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)

The renal proximal tubule (PT) in many ways resembles an APC. The PT is one of the few epithelial cells in the body reported to constitutively express the class II MHC molecules required to present Ag to CD4+ T cells. We questioned whether the PT could function as an APC in vitro and in vivo. Fluorescence cytometry demonstrated that the normal CBA/J PT constitutively expressed low levels of class II MHC and that this expression was markedly augmented by either IFN-gamma or systemic Listeria monocytogenes infection. Functionally, the PT from normal CBA/J mice also stimulated T cell hybridomas when cultured in vitro with Ag, and this ability was markedly up-regulated by both IFN-gamma as well as L. monocytogenes infection. To prove that the PT constitutively processed and presented self Ag in vivo, freshly isolated PT from mice transgenic for human alpha 1-antitrypsin were cultured with the appropriate T cell hybridoma in the absence of exogenous Ag. Strong stimulation of the T cell hybridoma occurred. Our data show that the renal proximal tubule processes and presents foreign Ag both in vitro and in vivo, and that it constitutively processes and presents the self Ag hAAT in vivo. These results have important implications for the understanding of renal interstitial autoimmune diseases as well as the interstitial nephritis that occurs in response to foreign Ag.
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PMID:Processing and presentation of self and foreign antigens by the renal proximal tubule. 156 Jan 95

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

The tumor suppressor gene APC was recently identified, and the cDNA was cloned from chromosome 5q21. Point mutations affecting APC are seen in the hereditary syndrome familial adenomatous polyposis, and point mutations in APC and a closely linked gene, MCC, as well as loss of heterozygosity involving chromosome 5q have been reported in sporadic colon cancer. To our knowledge, loss of heterozygosity involving APC or MCC or both has not yet been described in any other human cancer besides lung cancer. We used the polymerase chain reaction and DNA content flow cytometric nuclear sorting to examine 30 primary human esophageal cancers for loss of heterozygosity of APC or MCC or both. Loss of one allele was detected in 77% of 26 informative cases. These data suggest that loss of heterozygosity of regions on 5q including the APC and MCC genetic loci is involved in the development and/or progression of most human esophageal cancers. They imply that inactivation of APC, MCC, and/or a linked gene on chromosome 5q plays a role in the pathogenesis of some cancers of the upper gastrointestinal tract, as well as in colon cancer and familial adenomatous polyposis.
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PMID:Loss of heterozygosity involving the APC and MCC genetic loci occurs in the majority of human esophageal cancers. 156 31

The agents cyclosporine, tetranactin (TN), and didemnin B (DB) were compared for their ability to inhibit proliferative human T cell responses in vitro, using anti-CD3, PHA, alloantigen, or tetanus toxoid as stimuli and using monocytes or Langerhans cells as antigen-presenting cells/accessory cells (APC/AC). We found that all three agents suppressed T cell activation in a dose-dependent fashion, irrespective of the stimulus of APC/AC type used. Both T cells and APC/AC were affected by the drugs. DB appeared to be the most potent suppressive drug (IC50 = 1-4 ng/ml), whereas CsA and TN exerted approximately similar potency (IC50 = 50-60 ng/ml). Remarkably however, DB was toxic at a concentration of 10 ng/ml, which is quite close to the inhibition-inducing dose. No toxicity was observed with CsA and TN at doses up to 5000 ng/ml. The agents TN and DB could interrupt ongoing T cell responses and could block responsiveness to exogenous recombinant IL-2. Expression of IL-2 receptors was slightly inhibited by all three drugs. Expression of MHC class II molecule HLA-D and of adhesion molecules LFA-1, LFA-3, and ICAM-1 was clearly reduced by DB, giving an explanation for the observed inhibition of cluster formation between T cells and APC/AC. Except for a slight reduction of LFA-3 by TN, CsA and TN did not affect the expression of any of these cell surface markers or the formation of clusters. Differences in the effects of CsA, TN, and DB on immune responses in vitro and on the phenotype of T cells and APC/AC suggest that these immunosuppressive drugs have different inhibitory mechanisms.
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PMID:A comparison of the inhibitory effects of immunosuppressive agents cyclosporine, tetranactin, and didemnin B on human T cell responses in vitro. 156 53

Studies on the processing of insulin as an Ag for the presentation to MHC class II-restricted T cells revealed that the amino acid residues 1-14 of the insulin A chain are recognized by insulin-specific T cells. An A1-14 peptide containing three cys-residues that were protected by S-sulfonate groups still needed processing by APC for efficient presentation similar to native insulin. We suspected that reductive deblocking or opening of disulfide bonds that generates CysSH-residues may be an essential processing step for these Ag. Due to the instability of SH-groups it was not possible to test A chain peptides with free SH-groups in the usual way for processing-independent presentation by fixed APC. However, under acidic conditions (pH 5) during APC pulsing with the Ag we could demonstrate that the freshly reduced A1-14 fragment as well as reduced insulin are able to bind to Ia Ag and to stimulate appropriate T cells without further processing. Various substitutions of cys-residues by Ser within this peptide revealed that only CysA7 is critical for Ia binding and/or T cell recognition. In intact insulin, this residue links the A chain containing the T cell epitope to the B chain. Therefore, we propose that insulin processing is not dependent on proteolysis or on the generation of a conformational determinant but on the separation of A and B chains resulting in A chains whose cys-residues are converted into CysSH.
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PMID:In vitro processing of insulin for recognition by murine T cells results in the generation of A chains with free CysSH. 157 64

We have examined the role of 12 polymorphic residues of the beta-chain of the HLA-DR1 class II molecule in T cell recognition of an epitope of pertussis toxin. Murine L cell transfectants expressing wild-type or mutant DR1 molecules (containing single amino acid substitutions in DR(beta 1*0101)) were used as APC in proliferation assays involving nine DR1-restricted T cell clones specific for peptide 30-42 of pertussis toxin. Four different patterns of recognition of the mutants were found among the pertussis-specific clones. Residues in the third hypervariable region (HVR) of DR(beta 1*0101) are critically important for all the T cell clones; amino acid substitutions at positions 70 and 74 abrogated recognition by all of the T cell clones, and substitutions at positions 67 and 71 eliminated recognition by most of the clones. In contrast, most single amino acid substitutions in the first and second HVR, predicted to be located in the floor of the peptide binding groove, had little or no effect on the proliferative responses of these clones. However, the involvement of beta-chain first and second HVR residues was demonstrated by the inability of transfectants expressing wild-type DR(beta 1*0404) (DR4Dw14) or DR(beta 1*1402) (DR6Dw16) to present peptide to these clones. These beta-chains have completely different first and second HVR compared with DR(alpha,beta 1*0101) although the third HVR are identical. These results illustrate the functional importance of third HVR residues of DR(beta 1*0101) and allow definition of the molecular interactions of the DR1 molecule with the 30-42 peptide.
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PMID:Mutations in the third, but not the first or second, hypervariable regions of DR(beta 1*0101) eliminate DR1-restricted recognition of a pertussis toxin peptide. 157 65

The maturation of CD4+8- and CD4-8+ thymocytes from CD4+8+ thymocytes is dependent on the mandatory interaction of their alpha beta TCR with selecting ligands expressed on thymic epithelial cells (TE). This is referred to as positive selection. The deletion of CD4+8+ thymocytes that express autospecific TCR (negative selection) is mediated primarily by bone marrow-derived cells. Previous studies have shown that TE is relatively ineffective in mediating the deletion of CD4+8- thymocytes expressing autospecific TCR but TE can render them anergic, i.e., nonresponsive, to the self Ag. The mechanism by which anergy is induced in these cells is unknown. In this study, we used thymocytes expressing a transgenic TCR specific for the male Ag presented by H-2Db class I MHC molecules to examine how expression of the deleting ligand by TE affects thymocyte development and phenotype. The development of female TCR-transgenic thymocytes was examined in irradiated male hosts or in female hosts that had received male fetal thymic epithelial implants. It was observed that the development of transgenic-TCR+ thymocytes was affected in mice with male TE. CD4+8+ thymocytes with reduced CD8 expression and markedly enhanced transgenic TCR expression accumulated in mice with male TE. Development of CD4-8+ thymocytes was also affected in these mice in that fewer were present and they expressed an intermediate CD8 coreceptor level. These CD4-8+ thymocytes expressed a high level of the transgenic TCR, retained the ability to respond to anti-TCR antibodies, but were nonresponsive to male APC. However, the maturation of CD4+8- thymocytes, which are also derived from CD4+8+ precursor cells, was relatively unaffected. In an in vitro assay for assessing negative selection, male TE failed to delete CD4+8+ thymocytes expressing the transgenic TCR under conditions where they were efficiently deleted by male dendritic cells. Collectively these results support the conclusion that male TE was inefficient in mediating deletion. Furthermore, expression of the deleting ligand on thymic epithelium interferes with the maturation of functional male-specific T cells and results in the accumulation of CD4+8+ and CD4-8+ thymocytes expressing a lower level of the CD8 coreceptor but a high level of the transgenic TCR.
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PMID:Altered thymocyte development resulting from expressing a deleting ligand on selecting thymic epithelium. 157 26

Ag in the extracellular fluids can be internalized, processed, and presented in association with class I MHC molecules on specialized APC in normal spleen. We examine the fate of these APC after they present Ag to a CTL. When splenocytes present exogenous OVA to CTL, their ability to subsequently present native Ag in association with both class I and class II molecules is inhibited. CTL do not inhibit the ability of splenocytes to present processing independent peptides with class I or class II molecules. Inhibition of Ag presentation is only observed in the presence of the specific Ag recognized by the CTL. This inhibition is MHC-restricted. In the presence of specific Ag, CTL inhibit the ability of APC to present unrelated Ag. However, bystander APC are not affected by activated CTL. Taken together these results indicate that when APC present exogenous Ag to CTL, they are inhibited or killed. The CTL that mediates this activity has a conventional CD4-CD8+ phenotype and utilizes a TCR-alpha beta. The potential significance of these findings and their possible relationship to phenomena associated with Ts cells are discussed.
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PMID:Inhibition of class I and class II MHC-restricted antigen presentation by cytotoxic T lymphocytes specific for an exogenous antigen. 157 28

Two sets of ((resistant x susceptible) F1----parent) and (parent----F1) chimeric mice were prepared. In the chimeric combinations involving BALB/c and DBA/1 mice, all (F1----F1) chimeras developed arthritis as well as potent anticollagen responses after immunization with collagen, whereas all (F1----BALB/c) and (BALB/c----F1) chimeras induced neither arthritis nor immune responses. This type of F1 T cells could be activated with APC from DBA/1 but not from BALB/c mice. Thus, the failure of the [F1 in equilibrium with BALB/c] chimeras to mount anticollagen responses was due to a defect at the APC level. Another arthritis-resistant strain, C57BL/6, exhibited adequate APC function, but reduced T cell responsiveness, representing an intermediate responder. In the chimeric combinations involving C57BL/6 and DBA/1 mice, (F1----F1) and (C57BL/6----C57BL/6) chimeras developed very high and very low incidence of arthritis, respectively. (C57BL/6----F1) chimeras developed an appreciable incidence of arthritis under conditions in which this group of chimeras generated intermediate levels of anticollagen responses. In contrast, (F1----C57BL/6) chimeras developed low incidence of disease despite induction of strong responses. Moreover, cells from collagen-immunized (F1----C57BL/6) chimeras, when transferred into T cell-depleted B cell mice of F1 or C57BL/6 strain, produced comparable immune responses in both groups but induced much more severe arthritis in F1 than in C57BL/6 recipients. These results indicate that: i) two types of arthritis-resistant strains can be identified, each of which has anticollagen APC defect as a low responder and reduced T cell responsiveness as an intermediate responder and ii) a discrepancy between the degree of anticollagen responses and clinical arthritis is attributed to the differential susceptibility to anticollagen immune responses.
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PMID:Type II collagen-induced murine arthritis: induction of arthritis depends on antigen-presenting cell function as well as susceptibility of host to an anticollagen immune response. 157 34

Tolerant and nontolerant murine Th1 and Th2 clones, specific for human gamma-globulin (HGG), were compared for their ability to promote cell cycle entry and progression by B cells in vitro. When stimulated with HGG, nontolerant Th1 and Th2 clones induced similar increases in B cell membrane MHC class II levels--a phenomenon associated with early B cell activation. Nontolerant Th1 and Th2 clones also induced B cell DNA synthesis, an event associated with subsequent G1 phase traversal, although Th2 cells were more efficient than Th1 cells in stimulating this activity. Exposure of Th clones to tolerogen in the form of HGG-pulsed chemically fixed APC inhibited the ability of Th1 clones, but not Th2 clones to promote polyclonal B cell DNA synthesis in HGG-stimulated secondary cultures. However, Th1 clones exposed to tolerogen did not lose their ability to increase the expression of MHC class II molecules on B cells in these cultures. These results indicate that tolerance induction does not inhibit the ability of Th1 clones promote B cell cycle progression. In contrast, exposure of Th2 cells to tolerogen does not inhibit significantly the ability of these cells to stimulate B cell cycle entry or progression.
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PMID:Ability of tolerized Th1 and Th2 clones to stimulate B cell activation and cell cycle progression. 158 50


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