Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this article, the mechanisms by which infection at a distant site could lead to ReA and whether they could explain the association of ReA with HLA-B27 have been discussed. We propose that ReA synovitis is primarily due to specific synovial T-cell proliferation to fragments of the triggering bacterial found in the joint. Nonspecific T cells amplify synovitis with antibodies playing only a secondary role. First, we have shown that the triggering bacterial antigen is present in a nonviable form in ReA synovium and that this, not cross-reactive joint autoantigen, stimulates the specific synovial immune response. Second, the studies of the humoral immune response in ReA have been reviewed. Further evidence of bacterial persistence in the joint comes from work demonstrating intrasynovial bacteria-specific antibody synthesis. Continuing maturation of the antibody response also points to persisting antigen. In enteric but not genitourinary ReA, the humoral response is mainly IgA, implying chronic stimulation of the gut mucosa. Analysis of the molecules against which the humoral response is directed has shown no difference between yersinia arthritis and yersiniosis, but in CTA, the response to the 57kD and 59kD antigens differs from CT urethritis suggesting they may be arthritogenic. Finally, the antibody response may be absent in ReA patients rendering antibody titres diagnostically less useful and confirming their secondary role in the pathogenesis of synovitis. Third, studies of cellular response in ReA have been analyzed. We show there is a specific synovial MNC proliferative response to fragments of the triggering bacteria found in the joint, which is potentially of diagnostic use. The proliferation is due to CD4+ and CD8+ T cells and restricted by MHC class I and II antigens. This antigen-specific T-cell response is accompanied by an antigen-independent recruitment of nonspecific T cells, which may contribute to the amplification of synovitis. The importance of the synovial APC in determining the synovial immune response is unarguable but the exact mechanisms are unclear. Further details on the possible role of HLA-B27 in the presentation of arthritogenic peptides and on the exact identity of the antigenic epitopes recognized in ReA must await analysis of a large panel of T-cell clones. Finally, it is hoped that advances in this field will lead to specific and effective immunologic therapies or vaccines for this currently untreatable disease.
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PMID:Antigenic responses in reactive arthritis. 156 9

Murine gut epithelial cells, endowed with MHC class II-restricted antigen-presenting function, express membrane Ia molecules, which are not recognized by a panel of allospecific mAbs directed against determinants on the alpha or the beta chain of Ia heterodimers. These data indicate that intestinal epithelium bears surface Ia molecules antigenically distinct from those of conventional APC.
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PMID:Murine gut epithelial cells express Ia molecules antigenically distinct from those of conventional antigen-presenting cells. 195 59

Four BALB/c T cell clones from among a set propagated in the presence of concanavalin A (Con A) were selected on the basis of their ability to produce supernatant factors promoting high IgA plaque-forming cell (PFC) responses by 2,4,6-trinitrophenyl-conjugated keyhole limpet hemocyanin (TNP-KLH)-primed splenic B cells in the presence of TNP-SRBC. Such clones could be derived from cultures containing T cells not only from gut-associated lymphoid tissue, but also from the spleen. The selected clones all proliferated well in the presence of syngeneic, irradiated APC without either Con A or exogenous IL-2, but required both APC and Con A to produce helper factors. Factors from three of the clones helped B cells both to proliferate and to differentiate into IgM, IgG and IgA PFC. Factors from the fourth clone helped B cells differentiate into IgA and IgG PFC and may have promoted switching to these isotypes but did not support either B cell proliferation or generation of IgM PFC. Cross-linking of B cell receptors for antigen was not required for the response to the helper factors since TNP-SRBC were unnecessary and high concentrations of them were actually inhibitory.
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PMID:Con A-propagated, auto-reactive T cell clones that secrete factors promoting high IgA responses. 296 57

Mutations or loss of the APC tumor-suppressor gene is important for the development of colorectal polyps and cancers, but little is known about the function of this gene in normal tissue. To study the role of APC and other genes in colonocytes in vivo, a system was developed whereby transient expression of genes is established in normal rodent colonic epithelium, using liposomal gene delivery by rectal catheter infusion. Expression of a beta-galactosidase reporter gene and of the human APC gene under a constitutive promoter is demonstrated. A high efficiency of transfection is maintained, with close to 100% of epithelial cells expressing the introduced gene. Expression is transient and does not persist beyond 4 days, consistent with the normal turnover time of gut epithelium, but it can be maintained by repeated treatments. Human APC was expressed for three weeks under these conditions at approximately one-tenth the level of the endogenous APC gene, and no toxicity was observed beyond that attributed to repeated rectal enemas. These results reveal that in vivo expression of exogenous gene is feasible using a liposomal delivery system and suggest a method to further study the physiologic role of APC or other genes in the interrelated process of colonic epithelial proliferation and differentiation.
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PMID:Human APC gene expression in rodent colonic epithelium in vivo using liposomal gene delivery. 787 18

We have examined MHC class II molecules expression by murine gut epithelial cells using a large panel of anti-Ia antibodies. In contrast to conventional APC (i.e., B cells and macrophages), only two anti-Ia antibodies reacted with enterocytes: a xenogeneic rat anti-Ia mAb (CD311) directed against a monomorphic class II determinant, and a polyclonal antiserum directed against both I-A and I-E heterodimers. In contrast, allogeneic anti-Ia mAb were either unreactive (17 of 20) or reacted weakly (3 of 20) with enterocytes, even after in vivo treatment with IFN-gamma. This pattern of Ia reactivity of epithelial cells was tissue specific (restricted to gut mucosa) and cell specific (restricted to gut epithelial cells). Biochemical and molecular studies confirmed that enterocytes expressed I-A and I-E isotypes on their cell surface and contained mRNA of both subregion loci. Interestingly, enterocytes appeared deficient in expression of the MHC class II-associated invariant chain, and are not able to stimulate allogeneic T cells. These data suggest that gut epithelial cells express a conformation of class II molecules, antigenically distinct from that expressed on conventional APC.
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PMID:Unexpected lack of reactivity of allogeneic anti-Ia monoclonal antibodies with MHC class II molecules expressed by mouse intestinal epithelial cells. 840 25

It has long been known that mucosal responses are most effectively stimulated by local presentation of antigen but the mechanisms whereby the gut immune system is able to distinguish between potential pathogens and harmless dietary antigens are not clear. The gut immune system is capable of mounting both primary and secondary responses to potentially harmful antigens while avoiding the expression of damaging responses to harmless food proteins. Historically, most attention has focused on Peyer's patches and there is evidence of their role in the induction of both primary and secondary responses. Fed antigen can also be detected in the intestinal lamina propria (LP) and it has been shown that murine LP cells can stimulate allogenic mixed lymphocyte responses and present KLH to naive T cells. In contrast to guinea pigs, rodents and humans, pig intestinal epithelial cells do not express MHC Class II molecules, but they are present on a number of other cell types in the subepithelial LP. Amongst these are a significant proportion of non-professional APC including endothelial cells and eosinophils. Phenotypically pig LP T cells are a homogeneous population and the majority of CD4 T cells express the low molecular weight isoform of CD45. This is compatible with the suggestion that they are CD45RO-positive cells. A significant proportion of LP CD4 T cells are CD25 (IL-2R) positive, but following activation they secrete IL-4, with little or no IL-2 production. Based upon these observations, we would conclude that the lamina propria is a unique immunological microenvironment, and suggest that it may be of significance not only in surveillance and the provision of help during rapid responses to recall antigens but also in the down-regulation of local responses to food-derived peptides.
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PMID:Antigen presenting cells in the porcine gut. 898 62

The intestine is under perpetual challenge from both pathogens and essential nutrients, yet the mucosal immune system is able to discriminate effectively between harmful and innocuous Ags. It is likely that this selective immunoregulation is dependent on the nature of the APC at sites where gut Ags are processed and presented. Dendritic cells (DC) are considered the most potent of APC and are renowned for their immunostimulatory role in the initiation of immune responses. To investigate the role of DC in regulating the homeostatic balance between mucosal immunity and tolerance, we treated mice with Flt3 ligand (Flt3L), a growth factor that expands DC in vivo, and assessed subsequent systemic immune responsiveness using mouse models of oral tolerance. Surprisingly, mice treated with Flt3L to expand DC exhibited more profound systemic tolerance after they were fed soluble Ag. Most notably, tolerance could be induced in Flt3L-treated mice using very low doses of Ag that were ineffective in control animals. These findings contrast with the generally accepted view of DC as immunostimulatory APC and furthermore suggest a pivotal role for DC during the induction of tolerance following mucosal administration of Ag.
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PMID:Expanding dendritic cells in vivo enhances the induction of oral tolerance. 963 92

Endotoxin is physiologically present in portal venous blood at concentrations of 100 pg/ml to 1 ng/ml. Clearance of endotoxin from portal blood occurs through sinusoidal lining cells, i.e., Kupffer cells, and liver sinusoidal endothelial cells (LSEC). We have recently shown that LSEC are fully efficient APCs. Here, we studied the influence of endotoxin on the accessory function of LSEC. Incubation of Ag-presenting LSEC with physiological concentrations of endotoxin lead to >/=80% reduction of the accessory function, measured by release of IFN-gamma from CD4+ T cells. In contrast, conventional APC populations rather showed an increase of the accessory function after endotoxin treatment. Inhibition of the accessory function in LSEC by endotoxin was not due to lack of soluble costimulatory signals, because neither supplemental IL-1beta, IL-2, IFN-gamma, or IL-12 could rescue the accessory function. Ag uptake was not influenced by endotoxin in LSEC. However, we found that endotoxin led to alkalinization of the endosomal/lysomal compartment specifically in LSEC but not in bone marrow macrophages, which indicated that Ag processing, i.e., proteolytic cleavage of protein Ags into peptide fragments, was affected by endotoxin. Furthermore, endotoxin treatment down-regulated surface expression of constitutively expressed MHC class II, CD80, and CD86. In conclusion, it is conceivable that endotoxin does not alter the clearance function of LSEC to remove gut-derived Ags from portal blood but specifically affects Ag processing and expression of the accessory molecules in these cells. Consequently, Ag-specific immune responses by CD4+ T cells are efficiently down-regulated in the hepatic microenvironment.
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PMID:Endotoxin down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells. 997 95

Mutations in APC or beta-catenin inappropriately activate the transcription factor Tcf4, thereby transforming intestinal epithelial cells. Here it is shown that one of the target genes of Tcf4 in epithelial cells is Tcf1. The most abundant Tcf1 isoforms lack a beta-catenin interaction domain. Tcf1(-/-) mice develop adenomas in the gut and mammary glands. Introduction of a mutant APC allele into these mice substantially increases the number of these adenomas. Tcf1 may act as a feedback repressor of beta-catenin-Tcf4 target genes and thus may cooperate with APC to suppress malignant transformation of epithelial cells.
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PMID:Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1. 1048 74

We have previously reported that feeding OVA to C57BL/6 mice can lead to a weak CTL response that is dependent on CD4+ T cell help and is capable of causing autoimmunity. In this study, we investigated the basis of the class I and class II-restricted Ag presentation required for such CTL induction. Two days after feeding OVA, Ag-specific CD4+ and CD8+ T cells were seen to proliferate in the Peyer's patches and mesenteric lymph nodes. Little proliferation was evident in other lymphoid tissues, except at high Ags doses, in which case some dividing CD4+ T cells were observed in the spleen and peripheral lymph nodes. Using chimeric mice, the APC responsible for presenting orally derived Ags was shown to be derived from the bone marrow. Examination of the Ag dose required to activate either CD4+ or CD8+ T cells indicated that a single dose of 6 mg OVA was the minimum dose that consistently stimulated either T cell subset. These data indicate that oral Ags can be transported from the gut into the gut-associated lymphoid tissue, where they are captured by a bone marrow-derived APC and presented to both CD4+ and CD8+ T cells.
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PMID:A bone marrow-derived APC in the gut-associated lymphoid tissue captures oral antigens and presents them to both CD4+ and CD8+ T cells. 1070 74


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