Journal of leukocyte biology
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Toll-like receptors (TLRs) have been identified as a major class of pattern-recognition receptors. Recognition of pathogen-associated molecular patterns (PAMPs) by TLRs, alone or in heterodimerization with other TLR or non-TLR receptors, induces signals responsible for the activation of genes important for an effective host defense, especially proinflammatory cytokines. Although a certain degree of redundancy exists between signals induced by the various TLRs, recent studies have identified intracellular pathways specific for individual TLRs. ⋯ In addition to the activation of the innate-immune response, TLR-mediated recognition represents a link between the innate- and acquired-immune systems, by inducing the maturation of dendritic cells and directing the T helper responses. Alternatively, recent data have also suggested TLR-mediated escape mechanisms used by certain pathogenic microorganisms, especially through TLR2 induction of anti-inflammatory cytokines. Finally, the crucial role of TLRs for the host defense against infections has been strengthened recently by the description of patients partially defective in the TLR-activation pathways.
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Mast cells (MCs) have long been considered as critical effector cells during immunoglobulin (Ig)E-mediated allergic disease and immune response to parasites. Recent studies, however, suggest that this understanding of MC function is incomplete and does not consider the complex roles that MCs play in adaptive and innate immunity. The added function gives an innovative vision of regulation of immune responses and the development of autoimmune diseases. ⋯ However, MCs exhibit an array of molecules involved in cell-cell and cell-extracellular matrix adhesion, mediating delivery of costimulatory signals that empower those cells with an ability to react to multiple nonspecific and specific stimuli. Their tissue distribution and their capability to release many cytokines after stimulation indicate MCs as potential regulatory linkers between innate and acquired immunity. In this review, we will summarize some findings on the roles of MCs in innate and acquired immunity, on the molecular mechanism and signaling pathways, and on selective signals that induce discrete MC response and its ability to polarize adaptive-immune response.
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Although we tend to think that the immune system has evolved to protect the host from invading pathogens and to discriminate between self and nonself, there must also be an element of the immune system that has evolved to control the response to tissue injury. Moreover, these potential immune-regulatory pathways controlling the injury response have likely coevolved in concert with self and nonself discriminatory immune-regulatory networks with a similar level of complexity. ⋯ This remains a significant health care problem that has driven decades of basic and clinical research aimed at defining the functional effects of injury on the immune system. This review and update on our ongoing research efforts addressing the immunological response to injury will highlight some of the most recent advances in our understanding of the impact that severe injury has on the innate and adaptive immune system focusing on phenotypic changes in innate immune cell responses to Toll-like receptor stimulation.
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The CD14+CD16+ monocytes appear to be important to immune defense against infection, as these cells are very potent with respect to tumor necrosis factor (TNF) production, phagocytosis, and antigen presentation. Myeloablative high-dose chemotherapy (HDT) and subsequent autologous stem-cell transplantation (ASCT) are being used increasingly for therapy of hematological malignancies, but the pronounced immunosuppression renders the patients prone to infection. To determine the functional properties of CD14+CD16+ monocytes under these conditions, 15 patients with lymphoma or myeloma were examined. ⋯ The median fluorescence intensity of human leukocyte antigen (HLA)-DR expression on the CD14+CD16+ monocytes increased from 11 +/- 6 before Tx to 17 +/- 11 after Tx, and the production of TNF after lipopolysaccharide showed no remarkable difference (46+/-13 vs. 49+/-14 channels). At the same time, expression of TNF and of HLA-DR showed a dramatic decrease in the CD14++ monocytes. Taken together after stem-cell Tx, the function of the CD14++ monocytes is impaired, and the functional properties of CD14+CD16+ monocytes recover, indicating that these cells may be important for defense against infections post-ASCT.
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In recent studies, evidence has been provided for complement activation early during the onset of experimental sepsis. Excessive production of the anaphylatoxin C5a thereby appears to elicit various harmful effects. ⋯ Besides its known, other proinflammatory effects, recent work suggested an inhibitory role of C5a for innate-immune functions of phagocytic cells (phagocytosis, reactive oxygen species production, chemotaxis) during experimental sepsis. This review article provides an overview of the important role of C5a/C5aR activation for the onset and development of sepsis.