UMLS:C0026918 - FACTA Search

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Query: UMLS:C0026918 (Mycobacterium)
52,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both protective immunity and immunopathology induced by mycobacteria are dependent on Ag-specific, CD4+ MHC class II-restricted T lymphocytes. The identification of Ag recognized by T cells is fundamental to the understanding of protective and pathologic immunity as well as to the design of effective immunoprophylaxis and immunotherapy strategies. Although some T cell clones are known to respond to recombinant mycobacterial heat shock proteins (hsp) like hsp3 65, the specificity of most T cells has remained unknown. We therefore have undertaken a specificity analysis of 48 well defined Mycobacterium leprae- and/or Mycobacterium tuberculosis-reactive (Th-1-like) T cell clones. Most clones (n = 44) were derived from different leprosy patients, and the remainder from one healthy control. Their HLA restriction molecules were DR2, DR3, DR4, DR5, DR7, DQ, or DP. T cell clones were stimulated with large numbers (n = 20 to 40) of mycobacterial SDS-PAGE-separated fractions bound to nitrocellulose. Each clone recognized a single fraction or peak with a particular Mr range. Some of the clones (n = 7) recognized the fraction that contained the hsp 65 as confirmed with the recombinant Ag. Most clones (n = 41), however, responded to Ag other than the hsp 65. Nine clones responded to a 67- to 80-kDa fraction. Five of them responded also to an ATP-purified, 70-kDa M. leprae protein, but only one of these five (that was HLA-DR2 restricted and cross-reactive with M. tuberculosis) recognized the recombinant C-terminal half (amino acids 278-621) of the M. leprae hsp 70 molecule and also recognized the recombinant M. tuberculosis hsp 70. We therefore have used the 5' part of the M. leprae hsp 70 gene that we have cloned recently. This fragment (that encodes amino acids 6-279) was indeed recognized by the other four M. leprae-specific T cells that were all HLA-DR3 restricted and did not cross-react with the highly homologous (95%) M. tuberculosis hsp 70. These results suggest that this novel fragment is a relevant T cell-stimulating Ag for leprosy patients. A panel of other recombinant Ag, including hsp 18 was tested. The majority of T cell clones appeared to recognize antigenic fractions distinct from hsp. In conclusion, T cells of leprosy patients see a large variety of different Ag including non-hsp, and one newly recognized moiety is the N-terminal M. leprae hsp 70 fragment.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A systematic molecular analysis of the T cell-stimulating antigens from Mycobacterium leprae with T cell clones of leprosy patients. Identification of a novel M. leprae HSP 70 fragment by M. leprae-specific T cells. 194 Mar 53

Immunogold ultracytochemistry and Western immunoblotting showed that polyclonal antibodies against human lactoferrin bind to the highly immunogenic 65-kilodalton (kDa) heat shock protein of mycobacteria. The fast-growing mycobacterial species Mycobacterium smegmatis showed a higher density of these receptors for antilactoferrin sera than the slow-growing M. avium. Polyclonal antibodies against mycobacteria (M. bovis BCG) recognized human lactoferrin. Comparison of the amino acid sequence of lactoferrin with that of the 65-kDa protein of M. tuberculosis revealed seven instances of four amino acid sequence homology between the microbial and the human iron-binding protein. Four of these tetrapeptide sequences were also shared with the human transferrin molecule. The shared amino acid sequence KDLL was also present in the DR1, DR3, and DR4 subsets of the DR beta subregion of major histocompatibility complex (MHC) class II molecules. The molecular mimicry between the 65-kDa mycobacterial protein and the human proteins (lactoferrin, transferrin, and MHC class II molecules) offers a molecular setting for mycobacteria-associated, T-cell-dependent autoimmune disease, namely, for rheumatoid arthritis.
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PMID:Cross-reactivity and sequence homology between the 65-kilodalton mycobacterial heat shock protein and human lactoferrin, transferrin, and DR beta subsets of major histocompatibility complex class II molecules. 232 24

Antigens of Mycobacterium tuberculosis, M leprae, M scrofulaceum, and M vaccae were injected intradermally in 86 caucasoid leprosy patients, and skin responses (measured in mm of induration at 72 h) were analysed in relation to HLA class II phenotypes. HLA-DR4 was associated with high responsiveness to antigens specific to M tuberculosis but not to antigens shared with other mycobacteria (p = 0.0005). Because DR4 is associated with rheumatoid arthritis (RA) and because a role for M tuberculosis antigens has been suggested both in experimentally induced autoimmune arthritis in rats and in RA, the DR4 associated regulation of the immune response to M tuberculosis may be relevant to the pathogenesis of RA.
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PMID:Evidence for an HLA-DR4-associated immune-response gene for Mycobacterium tuberculosis. A clue to the pathogenesis of rheumatoid arthritis? 242 42

MHC class II molecules carry the restriction determinants (RDs) for antigen presentation to antigen-specific Th lymphocytes. This restriction of T cell activation endows those molecules with a key role in the induction and regulation of antigen-specific immune responses. Moreover, class II molecules are the products of class II immune response (Ir) genes. The polymorphism of these Ir genes leads to genetically controlled differences in immuneresponsiveness between different individuals. An important human example is leprosy, in which HLA class II-linked Ir genes determine the immune response against Mycobacterium leprae, the causative organism of the disease. Since the immune response against M. leprae is entirely dependent on Th cells, the HLA class II-linked Ir gene products may well regulate the immune response by controlling the presentation of M. leprae antigens to Th cells. We therefore have investigated the HLA class II RD repertoire of M. leprae-reactive Th cell clones (TLC) by means of extensive panel and inhibition studies with fully class II-typed allogeneic APCs and well-defined HLA class II-specific mAbs. The TLC studied (n, 36) proliferated specifically towards M. leprae, produced IFN-gamma upon activation, and had the CD3+CD4+CD8- phenotype. The results show in the first place that the majority of the RDs for M. leprae reside on DR and not on DP or DQ molecules. This indicates a major role for DR molecules in the immune response to M. leprae and suggests that these molecules are the main products of M. leprae-specific Ir genes. Furthermore, since the expression of DR molecules is much stronger than that of DP and DQ molecules, these findings suggest that the localization of RDs for M. leprae on class II molecules correlates with the quantitative expression of these molecules. The observation that the RDs on DR molecules coded by a DR4 haplotype were situated only on those DR molecules that are known to be highest in expression can be explained in the same way. Second, four distinct RDs related with but not identical to the Dw13 allodeterminant were carried by the DR+DRw53- (alpha beta 1) molecules of a DR4Dw13 haplotype. Since the known amino acid residue differences between the allelic DR4 related Dw beta 1 chains cannot explain the observed RD-polymorphism, this observation suggests that multiple distinct RDs unique for the DR4Dw13 haplotype are expressed by these molecules. Only 2 of 36 TLC were not restricted by DR.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular localization and polymorphism of HLA class II restriction determinants defined by Mycobacterium leprae-reactive helper T cell clones from leprosy patients. 243 Oct 92

Thirteen CD4+ T-cell clones raised against Mycobacterium leprae from three M. leprae-vaccinated subjects were studied for major histocompatibility complex (MHC) restriction in proliferative and cytotoxicity assays. These T-cell clones recognized at least nine different epitopes, ranging from M. leprae-specific to broadly crossreactive. Restriction studies with a panel of antigen-presenting cells (APCs) suggest that all of the T-cell clones recognized antigens in the context of the DR locus. Three T-cell clones with three different reactivities from a DR1, 2-positive subject responded to M. leprae in proliferation and cytotoxicity when the antigen was presented in the context of DR1-positive APCs. Four T-cell clones responding to M. leprae-specific or crossreactive epitopes from the second donor, who was DR4,DW4; DR4,Dw14-positive, and a single M. leprae-specific T-cell clone from the third subject, who was DR3,4:Dw4, recognized the antigens in the presence of Dw4 APCs. Four crossreactive T-cell clones from the second subject responded in the presence of Dw14-positive APCs, and one limited crossreactive clone recognized the antigen in the context of DR4 and DR7-positive cells, suggesting that its response was restricted by a common determinant. The T-cell clones that recognize the 65-kDa, 18-kDa, and 13B3 recombinant M. leprae antigens in proliferative assays were cytotoxic for autologous adherent cells pulsed with the respective antigens.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:HLA-DR-restricted antigen-induced proliferation and cytotoxicity mediated by CD4+ T-cell clones from subjects vaccinated with killed M. leprae. 265 94

An allele-specific motif has been identified in the sequence of several peptides which are recognized by T cells in association with HLA-DR1. In order to test the predictive values of such a motif we analyzed the 19-kDa antigen from Mycobacterium tuberculosis and identified a sequence containing a pattern characteristic of DR1 restriction. Peripheral blood mononuclear leukocytes from every DR1 and 4 individual tested responded to the corresponding synthetic peptide. Nine other donors, constituting seven different DR alleles, failed to recognize this sequence. Recognition of the peptide in association with DR1 and DR4 was confirmed using T cell clones and transfected murine L cell lines expressing DR molecules.
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PMID:Prediction and identification of an HLA-DR-restricted T cell determinant in the 19-kDa protein of Mycobacterium tuberculosis. 313 33

The human leucocyte antigen DR4-associated immune responses to Mycobacterium tuberculosis 65 kDa heat shock protein were considered to be relevant to the pathogenesis of rheumatoid arthritis (RA). In the Chinese population, DR4-Dw15 was found to be the predominant DR4 subtype in RA. To further define the immune responses associated with DR4-Dw15 molecules, the proliferative responses of peripheral (PBMC) and synovial mononuclear cells (SFMC) to mycobacterial 65 kDa antigen were evaluated. The SFMC of all of our RA patients responded significantly to 65 kDa mycobacterial antigen. The responses of PBMC to this antigen in RA were much lower than those of SFMC. Our results further indicated that relatively low numbers of peripheral antigen-specific T-cells, but not incompetence of peripheral antigen presenting cells, might be related to the observed low responsiveness to 65 kDa antigen in PBMC of RA patients. Of utmost importance, DR4-Dw15 was proved to be one of the major restrictive molecules in mycobacterial 65 kDa antigen-specific immune responses in Chinese RA patients.
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PMID:A dominant human leucocyte antigen DR4-Dw15 restricted mycobacterial 65 kDa antigen-specific T-cell immunity in Chinese patients with rheumatoid arthritis. 754 46

We identified functionally important regions of the DR(alpha, beta 1*0401) peptide binding site and present a model of bound peptide. DR(alpha, beta 1*0401)-restricted T cell recognition and peptide binding of Mycobacterium leprae (ML) peptide 38-50 and overlapping peptides from the 18-kDa heat-shock protein were analyzed. ML38-50 is unusual in its restricted binding pattern, binding to only one of five DR4 subtypes and no other DR molecules tested. Amino acid substitutions were introduced into ML38-50 and the DR(alpha, beta 1*0401) peptide binding site at positions likely to influence peptide-MHC or peptide- or MHC-TCR interactions. Peptide binding, T cell proliferation, and computer modeling studies suggest that residues 39F, 42E, and 44D of ML38-50 interact with pockets 1, 4, and 6, respectively, of the peptide binding site. Only DR(alpha, beta 1*0401) substitutions at residues in pockets 4 or 7 prevented binding of ML38-50, while multiple substitutions at other positions negatively affected its T cell recognition. In contrast, T cell recognition of some high affinity ML peptides that overlapped ML38-50, and contained N-terminal extensions, was only abolished with pocket 4 substitutions. An inverse correlation of peptide affinity for DR(alpha, beta 1*0401) with negative effects of MHC substitutions on T cell recognition of the overlapping ML peptides was observed. Thus, some regions, such as pocket 4, dominantly influence T cell recognition of multiple DR(alpha, beta 1*0401)-binding peptides. However, each DR(alpha, beta 1*0401)-binding peptide appears to have unique properties that determine the outcome of its MHC-peptide interactions and the relative importance of other polymorphic pockets.
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PMID:Structural requirements of peptide and MHC for DR(alpha, beta 1*0401)-restricted T cell antigen recognition. 763 46

By using a synthetic peptide approach, we mapped epitopes from the mycobacterial 65-kDa heat shock protein (HSP65) recognized by human T cells belonging to the Mycobacterium leprae memory repertoire. A panel of HSP65 reactive CD4(+) T-cell lines and clones were established from healthy donors 8 years after immunization with heat-killed M. leprae and then tested for proliferative reactivity against overlapping peptides comprising both the M. leprae and Mycobacterium tuberculosis HSP65 sequences. The results showed that the antigen-specific T-cell lines and clones established responded to 12 mycobacterial HSP65 peptides, of which 9 peptides represented epitopes crossreactive between the M. tuberculosis and M. leprae HSP65 (amino acids [aa] 61 to 75, 141 to 155, 151 to 165, 331 to 345, 371 to 385, 411 to 425, 431 to 445, 441 to 455, and 501 to 515) and 3 peptides (aa 343 to 355, 417 to 429, and 522 to 534) represented M. leprae HSP65-specific epitopes. Major histocompatibility complex restriction analysis showed that presentation of 9 of the 12 peptides to T cells were restricted by one of the 2 HLA-DR molecules expressed from self HLA-DRB1 genes, whereas 3 peptides with sequences completely identical between the M. leprae and M. tuberculosis HSP65 were presented to T cells by multiple HLA-DR molecules: peptide (aa 61 to 75) was presented by HLA-DR1, -DR2, and -DR7, peptide (aa 141 to 155) was presented by HLA-DR2, -DR7, and -DR53, whereas both HLA-DR2 and -DR4 (Dw4 and Dw14) were able to present peptide (aa 501 to 515) to T cells. In addition, the T-cell lines responding to these peptides in proliferation assays showed cytotoxic activity against autologous monocytes/macrophages pulsed with the same HSP65 peptides. In conclusion, we demonstrated that promiscuous peptide epitopes from the mycobacterial HSP65 antigen can serve as targets for cytotoxic CD4(+) T cells which belong to the human memory T-cell repertoire against M. leprae. The results suggest that such epitopes might be used in the peptide-based design of subunit vaccines against mycobacterial diseases.
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PMID:Identification of promiscuous epitopes from the Mycobacterial 65-kilodalton heat shock protein recognized by human CD4(+) T cells of the Mycobacterium leprae memory repertoire. 1053 Dec 16

This study explores whether MHC genes affect manifestations of opportunistic infections in HIV patients not treated with highly active antiretroviral therapy (HAART) and immunopathologic responses to pre-existing infections in patients who achieved immune reconstitution following HAART (i.e., "immune restoration diseases" or IRD). HLA-B27 and B17 were relatively rare in all HIV patients, but no HLA-B alleles significantly affected cytomegalovirus (CMV) or Mycobacterium avium complex (MAC) disease in patients who had not received HAART. However coexpression of alleles previously defined as the 44.1 ancestral haplotype (HLA-A2, -B44, and -DR4) was more common in the MAC and CMV patients. After HAART, HLA-B44 and (HLA-A2, -B44, -DR4) were found in 66% and 33%, respectively, of patients who experienced an IRD manifested as CMV retinitis and/or encephalomyelitis. This was confirmed by examination of microsatellite alleles, where the C1_2_5 locus in the class I region was most concordant with the 44.1 haplotype in the patients. HLA-B44 was not associated with IRD initiated by Mycobacterium sp, cutaneous VZV or HSV, or HCV infections, suggesting distinct pathologic mechanisms are responsible. CMV retinitis/encephalomyelitis IRD patients had marginally lower pretreatment CD4 T-cell counts, but indices of immune reconstitution were similar in all groups and independent of HLA-B44.
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PMID:MHC haplotypes affect the expression of opportunistic infections in HIV patients. 1118 26

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