Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026918 (Mycobacterium)
 52,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many major histocompatibility complex (MHC) polymorphisms originate from ancient structures that predate speciation. As a consequence, members of the Mhc-DRB1*03 allelic lineage are not only present in humans but in chimpanzees and rhesus macaques as well. This emphasizes that Mhc-DRB1*03 members must have been present in a common ancestor of these primate species that lived about 30 million years ago. Due to the accumulation of genetic variation, however, alleles of the Mhc-DRB1*03 lineage exhibit species-unique sequences. To investigate the biological importance of such conservation and variation, we have studied both the binding and antigen presentation capacity of various trans-species Mhc-DRB1*03 lineage members. Here we show that p3-13 of the 65-kD heat-shock protein (hsp65) of Mycobacterium leprae and M. tuberculosis binds not only to HLA-DR17(3) but also to some chimpanzee and rhesus macaque class II-positive cells. Comparison of the corresponding human, chimpanzee, and rhesus macaque Mhc-DRB1*03 lineage members revealed the presence of uniquely shared amino acid residues, at positions 9-13 and 26-31, of the antigen-binding site that are critical for p3-13 binding. In addition it is shown that several nonhuman primate antigen-presenting cells that bind p3-13 can activate HLA-DR17-restricted T cells. Certain amino acid replacements, however, in Mhc-DRB1*03 lineage members did not influence peptide binding or T cell recognition. Therefore, these studies demonstrate that some polymorphic amino acid residues (motifs) within the antigen-binding site of MHC class II molecules that are crucial for peptide binding and recognition by the T cell receptor have been conserved for over 30 million years.
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PMID:Evolutionary conservation of major histocompatibility complex-DR/peptide/T cell interactions in primates. 845 25

The immunomodulation of T cell recognition by mycobacterial antigens was investigated using T cell clones activated with peptide-pulsed EBV-B cells. An HLA-DR1-restricted T cell clone from a patient with tuberculosis responded to peptide 65-85 from the 65-kDa protein of Mycobacterium tuberculosis in a dose-dependent manner, while no significant response was induced by antigen-nonpulsed EBV-B cells or EBV-B cells pulsed with an unrelated antigen (streptokinase/streptodornase). The observed binding to HLA-DR1 could be inhibited when the EBV-B cells were cultured in the presence of an excess of an HLA-DR1-restricted T cell epitope (residues 1-20) from the 19-kDa protein of M. tuberculosis. This inhibition was dose-dependent. In other experiments, proliferation of a DR1-restricted T cell clone from a healthy individual which responded to peptide 1-20 was inhibited by an excess of peptide 65-85, confirming that these peptides are able to compete for the same DR1-binding site. Nevertheless, the T cell clone from the healthy individual showed a relatively lower percentage of inhibition compared with the T cell clone from a patient with tuberculosis. Furthermore, the intensity of this inhibition was reversed as the concentration of stimulatory peptide was increased. The experiments described in this paper demonstrate the immunomodulation of mycobacterial antigen presentation by peptide competition at the level of MHC-binding sites. These data may be important for an understanding of the interactions involved in the mycobacterial cell-mediated immune recognition.
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PMID:Antigen presentation of mycobacterial peptides to human T cell clones can be immunomodulated by adding an MHC-specific inhibitor. 849 81

The specificity of the T cell-immune repertoire at the level of individual antigenic determinants could play a fundamental role in the immunopathogenesis of tuberculous infections. Therefore, we analyzed the immunogenicity, genetic restriction, and epitope core structure of two adjacent, yet distinct, immunodominant T cell determinants from the 19-kDa Ag of Mycobacterium tuberculosis. After immunization with two peptides comprising residues 45 to 64 and 61 to 80, vigorous in vitro proliferative responses to the homologous peptide were elicited in five different strains of C57BL/10 mice (H-2b,k,d,s,f), indicating that both epitopes were recognized in a genetically permissive manner. When immunized with intact 19-kDa protein, lymph node cells from the same mouse strains responded to both peptides, with the exception of H-2b mice, which did not respond to p45-64. Delayed-type hypersensitivity responses in C57BL/10 (H-2b) mice were elicited by p61-80 only, whereas in H-2d mice both peptides were delayed-type hypersensitivity negative, despite eliciting pronounced proliferative responses. Analysis of the proliferative responses of human PBMC in purified protein derivative-positive healthy subjects and tuberculosis patients revealed significant differences in the antigenicity to the two peptides. All purified protein derivative-positive healthy and diseased individuals manifested strong responses to p45-64, indicating HLA permissive recognition. In contrast, pronounced responses to p61-80 were detected only in patients with lymphatic tuberculosis. Epitope core structures, composed of 6 or 7 residues within each peptide, have been mapped with peptides of overlapping sequence. Significantly, for both epitopes, the core sequences recognized by both human and murine T cells were almost identical. We conclude that despite many similarities between murine and human T cell epitope recognition, distinct differences in the responsiveness of the infected host could play a role in pathogenesis. Furthermore, the genetically permissive nature of the identified epitopes is a potentially important attribute for the development of peptide-based diagnostic reagents and vaccines.
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PMID:Genetically permissive recognition of adjacent epitopes from the 19-kDa antigen of Mycobacterium tuberculosis by human and murine T cells. 849 4

Mycobacterium leprae heat-shock proteins hsp65 and hsp18 have received immense attention as major T-cell target antigens in leprosy. Both of these hsps and their tryptic fragments were characterized for their ability to stimulate CD4+ T cells derived from polar leprosy cases and healthy contacts. The optimal digestion of hsps with trypsin yielded four fragments of hsp65--TDB65-1 (24 kDa), TDB65-2 (18 kDa), TDB65-3 (17 kDa), TDB65-4 (14 kDa)-- and three of hsp18--TDB18-1 (10 kDa), TDB18-2 (5 kDa), TDB18-3 (3 kDa). While all of these tryptic fragments and undigested hsps triggered CD4+ T cells from tuberculoid (TT) leprosy patients and healthy contacts (SI > 2), only two fragments--TDB65-2 and TDB18-3--were found to be stimulatory in anergic lepromatous (LL) leprosy patients (SI = 5.27 and 3.0, respectively). Blocking studies using allele-specific anti-DR monoclonal antibodies revealed multiple HLA-Dr restriction, with DR2 providing the strongest restriction in both TT as well as LL leprosy. These findings indicate that M. leprae hsps and their trypsin-digested fragments are promiscuous and recognizable in the context of diverse HLA alleles, of which DR2 is the most efficient restriction element. The 18-kDa fragment of hsp65 and the 3-kDa fragment of hsp18 are the most versatile fragments that could elicit in vitro proliferation in both polar forms of leprosy.
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PMID:CD4+ T-cell responses to recombinant hsp65 and hsp18 of M. leprae and their trypsin-digested fragments in leprosy: diversity in HLA-DR restriction. 864 14

A 74-year-old woman developed angioimmunoblastic lymphadenopathy (AILD) with involvement of intra-abdominal and retroperitoneal lymph nodes. Southern blot analysis showed germline configuration of the JH genes and an oligoclonal pattern of the TcR beta genes. The immunoblasts were of B-cell phenotype and often expressed the CD30 antigen and the latent membrane protein 1 (LMP1) oncogene. Six nonsilent point mutations were identified near the 3' end of the LMP1 gene, leading to a cluster of six amino acid changes within a protein domain needed for maximal NF-kappa B stimulation. After a clinical remission of 8 months the patient relapsed with generalized lymphadenopathy and died secondary to tuberculosis. The oligoclonal rearrangements of the TcR beta genes may reflect an unsuccessful cellular immune response to Mycobacterium tuberculosis or an HLA-restricted T-cell response to B-immunoblasts expressing mutated viral antigens. A positive percutaneous tuberculin test observed 6 months prior to the onset of AILD is in favor of the first possibility.
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PMID:Miliary tuberculosis in a patient with Epstein-Barr virus-associated angioimmunoblastic lymphadenopathy. 864 48

Induction of suppressor cells has been hypothesized to explain the variability in the efficacy of Mycobacterium bovis BCG vaccination against mycobacterial diseases. In this study, we induced suppressor T cells by in vitro stimulation of peripheral blood mononuclear cells obtained from BCG-vaccinated healthy subjects. These suppressor T cells were CD4+ and did not affect interleukin-1 production by adherent cells in response to BCG. However, they suppressed interleukin-2 (IL-2) production and IL-2 receptor expression by the responding cells. Exogenous addition of IL-2 could partially restore the responsiveness of the indicator cells. To further characterize the cells responsible for suppression, T cell clones were established by limiting dilution. All the established T cell clones expressed CD4 marker, proliferated in response to BCG, were cytotoxic for antigen-presenting cells, and suppressed the antigen-induced proliferation of the indicator cells. Both suppression and cytotoxicity were not mediated by soluble factors but required cell-to-cell contact and were HLA-class II restricted. These results suggest that preferential killing of antigen-presenting cells by CD4+ T cells may be responsible for in vitro observed suppression in our system.
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PMID:Mycobacterium bovis BCG-induced Th1 type CD4+ suppressor T cells act by suppressing IL-2 production and IL-2 receptor expression. 874 54

The T cell response to a mixture of eight peptides derived from sequences of the Mycobacterium tuberculosis 16-, 19- and 38-kD antigens (MTBmix-8) has been studied. The peptides were selected on the basis of complementary binding to nine HLA-DR molecules (HLA-DR1 to DR9). MTBmix-8 at 6.25 and 50 micrograms/ml gave rise to significant stimulation (P < 0.05) of peripheral blood mononuclear cells (PBMC) from healthy tuberculin-positive and both untreated and treated diseased subjects, but not in any of a control group of healthy tuberculin-negative subjects. MTB-mix-8 stimulated proliferation of PBMC from healthy tuberculin-positive individuals at lower concentrations than the individual component peptides. However, the maximal stimulation achieved was only slightly higher than that achieved with individual peptides. MTBmix-8 also stimulated the production of interferon-gamma (IFN-gamma) in vitro. Using the mean +/- 2 s.d. of the values for IFN-gamma production in the tuberculin-negative population as a cut-off, MTBmix-8 at 6.25 micrograms/ml was able to detect infection with a sensitivity of 100% in untreated patients, 87% in treated patients, and 82% in tuberculin-positive controls. The corresponding figures for the most potent single peptide (16p91-110) were: 66% in untreated patients, 71% in treated patients and only 42% in controls. Thus, using the IFN-gamma-based assay, which has the additional advantages of speed and does not require radioactivity, the mixture of peptides is more sensitive than single peptides in diagnosing infection.
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PMID:T cell responses to a mixture of Mycobacterium tuberculosis peptides with complementary HLA-DR binding profiles. 880 28

Understanding the extent to which genetic factors influence the immune response is important in the development of subunit vaccines. Associations with HLA gene polymorphisms appear insufficient to explain the range of variation in immune responses to vaccines and to infections by major pathogens. In this study of Gambian twins we report that regulation of the immune response to a variety of antigens from Plasmodium falciparum and Mycobacterium tuberculosis is controlled by factors which are encoded by genes that lie both within and outside the major histocompatibility complex (MHC). We define the relative contribution of these genes, which varies for different antigens. The cumulative genetic contribution of non-MHC genes to the total phenotypic variance exceeds that of the MHC-encoded genes.
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PMID:Quantification of the relative contribution of major histocompatibility complex (MHC) and non-MHC genes to human immune responses to foreign antigens. 903 90

The mycobacterial 70-kDa heat shock protein (Hsp70) is a dominant antigen during the human T-cell response to mycobacterial infection despite the conserved sequence with the human homolog. To determine whether this response is pathogen specific, CD4+ T-cell clones were isolated from Mycobacterium leprae Hsp70-reactive individuals. The cytokine profile of the clones was mixed, with all of the clones releasing interferon gamma and half releasing interleukin-4 on stimulation, while six demonstrated cytolytic activity. Five clones reacted with the N-terminal half of the molecule, and the epitopes identified were mycobacterium specific. Residues 241 to 260 were identified by three clones, one of which was restricted by HLA-DR7 (DR7), while a DR1-restricted clone identified residues 71 to 90 and residues 261 to 280 were recognized in the context of DR3. The remaining five T-cell clones reacted with the C-terminal half of the molecule, and the precise position of these epitopes was mapped with 12-mer peptides overlapping by 11 residues. Two of these clones identified overlapping epitopes from residues 411 to 425 and 412 to 428, the latter restricted by DR3. Further epitopes were mapped to residues 298 to 313 restricted by DRw53, residues 388 to 406 restricted by DRw52 or DQ2, and residues 471 to 486 restricted by DR1. The sequences of three epitopes, residues 411 to 425, 412 to 428, and 471 to 486, showed significant identity with the equivalent regions of the prototype human Hsp70. However, when amino acid substitutions that made the sequence more like the human sequence were introduced, the changes were tolerated poorly as measured by proliferation, cytokine production, and cytotoxic potential. Therefore, T-cell recognition of the M. leprae Hsp70 antigen occurs in the context of multiple HLA-DR phenotypes and is exquisitely species specific.
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PMID:Human T-cell clones to the 70-kilodalton heat shock protein of Mycobacterium leprae define mycobacterium-specific epitopes rather than shared epitopes. 903 16

The assembly of peptide-major histocompatability class II complexes in vitro is accelerated at low pH, comparable to that found in the intracellular compartments of metabolically active antigen-presenting cells (APC). Mycobacteria such as Mycobacterium tuberculosis reside in phagosomes with only mildly acidic pH. Therefore, we investigated the pH dependency of peptide-HLA-DR binding for several T cell epitopes of mycobacterial proteins, focussing particularly on well-defined, immunodominant HLA-DR17(3)-restricted T cell epitopes: peptide (p) 3-13 from the cytoplasmic 65-kDa heat shock protein of M. tuberculosis/M. leprae, and peptide 56-65 from the secreted 30/31-kDa protein from M. tuberculosis/M. leprae. p3-13 bound to purified, cell-free DR17 under both acidic and neutral conditions. Four other, unrelated DR17-binding peptides showed the same pH-dependent binding characteristics as p3-13. p56-65, however, only bound to purified DR17 at pH 7 but not at all at pH 4.5. These DR17 peptide binding data were confirmed in cell-bound DR17, in T cell stimulation assays in which fixed APC were peptide-pulsed at acidic or neutral pH before addition of peptide-specific DR17-restricted T cells. As far as we are aware, p56-65 is the only human T cell epitope binding to HLA exclusively at neutral pH. The binding characteristics of p56-65 may reflect dominant processing in alternative, less acidic vacuolar compartments specifically related to the generation of epitopes from (secreted) mycobacterial proteins. The observation that p56-65 is an immunodominant epitope for anti-mycobacterial T cells suggests the relevance of such novel processing compartments in T cell-mediated immunity.
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PMID:A DR17-restricted T cell epitope from a secreted Mycobacterium tuberculosis antigen only binds to DR17 molecules at neutral pH. 913 Jun 33


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