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APC Function (apc + function)
Selected AbstractsThe immune status of Kupffer cells profoundly influences their responses to infectious Plasmodium berghei sporozoitesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2005Nick Steers Abstract Multi-factorial immune mechanisms underlie protection induced with radiation-attenuated Plasmodia sporozoites (,-spz). Spz pass through Kupffer cells (KC) before invading hepatocytes but the involvement of KC in protection is poorly understood. In this study we investigated whether ,-spz-immune KC respond to infectious spz in a manner that is distinct from the response of naive KC to infectious spz. KC were isolated from (1) naive, (2) spz-infected, (3) ,-spz-immune, and (4) ,-spz-immune-challenged C57BL/6 mice and examined for the expression of MHC class I and II, CD40 and CD80/CD86, IL-10 and IL-12 responses and antigen-presenting cell (APC) function. KC from ,-spz-immune-challenged mice up-regulated class I and costimulatory molecules and produced elevated IL-12p40, relative to naive KC. In contrast, KC from naive mice exposed to infectious spz down-modulated class I and IL-12p40 was undetectable. Accordingly, KC from spz-infected mice had reduced APC function, while KC from ,-spz-immune-challenged mice exhibited augmented APC activity. The nearly opposite responses are consistent with the fact that spz challenge of ,-spz-immune mice results in long-lasting sterile protection, while infection of naive mice always results in malaria. [source] Analysis of somatic APC mutations in rare extracolonic tumors of patients with familial adenomatous polyposis coliGENES, CHROMOSOMES AND CANCER, Issue 2 2004Hendrik Bläker Patients with familial adenomatous polyposis coli (FAP) carry heterozygous mutations of the APC gene. At a young age, these patients develop multiple colorectal adenomas that consistently display a second somatic mutation in the remaining APC wild-type allele. Inactivation of APC leads to impaired degradation of ,-catenin, thereby promoting continuous cell-cycle progression. The role of APC inactivation in rare extracolonic tumors of FAP patients has not been characterized sufficiently. Among tissue specimen from 174 patients with known APC germ-line mutations, we identified 8 tumors infrequently seen in FAP. To investigate the pathogenic role of APC pathway deregulation in these lesions, they were analyzed for second-hit somatic mutations in the mutational cluster region of the APC gene. Immunohistochemistry was performed to compare the expression pattern of ,-catenin to the mutational status of the APC gene. Exon 3 of the ,-catenin gene (CTNNB1) was analyzed for activating mutations to investigate alternative mechanisms of elevated ,-catenin concentration. Although CTNNB1 mutations were not observed, second somatic APC mutations were found in 4 of the 8 tumors: a uterine adenocarcinoma, a hepatocellular adenoma, an adrenocortical adenoma, and an epidermal cyst. These tumors showed an elevated concentration of ,-catenin. No APC mutations were seen in focal nodular hyperplasia of the liver, angiofibrolipoma, and seborrheic wart. This is the first study reporting second somatic APC mutations in FAP-associated uterine adenocarcinoma and epidermal cysts. Furthermore, our data strengthen a role for impaired APC function in the pathogenesis of adrenal and hepatic neoplasms in FAP patients. © 2004 Wiley-Liss, Inc. [source] Upregulation of co-stimulatory molecule expression and dendritic cell marker (CD83) on B cells in periodontal diseaseJOURNAL OF PERIODONTAL RESEARCH, Issue 3 2002Rangsini Mahanonda T cells and their cytokines are well known for their important role in the pathogenesis of periodontitis. To date, the role of antigen presenting cells (APCs), which are known to be critical in the regulation of T cell response, has been poorly investigated in periodontitis. In this study, we analyzed the expression of co-stimulatory molecules (CD80 and CD86) and CD83, which is a marker of mature dendritic cells, on gingival cells that were isolated from severe periodontitis tissues, with the use of flow cytometry. Significant upregulation of CD86 and CD83 expression was detected in periodontitis lesions, and most of this occurred on B cells. In vitro peripheral blood mononuclear cell cultures showed that stimulation with different periodontopathic bacteria, that included Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Prevotella intermedia, and Actinomyces viscosus, upregulated both CD86 and CD83 expression on B cells. Therefore, the presence of plaque bacteria may be responsible for the enhanced expression seen in vivo on gingival B cells. APC function by bacterial-activated B cells was further investigated using allogeneic mixed leukocyte reactions. After 24 h culture with either A. actinomycetemcomitans or P. gingivalis, these activated B cells performed as potent APCs in mixed leukocyte reactions, and they stimulated T cells to produce high levels of gamma interferon and minimal interleukin-5. In conclusion, periodontopathic bacterial-induced B cell activation with upregulation of CD86 and CD83 may be associated with enhanced APC function. The results of this study suggest, therefore, that infiltrated gingival B cells have a possible role as APCs in the regulation and maintenance of local T cell response in periodontitis. [source] Functional immaturity of cord blood monocytes as detected by impaired response to hepatocyte growth factorPEDIATRICS INTERNATIONAL, Issue 4 2001Qi Jiang AbstractBackground: Monocytes as antigen-presenting cells play an important role in host defense and transplantation. However, there are little reports on cord blood monocytes, and the role of monocytes in cord blood transplantation is largely unknown. Methods and Results: There are several cytokines affecting monocyte function. These include interferon-,, interleukin-4, interleukin-10, granulocyte macrophage-colony stimulating factor and hepatocyte growth factor (HGF). We investigated the effect of these cytokines on antigen-presenting capacity (APC) of cord and adult blood monocytes. Using either mononuclear cells or purified CD4+ T cells as responder cells, HGF enhanced APC of adult monocytes most effectively among these cytokines. In contrast, cord blood monocytes failed to respond to HGF. As HLA, costimulatory and adhesion molecules may affect APC function, we examined these antigens of monocytes following HGF stimulation. The HGF upregulated integrin ,5 subunit (CD49e) and intercellular adhesion molecule-1 (CD54) was expressed in adult blood monocytes, but not in cord blood. In kinetic studies, HGF downregulated c-met protein/HGF receptor expression of adult monocytes in lower concentrations and at shorter incubation time as compared with that of cord blood. Conclusions: The results suggest that impaired response of cord blood monocytes to HGF may be responsible, in large part, for their functional immaturity. [source] B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity,ANNALS OF NEUROLOGY, Issue 3 2010Martin S. Weber MD Objective Clinical studies indicate that anti-CD20 B-cell depletion may be an effective multiple sclerosis (MS) therapy. We investigated mechanisms of anti-CD20-mediated immune modulation using 2 paradigms of experimental autoimmune encephalomyelitis (EAE). Methods Murine EAE was induced by recombinant myelin oligodendrocyte glycoprotein (rMOG), a model in which B cells are considered to contribute pathogenically, or MOG peptide (p)35-55, which does not require B cells. Results In EAE induced by rMOG, B cells became activated and, when serving as antigen-presenting cells (APCs), promoted differentiation of proinflammatory MOG-specific Th1 and Th17 cells. B-cell depletion prevented or reversed established rMOG-induced EAE, which was associated with less central nervous system (CNS) inflammation, elimination of meningeal B cells, and reduction of MOG-specific Th1 and Th17 cells. In contrast, in MOG p35-55-induced EAE, B cells did not become activated or efficiently polarize proinflammatory MOG-specific T cells, similar to naive B cells. In this setting, anti-CD20 treatment exacerbated EAE, and did not impede development of Th1 or Th17 cells. Irrespective of the EAE model used, B-cell depletion reduced the frequency of CD4+CD25+Foxp3+ regulatory T cells (Treg), and increased the proinflammatory polarizing capacity of remaining myeloid APCs. Interpretation Our study highlights distinct roles for B cells in CNS autoimmunity. Clinical benefit from anti-CD20 treatment may relate to inhibition of proinflammatory B cell APC function. In certain clinical settings, however, elimination of unactivated B cells, which participate in regulation of T cells and other APC, may be undesirable. Differences in immune responses to MOG protein and peptide may be important considerations when choosing an EAE model for testing novel B cell-targeting agents for MS. ANN NEUROL 2010 [source] Presentation of arthritogenic peptide to antigen-specific T cells by fibroblast-like synoviocytesARTHRITIS & RHEUMATISM, Issue 5 2007Chinh N. Tran Objective To assess the ability of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) to function as antigen-presenting cells (APCs) for arthritogenic autoantigens found within inflamed joint tissues. Methods Human class II major histocompatibility complex (MHC),typed FLS were used as APCs for murine class II MHC,restricted CD4 T cell hybridomas. Interferon-, (IFN,),treated, antigen-loaded FLS were cocultured with T cell hybridomas specific for immunodominant portions of human cartilage gp-39 (HC gp-39) or human type II collagen (CII). T cell hybridoma activation was measured by enzyme-linked immunosorbent assay of culture supernatants for interleukin-2. Both synthetic peptide and synovial fluid (SF) were used as sources of antigen. APC function in cocultures was inhibited by using blocking antibodies to human class II MHC, CD54, or CD58, or to murine CD4, CD11a, or CD2. Results Human FLS could present peptides from the autoantigens HC gp-39 and human CII to antigen-specific MHC-restricted T cell hybridomas. This response required pretreatment of FLS with IFN,, showed MHC restriction, and was dependent on human class II MHC and murine CD4 for effective antigen presentation. Furthermore, FLS were able to extract and present antigens found within human SF to both the HC gp-39 and human CII T cell hybridomas in an IFN,-dependent and MHC-restricted manner. Conclusion RA FLS can function as APCs and are able to present peptides derived from autoantigens found within joint tissues to activated T cells in vitro. In the context of inflamed synovial tissues, FLS may be an important and hitherto overlooked subset of APCs that could contribute to autoreactive immune responses. [source] What can humans learn from flies about adenomatous polyposis coli?BIOESSAYS, Issue 9 2002Angela I.M. Barth Somatic or inherited mutations in the adenomatous polyposis coli (APC) gene are a frequent cause of colorectal cancer in humans. APC protein has an important tumor suppression function to reduce cellular levels of the signaling protein ,-catenin and, thereby, inhibit ,-catenin and T-cell-factor-mediated gene expression. In addition, APC protein binds to microtubules in vertebrate cells and localizes to actin-rich adherens junctions in epithelial cells of the fruit fly Drosophila (Fig. 1). Very little is known, however, about the function of these cytoskeletal associations. Recently, Hamada and Bienz have described a potential role for Drosophila E-APC in cellular adhesion,1 which offers new clues to APC function in embryonic development, and potentially colorectal adenoma formation and tumor progression in humans. BioEssays 24:771,774, 2002. © 2002 Wiley Periodicals, Inc. [source] Novel function of DUSP14/MKP6 (dual specific phosphatase 14) as a nonspecific regulatory molecule for delayed-type hypersensitivityBRITISH JOURNAL OF DERMATOLOGY, Issue 5 2007Y. Nakano Summary Background, Nonspecific unresponsive states of delayed-type hypersensitivity (DTH) to unrelated antigens are induced in mice by a single administration of hapten. In these studies, we found a unique regulatory mechanism of contact hypersensitivity (CHS) mediated by nonspecific suppressor factor (NSF) induced by the intravenous injection of hapten-conjugated syngeneic spleen cells. NSF is a , 45-kDa protein released from the macrophage-like suppressor cells and binds selectively to dendritic cells (DCs). Moreover, NSF-treated DCs release a second , 20-kDa NSF (NSFint). Objectives, To try and identify NSF and characterize its function. Methods, The suppressor activity was evaluated by inhibition of the passive transfer of CHS by the effector cells sensitized with hapten and the antigen-presenting cell (APC) activity of hapten-primed draining lymph node cells (DLNCs) to induce CHS. NSF-containing supernatants obtained from the culture of spleen cells from mice that had been injected intravenously with oxazolone-conjugated syngeneic spleen cells 7 days before were prepared and purified with a Green A dye-affinity column, DEAE column and Sephacryl S-200 column. Then, samples of molecular mass of , 45 kDa were separated by native-PAGE (polyacrylamide gel electrophoresis) and nonreducing sodium dodecyl sulphate (SDS)-PAGE. After confirming the suppressor activity of proteins of , 45 kDa separated by native-PAGE, samples were separated by nonreducing SDS-PAGE, transferred onto polyvinylidene difluoride membranes and analysed using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Results, Proteins of , 45 kDa eluted from a Sephacryl S-200 column and the slice of native-PAGE gel exhibited the strong suppressor activity. Analyses using MALDI-TOF mass spectrometry and MASCOT algorithm of the protein bands around 45 kDa separated by nonreducing SDS-PAGE identified NSF as a 22·5-kDa protein, dual specific phosphatase 14/MAP-kinase phophatase-6 (DUSP14/MKP6), which functions as a negative regulator of the MAP-kinase signalling. Western blot analyses revealed that recombinant DUSP14 (rDUSP14) exists as the mixture of 22·5-kDa monomer and 45-kDa dimer under nonreducing conditions, and monomers under reducing conditions. Treatment with rDUSP14 at 4 °C for 2 h suppressed the ability of effector cells to transfer CHS dose dependently and the APC function of DLNCs to induce CHS. Epicutaneous application of rDUSP14 immediately after challenge inhibited the subsequent CHS expression. rDUSP14 was bound specifically by major histocompatibility complex class II (Ia)-positive spleen cells (presumably DCs). The suppressor activity of NSF was neutralized by anti-DUSP14 monoclonal antibody. Expression of DUSP14 mRNA in the spleen was upregulated parallel to the unresponsive state induced by hapten-conjugated cells. NSF, NSFint and rDUSP14 exhibited the phosphatase activity towards p -nitrophenyl phosphate in vitro as alkaline phosphatase. Conclusions, These studies indicate for the first time that NSF is a dimer of DUSP14 secreted by macrophage-like suppressor cells by stimulation with hapten-conjugated cells and exerts a regulatory function on CHS through DCs as a secreted phosphatase. [source] |