Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have found that the low immune response to streptococcal cell wall Ag (SCW) was inherited as a dominant trait and was linked to HLA, as deduced from family analysis. In the present report, HLA class II alleles of healthy donors were determined by serology and DNA typing to identify the HLA alleles controlling low or high immune responses to SCW. HLA-DR2-DQA1*0102-DQB1*0602(DQw6)-Dw2 haplotype or HLA-DR2-DQA1*0103-DQB1*0601(DQw6)-DW12 haplotype was increased in frequency in the low responders and the frequency of HLA-DR4-DRw53-DQA1*0301-DQB1*0401(DQw4)-Dw15 haplotype or HLA-DR9-DRw53-DQA1*0301-DQB1*0303(DQw3)-Dw23 haplotype was increased in the high responders to SCW. Homozygotes of either DQA1*0102 or DQA1*0103 exhibited a low responsiveness to SCW and those of DQA1*0301 were high responders. The heterozygotes of DQA1*0102 or 0103 and DQA1*0301 showed a low response to SCW, thereby confirming that the HLA-linked gene controls the low response to SCW, as a dominant trait. Using mouse L cell transfectants expressing a single class II molecule as the APC, we found that DQw6(DQA1*0103 DQB1*0601) from the low responder haplotype (DR2-DQA1*0103-DQB1*0601(DQw6)-Dw12) activated SCW-specific T cell lines whereas DQw4(DQA1*0301 DQB1*0401) from the high responder haplotype (DR4-DRw53-DQA1*0301-DQB1*0401(DQw4)-Dw15) did not activate T cell lines specific to SCW. However, DR4 and DR2 presented SCW to CD4+ T cells in both the high and low responders to SCW, hence the DR molecule even from the low responder haplotype functions as an restriction molecule in the low responders. Putative mechanisms linked to the association between the existence of DQ-restricted CD4+ T cells specific to SCW, and low responsiveness to SCW are discussed.
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PMID:HLA-DQ-restricted CD4+ T cells specific to streptococcal antigen present in low but not in high responders. 167 41

The propensity of HIV-1 to undergo sequence variation, particularly in the envelope glycoprotein gp120, complicates vaccine development and may enable the virus to evade ongoing immune responses in infected individuals. We present here a molecular analysis of the effects of this variability on human T cell recognition of HIV-1 gp120. Synthetic peptides representing a defined CD4+ human T cell epitope in gp120 were used to survey gp120 molecules from various HIV-1 strains for the capacity to be recognized in the context of a single human MHC molecule, DR4. Variation affected recognition at two levels. For some strains, variation in this epitope was sufficient to alter the interaction of Ag receptors on gp120-specific human T cell clones with peptide-DR4 complexes on APC. In the case of two strains, the natural variation was sufficient to prevent the critical initial interaction between the relevant gp120 peptides and DR4 on the APC. However, these strains were highly divergent from the reference strain. Thus it is encouraging to note that the range of natural sequence variation in this T cell epitope falls, for the most part, within the range of peptide sequences that can be accommodated by the relevant human MHC molecule.
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PMID:Genetic variability in HIV-1 gp120 affects interactions with HLA molecules and T cell receptor. 197 Mar 52

The contributions of the amino acids at 13 polymorphic positions in the HLA-DR7 beta 1 chain to T cell recognition of two antigenic peptides of tetanus toxin (p2 and p30) were assessed using transfectants expressing mutant DR7 beta 1 chains as APC for six toxin-specific T cell clones with two different restriction patterns: monogamous (restricted by DR7 only) or promiscuous (restricted by DR7; DR1; DR2, Dw21; and DR4, Dw4). Each of the 13 substitutions significantly decreased or eliminated the ability of the DR7 molecule to present a peptide to one or more of the T cell clones, but none of the substitutions abolished recognition by all clones. Interestingly, substitutions at positions 4 and 25, which are predicted in the class II model to be located outside the peptide binding groove, decreased the ability of the DR7 molecule to present Ag to some clones but not to others. Each of the four clones specific for the p2 peptide and the two clones specific for peptide p30 had a different reactivity pattern to the panel of DR7 beta 1 mutants, indicating that the TCR of each clone has a different view of the p2/DR7 or p30/DR7 complex. These data emphasize the complexity of the interactions of multiple residues in DR7 beta 1 chains in Ag-specific T cell recognition.
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PMID:Antigen-specific T cells with monogamous or promiscuous restriction patterns are sensitive to different HLA-DR beta chain substitutions. 204 Jul 99

T helper cells, which recognize allopeptides processed and presented by self APC, contribute to the generation of both cellular and humoral immune responses against allogeneic transplants. We have explored the hypothesis that the indirect T cell recognition pathway is initiated by soluble MHC antigens and that it can be suppressed by high doses of synthetic peptides corresponding to the dominant alloepitope. T cells from a DR11/7 responder were immunized in vitro with recombinant HLA-DR4 (rDR4). Experiments using partially overlapping synthetic peptides showed that the resulting T cell line (TCL) recognized a single dominant epitope mapping within residues 69-88 of the first domain of the DR4 molecule. In vitro immunization with synthetic allopeptides corresponding to other polymorphic regions, were unable to elicit T cell reactivity against rDR4, although at least one of these peptides (corresponding to residues 13-27) was immunogenic, behaving like a cryptic epitope. The rDR4-specific TCL expressed a limited TCR repertoire and provided help to autologous B cells for the production of specific antibodies. The T cell blastogenic response as well as the transcription and secretion of IL-4 (but not IL-2) was efficiently suppressed by high doses of the dominant allopeptide. These findings support the concept that selective immunointervention of indirect allorecognition can be achieved by use of high doses of antigen or TCR vaccination, as proposed for autoimmune diseases.
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PMID:Suppression of the indirect pathway of T cell reactivity by high doses of allopeptide. 882 75

HLA-DM- APC are unable to present soluble Ags to T cells in the context of class II DR molecules. This defect in DM- APC can be overcome by receptor-mediated delivery of Ag into cells. Ag conjugated to ligands for cell surface receptors, such as transferrin or goat anti-human Ig, was processed and presented by DM- T2.DR4 cells. Intracellular processing of Ag conjugates was required, as receptor cross-linking alone did not restore presentation by DM- APC. Ag conjugates targeted by transferrin receptors to endosomes or via surface Ig to endosomal and lysosomal compartments, were each efficiently presented by DM- cells. These Ag conjugates were predominantly localized in light density endosomes in T2.DR4 cells. This study demonstrates that the facilitated uptake and sorting of exogenous Ag by cell surface receptors allow efficient class II-restricted presentation even in the absence of HLA-DM.
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PMID:Receptor-mediated endocytosis of antigens overcomes the requirement for HLA-DM in class II-restricted antigen presentation. 897 67

Glutamic acid decarboxylase 65 (GAD65) is one of the major autoantigens in type 1 diabetes. We investigated whether there is variation in the processing of GAD65 epitopes between individuals with similar HLA backgrounds and whether the processing characteristics of certain immunogenic epitopes are different in distinct APC subpopulations. Using DR401-restricted T cell hybridomas specific for two immunogenic GAD65 epitopes (115-127 and 274-286), we demonstrate an epitope-specific presentation pattern in human B-lymphoblastoid cell lines (B-LCL). When pulsed with the GAD protein, some DRB1*0401-positive B-LCL, which presented GAD65 274-286 epitope efficiently, were unable to present the GAD65 115-127 epitope. However, all B-LCL presented synthetic peptides corresponding to either GAD epitope. In addition, when pulsed with human serum albumin, all cell lines gave equal stimulation of a DR4-restricted human serum albumin-specific T hybridoma. GAD65-transfected cell lines displayed the same presentation phenotype, showing that lack of the presentation of the 115-127 epitope was not due to inefficient uptake of the protein. Blood mononuclear adherent cells, B cells, or dendritic cells derived from the same individual displayed the same presentation pattern as observed in B cell lines, suggesting that the defect most likely is genetically determined. Therefore, individual differences in Ag processing may result in the presentation of distinct set of peptides derived from an autoantigen such as GAD65. This may be an important mechanism for the deviation of the immune response either into a regulatory pathway or into an inflammatory autoimmune reactivity.
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PMID:Differential presentation of glutamic acid decarboxylase 65 (GAD65) T cell epitopes among HLA-DRB1*0401-positive individuals. 1041 74

Following antigenic challenge, MHC-restricted T cell responses are directed against a few dominant antigenic epitopes. Here, evidence is provided demonstrating the importance of APC in modulating the hierarchy of MHC class II-restricted T cell responses. Biochemical analysis of class II:peptide complexes in B cells revealed the presentation of a hierarchy of peptides derived from the Ig self Ag. Functional studies of kappa peptide:class II complexes from these cells indicated that nearly 20-fold more of an immunodominant epitope derived from kappa L chains was bound to class II DR4 compared with a subdominant epitope from this same Ag. In vivo, T cell responses were preferentially directed against the dominant kappa epitope as shown using Ig-primed DR4 transgenic mice. The bias in kappa epitope presentation was not linked to differences in class II:kappa peptide-binding affinity or epitope editing by HLA-DM. Rather, changes in native Ag structure were found to disrupt presentation of the immunodominant but not the subdominant kappa epitope; Ag refolding restored kappa epitope presentation. Thus, Ag tertiary conformation along with processing reactions within APC contribute to the selective presentation of a hierarchy of epitopes by MHC class II molecules.
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PMID:Role of APC in the selection of immunodominant T cell epitopes. 1058 31

Predisposition to rheumatoid arthritis (RA) is thought to be associated with HLA-DR1, -DR4, and -DR10. However, many epidemiological observations are better explained by a model in which the DQ alleles that are linked to these DR alleles, i.e., DQ5, DQ7, and DQ8, predispose to RA, while certain DR alleles have a dominant protective effect. All protective DRB1 alleles, e.g., *0402, *1301, and *1302, encode a unique motif, (70)DERAA(74). The protection may be explained by the presentation of DRB1-derived peptides by DQ to immunoregulatory T cells, because it was demonstrated in various autoimmune disease models that T cell responses to certain self-Ags can be involved in disease suppression. The aim of this study was to analyze whether peptides carrying the DERAA motif are naturally processed by human APC and presented in the context of the RA-predisposing DQ. Using a synthetic peptide carrying the DRB1*0402-derived sequence (65)KDILEDERAAVDTYC(79), we generated DERAA peptide-specific DQ-restricted T cell clones (TCC) from a DQ8 homozygous individual carrying DERAA-negative DR4 alleles. By analyzing the proliferation of these TCC, we demonstrated natural processing and presentation of the DERAA sequence by the APC of all the individuals (n = 12) carrying a DERAA-positive DRB1 allele and either DQ8 or the DQ8-related DQ7. Using a panel of truncated synthetic peptides, we identified the sequence (67)(I)LEDERAAVD(TY)(78) as the minimal determinant for binding to DQ8 and for recognition by the TCC. These findings support a model in which self-MHC-derived peptide can modulate predisposition to autoimmune disease in humans.
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PMID:An HLA-DRB1-derived peptide associated with protection against rheumatoid arthritis is naturally processed by human APCs. 1129 Jul 78

The rat monoclonal antibody LMR-42 has previously been shown to react with an external epitope of a plasma membrane protein with a M(r) of approximately 55,000 that was upregulated in multidrug-resistant (MDR) tumour cells. Here, we report the isolation of the cDNA encoding the LMR-42 antigen from the MDR human fibrosarcoma cell line HT1080/DR4 and the lung cancer cell line GLC4/ADR by expression cloning. Sequence analysis showed that the LMR-42 antigen is identical to the endothelial cell protein C receptor (EPCR). Using the LMR-42 Mab for cytochemical analyses of a disease-oriented panel of 45 non-drug selected tumour cell lines of the National Cancer Institute (NCI), we found high EPCR expression in 47% of the primary tumour cell lines, including melanomas, renal- and colon carcinomas. In a small panel of human tumours, occasionally very high EPCR expression was detected in endothelial vessels, but expression in the tumour cells was a rare event. The functional significance of overexpression of EPCR on both primary and drug-selected tumour cells is still unclear. As the protein is related to MHC class I molecules and shares no characteristics with any of the currently known transporter proteins, EPCR is not expected to play a causal role in the resistant phenotype of the MDR tumour cells. Nevertheless, exposure of tumour cells to cytostatic drugs may frequently lead to EPCR overexpression. Since EPCR is known to play a pivotal role in preventing blood coagulation through binding of (activated) protein C, it might endow tumour cells, both of mesenchymal and epithelial derivations, with increased growth potential by local anti-coagulant activity.
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PMID:Expression of the vascular endothelial cell protein C receptor in epithelial tumour cells. 1211 May 1

Rheumatoid arthritis is characterized by synovial joint infiltration of activated CD4(+) T cells and MHC class II(+) APC, and is linked to specific HLA-DR alleles. Candidate autoantigens in synovial fluid and cartilage include type II collagen (CII) and cartilage gp39 (HCgp39). Using preparations of native Ag and T cells derived from Ag-immunized DR4-transgenic mice, we determined that human ex vivo differentiated DR4(+) dendritic cells (DC) and macrophages (Mphi) can mediate MHC class II presentation of CII or HCgp39 epitopes. The form of the Ag (soluble, partially degraded, or particulate) delivered to the APC influenced its presentation by DC and Mphi. DC efficiently presented partially degraded, but not native CII alpha-chains, while Mphi presentation was most efficient after phagocytosis of bead-conjugated CII. Both DC and Mphi presented soluble HCgp39, and activated Mphi from some donors presented epitopes derived from endogenously synthesized HCgp39. When synovial fluid from rheumatoid arthritis patients was used as a source of Ag, DC presentation of HCgp39 and CII epitopes was efficient, indicating that synovial fluid contains soluble forms of CII and HCgp39 amenable to internalization, processing, and presentation. These data support the hypothesis that CII and HCgp39 are autoantigens and that their class II-mediated presentation by DC and Mphi to T cells in vivo has a critical role in the pathogenesis of human rheumatoid arthritis.
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PMID:Differential MHC class II-mediated presentation of rheumatoid arthritis autoantigens by human dendritic cells and macrophages. 1244 76


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