCs and dendritic cells including an evaluation of the consequences of antigen delivery within anti-CD207 mAbs in vivo...

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..Macrophages accumulate in adipose tissue and possibly participate in metabolic complications in obesity. Macrophage number varies with adipose tissue site and weight loss, but whether this is accompanied by phenotypic changes is unknown...

..The putative LC-derived DC among skin emigrants and in LN also showed strong intracellular staining of langerin...

..In the mannose receptor, these multiple weak interactions are achieved through several active CRDs in a single polypeptide chain rather than by oligomerization of polypeptides each containing a single CRD...

..Differences obtained here are due to the unique arrangement of carbohydrate recognition domains on each mannose-specific lectin available for mannosylated ligand recognition...

..Blocking of MR may provide a new approach to controlling inflammation and cancer metastasis by targeting the lymphatic vasculature...

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..This protein does not appear to be STAT6 since neither an anti-STAT6 antibody nor a STAT6 consensus oligonucleotide altered factor binding...

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..Within the last two decades, these receptors have been the subject of considerable research. This article focuses on the rapidly growing body of knowledge with respect to the functions of LC receptors...

..In order to gain insight into the mechanisms responsible for this observation, the present study examined the cellular uptake of the mannosylated and deglycosylated recombinant proteins...

..It will be of interest to determine the role of lymphoid tissue-resident compared to skin-derived langerin+ DC...

..Moreover, the identification of SIGNR1 as a receptor for ManLAM will enable in vivo studies to investigate the role of DC-SIGN in M. tuberculosis pathogenesis...

..Generation of tolerogenic DCs may aid the exploration of new therapeutic strategies to promote tolerance to autoantigens and prevent disease development...

..These data suggest that dermal dendritic-appearing macrophages comprise a novel part of the innate immune response in the resident skin immune system...

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..We suggest that this property of KLH may represent a novel further mechanism by which this molecule may exert its efficacy when co-administered with others antigens in immunotherapeutic protocols...

..These findings imply that antigen does not require intracellular diversion to access the cross-presentation pathway, because it can enter the pathway already during endocytosis...

..Such a link would be of special relevance in the context of replacement therapy where mechanisms of central and peripheral tolerance have not been established during ontogeny because of the absence of the antigen...

..These findings expand our current understanding of the immunopharmacological functions of silibinin, and may prove useful in the development of therapeutic adjuvants for acute and chronic DC-associated diseases...

..This work reveals a new role for CRP in modulating the immune system by inhibiting DC differentiation, maturation and functions mainly through FcgammaRIIa/CD32...

..The broader DEC-205 tissue expression in man is relevant to clinical DC targeting strategies and DEC-205 functional studies...

..They exhibit an activated phenotype in allergen-induced lung inflammation and may play significant roles in asthma pathogenesis...

..Cumulatively, our results show for the first time that PTX might impair differentiation, maturation and function of human MDDCs in vitro, suggesting an additional mechanism of its immunomodulatory activity...

..i) It is required for mannose recognition; and (ii) it modulates the tendency of MR to self-associate, effectively regulating the avidity of the CR domain for sulfated sugar ligands...

..This study is the first demonstration that although SARS-CoV does not productively infect human Mphi or DC, it appears to exert differential effects on Mphi and DC maturation and functions, which might contribute to SARS pathogenesis...

..Our results establish Langerin-DTR mice as a unique tool to study LC function in the steady state and to explore their relative importance compared with dDC in orchestrating skin immunity and tolerance...

..By using a similar knockin strategy involving a diphtheria toxin receptor (DTR) fused to EGFP, we demonstrated that LCs were dispensable for triggering hapten-specific T cell effectors through skin immunization...

..The actual role of Langerhans cells in local immunity seems to be to suppress unfavorable reactions initiated by virus intrusion...

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..Our data support the hypothesis that DEP (and to a lesser extent CEP) regulate important functional aspects of human DC, supporting an adjuvant role for this material...

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..These data suggest fundamentally different routes of VLP uptake by DC and LC. Despite these differences, VLP taken up by DC and LC were each able to prime naive CD8(+) T cells and induce cytolytic effector T cells in vitro...

..Finally, in situ hybridization analysis demonstrated that the transcript encoding this lectin was found in a number of highly endothelialized sites as well as in chondrocytes in cartilaginous regions of the embryo...

..Together, these results suggest a substantial role for MMR in the binding and transmission of HIV-1 by macrophages...

..Indeed, Nef induces CD4(+) T cell bystander activation by a novel mechanism involving DCs, thus promoting virus dissemination...

..We suggest that several clinical situations, including autoimmunity and certain infectious diseases, can be influenced by the antigen-specific tolerogenic role of DCs...

..Thus, as for human immunodeficiency virus (HIV), which is captured by the same receptor, DC-SIGN-mediated entry of M. tuberculosis in DCs in vivo is likely to influence bacterial persistence and host immunity...

..neoformans and lymphocyte proliferation in response to CnM. These studies demonstrate the surprising fact that dendritic cells are the most efficient accessory cells for CnM...

..In addition, they differ in their ability to mediate endocytic and phagocytic events and in their intracellular destinations. Together, they represent a unique group of multidomain, multifunctional receptors...

..Langerin gene transfected into mouse fibroblasts induces the formation of Birbeck granule-like structures, that would permit a better understanding of the function of Birbeck granules...

..These findings suggest that concatenation between MMR and TMC may play an important role in the activation of monocytic leukemia cells. TMC may become a good candidate to target MMRs of leukemia cells...

..The goal is to understand how this transport receptor controls two different blood coagulation factors and hopefully use the knowledge to benefit people with hemophilia A and venous thrombosis. ..

..The strength application include the expertise and experience of the principal investigator Dr. Benoff and her research team, the novel approach to analysis of the problem. ..

..Without this exposure, many of them would have likely pursued different career paths. ..

..Outcome is test of hypothesis, and possible mechanism explaining infertility associated with low sperm counts or idiopathic male infertility, tools for diagnosis, and hope for treatment. ..

..Controls will include fertile donors and fertile men with varicocele. ..

..Without this exposure, many of them would have likely pursued different career paths. ..

..The goal is to understand how this transport receptor controls two different blood coagulation factors and hopefully use the knowledge to benefit people with hemophilia A and venous thrombosis. ..

..The answers sought have fundamental significance, and should provide information leading to novel therapeutic approaches to enzyme replacement and gene therapy for lysosomal storage diseases. ..

..These studies will not only improve our understanding of how iron absorption is normally regulated, but may also suggest new strategies for treating disorders of excessive iron absorption. ..

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..We will determine genetic changes that contribute to emergence of Salmonella that are infecting warm-blooded animals and cause typhoid or non-typhoid disease in humans. ..

..The training faculty for this program work in approximately 30,000 square feet of laboratory space used exclusively for biomedical research ..

..By understanding how the fim genes are regulated, we may be able to treat urinary tract infections in the future through dietary changes or drugs that affect the regulatory cascade that leads to type 1 pilus expression. ..

..Studies proposed here will serve as model ones to provide a spectrum of novel information regarding shear effects on bacterial adhesion, particularly in connection to the bacterial pathogenesis. ..

..This proposed 5 year mentored program will allow me to develop a unique model system that will provide the basis for many long term projects and collaborations and further my development into an independent investigator. ..

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..The goal is to develop a formulation of rhMBL or a derivative that could be used as prophylactic and/or therapeutic agents against influenza virus infection. ..

..The results of this study will help us understand the role of proline transport in S. aureus infections. ..

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..Completion of these aims will add significantly to our understanding of the immunopathogenesis of cryptococcosis and may suggest novel approaches to the prevention and treatment of this life-threatening mycosis. ..

..In particular, electron microscopy and light microscopy will be used to attempt to demonstrate the development of Gaucher cells in the chimeric mice. ..

..It is anticipated that findings in this animal model will provide a basis for investigation of wound macrophage phenotypes in human disease, and may identify targets for therapeutic interventions in abnormal healing. ..

..neoformans and Cryptococcosis and to recommend new and future research initiatives and prioritize these. ..

..Targeted mutagenesis in ES cells will be exploited to produce animal models of selected CA deficiencies...

..Finally, our finding that induction of DC chimerism is critical to prevent GVHD leads us, in aim 3, to determine the nature of the circulating precursor that repopulates DCs in a clinically relevant model for allo-BMT. ..

..As broad concepts are being studied, the knowledge gained should also be applicable to the development of vaccines against other infectious diseases. ..

..This type of study could also highlight the specific inflammatory processes that may be useful therapeutic targets in preventing treatable acute lung infections from becoming chronic debilitating diseases. ..

..Continued research on this project will identify novel therapeutic targets for the prevention and treatment of AIDS- related lung infections and improve the health of persons living with HIV. ..

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..In some cases, the genomic DNA specifying the enzymes will be isolated to characterize the genomic organization, gene localization, and the nature of the mutation underlying the altered expression of the carbonic anhydrase gene...

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..These studies should provide valuable insights into LC regulation of skin immune responses and may lead to improved prevention or treatment of skin GVHD, a major medical problem in transplantation therapy of patients with malignancies. ..

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..We are proposing to use Langerhans cell deficient mice that we have recently developed to investigate the precise molecular mechanisms that underlie the function of these cells. ..

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..Finally, our finding that induction of DC chimerism is critical to prevent GVHD leads us, in aim 3, to determine the nature of the circulating precursor that repopulates DCs in a clinically relevant model for allo-BMT. ..

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