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PubMed2002

Mice lacking the multidrug resistance protein 1 have a transiently impaired immune response during tuberculosis.

A T helper (Th) 1 immune response is important for host defense against tuberculosis. The multidrug resistance protein (Mrp) 1 is constitutively present at low levels on Th2 lymphocytes, and is expressed on Th1 lymphocytes upon activation. To determine the role of Mrp1 in the pathogenesis of tuberculosis, Mrp1 deficient (-/-) and normal wild type mice were intranasally infected with Mycobacterium tuberculosis. At 2 weeks after infection, Mrp1(-/-) mice had reduced levels of the Th1 cytokine interferon-gamma and an impaired granuloma formation in their lungs. At 5 weeks postinfection, M. tuberculosis outgrowth was enhanced in lungs and livers of Mrp1(-/-) mice. A more prolonged observation of these mice, up to 4 months, revealed no differences in survival or mycobacterial outgrowth. These data suggest that Mrp1 plays an early but dispensable role in the protective immune response to pulmonary tuberculosis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1983

Immune thrombocytopenia associated with tuberculosis.

Thrombocytopenia associated with Mycobacterium tuberculosis infection developed concurrently in a mother and son. Antiplatelet antibodies were demonstrated in the serum of both patients. It is suggested that this and possibly other hematologic complications associated with tuberculosis are immune mediated.

Adult↗
PubMed1995

Recall of long-lived immunity to Mycobacterium tuberculosis infection in mice.

Our study investigates the recall of immunity in the mouse model of memory immunity to tuberculosis infection. The results provide evidence that recall of immunity is expressed as an accelerated accumulation of potent effector cells in the infected target organs. These effector cells were recruited from the resting pool of memory cells and were immediately triggered to exert their effector functions, leading to a massive release of Th1 cytokines detectable both in splenic extracts and in the serum within the first 24 h of infection. During a primary infection, in contrast, a 14-day delay was observed before significant cytokine levels were reached. After the initial effector phase, the cells blasted and entered into clonal expansion, resulting in a rapid increase in the total number of CD4 CD45RBlow cells in the spleen. The recall of memory immunity was highly efficient and controlled an infectious challenge within the first week. The molecules recognized by the memory effector subset were the proteins secreted from Mycobacterium tuberculosis during growth. By separating the CD4 population into CD45RBhigh and CD45RBlow subsets, the memory effector cells were demonstrated to reside predominantly in the activated population of CD45RBlow CD44high LFA-1high L-selectinlow cells. The key antigenic targets recognized by these cells were identified as Ag85B and a secreted 6-kDa protein (ESAT-6) that elicited the release of exceedingly high levels of IFN-gamma. ESAT-6 was biochemically purified, characterized, and the gene encoding the protein was cloned.

Amino Acid Sequence↗
PubMed2002

Innate immunity to Mycobacterium tuberculosis.

The different manifestations of infection with Mycobacterium tuberculosis reflect the balance between the bacillus and host defense mechanisms. Traditionally, protective immunity to tuberculosis has been ascribed to T-cell-mediated immunity, with CD4(+) T cells playing a crucial role. Recent immunological and genetic studies support the long-standing notion that innate immunity is also relevant in tuberculosis. In this review, emphasis is on these natural, innate host defense mechanisms, referring to experimental data (e.g., studies in gene knockout mice) and epidemiological, immunological, and genetic studies in human tuberculosis. The first step in the innate host defense is cellular uptake of M. tuberculosis, which involves different cellular receptors and humoral factors. Toll-like receptors seem to play a crucial role in immune recognition of M. tuberculosis, which is the next step. The subsequent inflammatory response is regulated by production of pro- and anti-inflammatory cytokines and chemokines. Different natural effector mechanisms for killing of M. tuberculosis have now been identified. Finally, the innate host response is necessary for induction of adaptive immunity to M. tuberculosis. These basic mechanisms augment our understanding of disease pathogenesis and clinical course and will be of help in designing adjunctive treatment strategies.

Cytokines↗
PubMed1981

Circulating immune complexes in tuberculosis.

Using a polyethylene glycol precipitation method, immune complexes were detected in 56% of patients with active tuberculosis. After antituberculous treatment, 29% remained positive for immune complexes, a frequency similar to that in a group of racially matched clinic controls (35%). In a study of 17 patients whose immune complex levels were determined soon after diagnosis and again when the therapy had ceased, there was a significant decrease in complexed IgM and Clq. Sequential studies of immune complex levels in tuberculosis merit further investigation, their persistence may indicate the continued presence of antigens, and their disappearance from the circulation may be a guide to successful treatment.

Adolescent↗
PubMed2001

Human immunodeficiency virus-seronegative adults with extrapulmonary tuberculosis have abnormal innate immune responses.

Extrapulmonary tuberculosis is presumably a marker of underlying immunodeficiency, but cytokine response pathways in these patients have not been well studied. Cytokine responses of peripheral blood mononuclear cells from human immunodeficiency virus-seronegative adults with prior culture-confirmed extrapulmonary tuberculosis were compared with those of persons with latent Mycobacterium tuberculosis infection. Mitogen-stimulated interferon (IFN)-gamma production, interleukin (IL)-12 production, and IFN-gamma receptor- and IL-12 receptor-mediated cytokine production did not differ between case patients and control patients. However, median resting IL-8 production was significantly lower in case patients than control patients (8051 vs. 19,290 pg/mL; P=.009). In addition, the median tumor necrosis factor (TNF)-alpha response was lower in case patients than control patients after stimulation with lipopolysaccharide (833 vs. 1149 pg/mL; P=.06) and lipopolysaccharide plus IFN-gamma (3301 vs. 4411 pg/mL; P=.04). These abnormalities in resting IL-8 and lipopolysaccharide-induced TNF-alpha production were not associated with IFN-gamma or IL-12 abnormalities and were detected up to several years after cure of disease, suggesting an abnormality in innate immunity.

Case-Control Studies↗
PubMed1996

[Cellular immune response in tuberculosis: analysis of T-lymphocytes and their subsets, B-lymphocytes and natural cytotoxic cells in different tuberculosis states and body fluids].

BACKGROUND: The immune response to Mycobacterium tuberculosis is primarily mediated by T lymphocytes. In this study an investigation was made of T lymphocytes and their subsets, B lymphocytes and natural cytotoxic cells (Natural Killer, NK) in blood and organic fluids in different tuberculosis conditions. METHODS: Patients with localized pulmonary tuberculosis (LPT, n = 12), extensive pulmonary tuberculosis (EPT, n = 24), pleural tuberculosis (PLE, n = 14), disseminated tuberculosis (DIS, n = 10), recent Mantoux converters (MAN, n = 15) and healthy subjects (CON, n = 19) were studied. HIV+ and immunosuppressed patients were excluded. Total lymphocytes and T subsets (CD3, CD4, CD8, TCR alpha beta and gamma delta), B (CD19) and NK cells (CD56) in blood and pleural fluid (n = 7) and ascitic fluid (n = 3) were determined. RESULTS: An increase was observed in total lymphocytes and all T subsets (CD3, CD4, CD8, alpha beta and gamma delta) in MAN group compared with CON group (p < 0.05 for all determinations). A progressive lymphopenia of total lymphocytes and CD4 was observed with more extensive disease, particularly in the DIS group (p < 0.05). No differences were observed between groups regarding B lymphocytes and NK cells. In pleural effusions and ascitic exudates an accumulation of T lymphocytes, mainly CD4, was observed, with no increase in gamma delta T lymphocytes. CONCLUSIONS: 1) In patients with recent tuberculosis infection T lymphocytosis (total and subsets) occurs. 2) In the absence of HIV infection, a progressive lymphopenia occurs, particularly CD4, with extending disease. 3) In tuberculous pleural effusions and ascitic exudates and accumulation of CD4 T lymphocytes occurs, but not TCR gamma delta lymphocytes.

Adolescent↗
PubMed2003

Seroreactivity of 31 kDa and 41 kDa mycobacterial secretory proteins isolated from culture filtrate in extra pulmonary tuberculosis.

Despite rapid advances in molecular genetics for detection of mycobacteria, it is clear that interest in serodiagnosis remains high, especially for those situations in which a specimen may not contain the infecting agent in particular in extrapulmonary tuberculosis. Immune response to excretory-secretory (ES) proteins of Mycobacterium tuberculosis (M.tb) has been of diagnostic interest in tuberculosis. In earlier study from our laboratory, a secretory protein M.tb ES-31 has been shown to have diagnostic potential in pulmonary tuberculosis. Further, another M.tb H37Ra ES protein (ES-41) was isolated and purified by trichloroacetic acid solubilization followed by Fast Performance Liquid Chromatography (FPLC). These two protein fractions viz ES-31 and ES-41 secreted by M.tb H37 Ra bacilli were employed in stick indirect penicillinase ELISA to study seroreactivity in extra pulmonary tuberculosis namely tuberculous lymphadenopathy, tuberculous meningitis, abdominal tuberculosis and bone & joint tuberculosis. While using ES-31 antigen 88% (22/25) of tuberculous lymphadenopathy and 90% (9/10) of tuberculous meningitis cases showed positive reaction for tuberculous IgG antibody, ES-41 showed 80% positivity in both groups. In abdominal and bone & joint tuberculosis cases, ES-41 antigen showed better sensitivity of 81.5% (22/27) and 84.6% (22/26) respectively in IgG antibody detection compared to 70% (19/27) and 69.2% (18/26) shown by ES-31. This study is of interest that different antigen protein fractions of M.tb exhibit differential seroreactivity, as ES-31 protein showed good potential in detecting tuberculous IgG antibodies in tuberculous lymphadenopathy (TBLN) & tuberculous meningitis (TBM), while ES-41 in abdominal and bone & joint tuberculosis cases.

Antibodies, Bacterial↗
PubMedDate not supplied

Circulating immune complexes in tuberculosis--an indicator of activity.

Circulating immune complexes (CIC) were assayed in 100 cases of tuberculosis and 30 age matched control children. The estimation was done by PEG assay before the commencement of antitubercular therapy. CIC were present in only 3.3% of the control children as compared to 68% of children with tuberculosis. The presence of CIC was observed to vary with the type of tuberculosis. The percentage positivity was highest (100%) in children with miliary tuberculosis. Subsequent estimation of CIC done after one and three months of antitubercular therapy showed a marked decrease in the percentage of positive cases (6.1 and zero percent respectively).

Antigen-Antibody Complex↗
PubMed1995

The role of interleukin-12 in acquired immunity to Mycobacterium tuberculosis infection.

The early phase of acquired cellular immunity to Mycobacterium tuberculosis infection is mediated by the emergence of protective CD4 T lymphocytes that secrete cytokines including interferon-gamma (IFN-gamma), a molecule which is pivotal in the expression of resistance to tuberculosis. Recent evidence demonstrates that infection with M. tuberculosis induces peripheral blood mononuclear cells to release the cytokine interleukin-12 (IL-12), a molecule that promotes the emergence of T-helper type-1 (Th1), IFN-gamma-producing T cells. We demonstrate here that IL-12 mRNA expression was induced by M. tuberculosis infection both in vivo and in vitro and that exogenous administration of IL-12 to mice transiently resulted in increased resistance to the infection. IL-12 also increased the production of IFN-gamma by both splenocytes derived from infected animals treated in vivo and by antigen-stimulated CD4 cells from untreated infected animals, with maximal effects at times associated with the expansion of antigen-specific CD4 T cells in vivo. In the absence of a T-cell response, as seen in SCID mice or nude mice, IL-12 only slightly augmented the moderate bacteriostatic capacity of these immunocompromised mice. Neutralization of IL-12 by specific monoclonal antibodies resulted in a reduction in granuloma integrity and slowing of the capacity of the animal to control bacterial growth.

Animals↗
PubMed1998

Cytotoxic T-lymphocytes against malaria and tuberculosis: from natural immunity to vaccine design.

1. Mycobacterium tuberculosis and the liver stage of Plasmodium falciparum are intracellular pathogens which are potentially susceptible to cytotoxic T-lymphocytes, a crucial component of the protective immune response to viral infections. Evidence from animal models points to a protective role for cytotoxic T-lymphocytes against M. tuberculosis and P. falciparum, but cytotoxic T-lymphocytes specific for these pathogens have been difficult to identify in man.2. Using a reverse immunogenetic approach, candidate epitopes from selected antigens of P. falciparum and M. tuberculosis were used to detect peptide-specific cytotoxic T-lymphocyte responses in individuals exposed to these pathogens. Cytotoxic T-lymphocyte activity was detected by the 51Cr release cytotoxicity assay and a sensitive ELISPOT assay for single-cell interferon-gamma release.3. In naturally exposed, partially immune Africans in The Gambia, eight largely conserved cytotoxic T-lymphocyte epitopes in P. falciparum, restricted by several different HLA class I alleles, were identified. Several epitopes were also recognized in Tanzanians and cytotoxic T-lymphocytes recognized endogenously processed antigen.4. In tuberculosis patients with HLA-B52, a CD8+ cytotoxic T-lymphocyte epitope was identified in ESAT-6, a secreted antigen specific for M. tuberculosis complex but absent in BCG. Cytotoxic T-lymphocytes exhibited HLA-B52-restricted peptide-specific interferon-gamma release and lytic activity and recognized endogenously processed antigen.5. These studies demonstrate that CD8+ cytotoxic T-lymphocytes specific for mycobacterial and protozoal antigens are induced during natural infections in humans. The identification of these T-cells endorses current strategies to develop cytotoxic T-lymphocyte-inducing vaccines against P. falciparum and M. tuberculosis and highlights candidate antigens for inclusion in subunit vaccines.

Animals↗
PubMed1995

[Immunology of tuberculosis].

Protective immunity against Mycobacterium tuberculosis is mediated by specific T lymphocytes and executed by mononuclear phagocytes. The crosstalk between distinct T cell subsets and macrophages involves various cytokines. Attraction of blood monocytes to the site of mycobacterial replication and local macrophage activation result in granuloma formation. Interactions between T cell subsets and macrophages within granulomas enable the host to restrict mycobacterial growth, but only rarely cause sterile eradication. Therefore, at later time points, active tuberculosis may develop as a consequence of weakened immunity.

Humans↗
PubMed1996

Key epitopes on the ESAT-6 antigen recognized in mice during the recall of protective immunity to Mycobacterium tuberculosis.

The recall of long-lived immunity in a mouse model of tuberculosis (TB) is defined as an accelerated accumulation of reactive T cells in the target organs. We have recently identified Ag 85B and a 6-kilodalton early secretory antigenic target, designated ESAT-6, as key antigenic targets recognized by these cells. In the present study, preferential recognition of the ESAT-6 Ag during the recall of immunity was found to be shared by five of six genetically different strains of mice. Overlapping peptides spanning the sequence of ESAT-6 were used to map two T cell epitopes on this molecule. One epitope recognized in the context of H-2b,d was located in the N-terminal part of the molecule, whereas an epitope recognized in the context of H-2a,k covered amino acids 51 to 60. Shorter versions of the N-terminal epitope allowed the precise definition of a 13-amino acid core sequence recognized in the context of H-2b. The peptide covering the N-terminal epitope was immunogenic, and a T cell response with the same fine specificity as that induced during TB infection was generated by immunization with the peptide in IFA. In the C57BL/6j strain, this single epitope was recognized by an exceedingly high frequency of splenic T cells (approximately 1:1000), representing 25 to 35% of the total culture filtrate-reactive T cells recruited to the site of infection during the first phase of the recall response. These findings emphasize the relevance of this Ag in the immune response to TB and suggest that immunologic recognition in the first phase of infection is a highly restricted event dominated by a limited number of T cell clones.

Amino Acid Sequence↗
PubMed2005

Diabetes and tuberculosis interface.

Diabetes mellitus is often complicated by acute or chronic infections, as it is a secondary immune deficiency disorder. Diabetes mellitus produces immune alterations of both cellular and humoral immunity. Tuberculosis in diabetes mellitus is 2-5 times higher. Chances of recurrence with multidrug resistant bacteria are common. More cavitary lesions, less sputum positivity and with relative paucity of symptoms and signs are the features. Treatment for diabetes mellitus should be done with insulin. Every diabetic person should be screened for tuberculosis and every tuberculosis patient should also be searched for diabetes.

Comorbidity↗
PubMed1984

Staphylococcus aureus protein A antibody-mediated haemagglutination assay. A study on the interaction between protein A-bound specific antibodies and red-cell-bound specific antigens.

A method has been described for the enhancement of the sensitivity of the passive haemagglutination (PHA) reaction through intact cells of Staphylococcus aureus (Cowan I) bearing protein A (SAPA) which bind Fc portion of IgG derived from many mammalian species. Interactions between Mycobacterium tuberculosis sonicate antigen-sensitized red cells and antimycobacterial antibodies derived from M. tuberculosis immunized goat, rabbit, guinea pig and mouse sera and sera from human tuberculosis patients have been used as model systems. SAPA cells were allowed to bind antibodies from sera and subsequently cross-react with antigen-sensitized red cells. Co-haemagglutination occurred only when specific antibodies were bound by SAPA cells. The sensitivity of this SAPA antibody-mediated haemagglutination assay (SAPA-AMHA) was found to be higher than that of PHA reaction and it depended upon protein A antibody affinity. The specificity of the interaction between SAPA cell-bound antibodies and red-cell-bound antigens suggests that these two reagents offer a simple and sensitive approach for the study of antigen-antibody reactions.

Animals↗
PubMed2003

Advances in antibody-mediated immunity against Mycobacterium tuberculosis: implications for a novel vaccine strategy.

Cell-mediated immunity is considered to be the major component of the host response against Mycobacterium tuberculosis, whereas antibody-mediated immunity historically has been considered inconsequential. In recent years, studies from several groups have challenged the traditional dogma and demonstrated that monoclonal antibodies can modify various aspects of mycobacterial infections. This review describes the experimental evidence supporting a role for antibodies in defense against mycobacterial infections and outlines future challenges to the field of antibody-mediated immunity against M. tuberculosis, with particular emphasis on the implications of these findings for a novel vaccine strategy.

Antibodies, Bacterial↗
PubMed2002

Comparative affects of plasmid-encoded interleukin 12 and interleukin 18 on the protective efficacy of DNA vaccination against Mycobacterium tuberculosis.

Protective immunity against Mycobacterium tuberculosis infection requires the induction and maintenance of mycobacteria-specific, IFN-gamma-secreting CD4+ and CD8+ T lymphocytes. The development of Th1-like T cells is promoted by the early secretion and synergistic action of interleukin (IL)-12 and IL-18. This study compares the effects of plasmid-encoded IL-12 and IL-18 on the immunogenicity and protective efficacy of a DNA vaccine expressing the M. tuberculosis-secreted protein antigen 85B (DNA-85B). Co-immunization with either IL-12- or IL-18-expressing plasmids augmented the IFN-gamma-secreting T-cell response, and the maximum effect was observed with plasmids encoding both cytokines. Further the IL-12, but not the IL-18-expressing plasmid, significantly increased the protective efficacy of DNA-85B against pulmonary M. tuberculosis infection. Therefore co-administration of plasmid-encoded cytokines provides a potential method for optimizing the protective efficacy of DNA vaccination against tuberculosis.

Acyltransferases↗