Differential B-Cell Responses Are Induced by Mycobacterium tuberculosis PE Antigens Rv1169c, Rv0978c, and Rv1818c

Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India.
Clinical and Vaccine Immunology (Impact Factor: 2.47). 11/2007; 14(10):1334-41. DOI: 10.1128/CVI.00181-07
Source: PubMed


The multigene PE and PPE family represents about 10% of the genome of Mycobacterium tuberculosis. Here, we report that three members of the PE family, namely, Rv1169c, Rv0978c, and Rv1818c, elicit a strong, but differential,
B-cell humoral response among different clinical categories of tuberculosis patients. The study population (n = 211) was comprised of different clinical groups of both adult and child patients: group 1 (n = 94) patients with pulmonary infection, group 2 (n = 30) patients with relapsed infection, group 3 (n = 31) patients with extrapulmonary infections, and clinically healthy donors (n = 56). Among the PE proteins studied, group 1 adult patient sera reacted to Rv1818c and Rv0978c, while Rv1169c elicited immunoreactivity
in group 3 children. However, all three PE antigens studied as well as the 19-kDa antigen did not demonstrate humoral reactivity
with sera from group 2 patients with relapsed infection. The current study shows that while responsiveness to all three PE
antigens is a good marker for M. tuberculosis infection, a strong response to Rv0978c or to Rv1818c by group 1 adult patients with pulmonary infection or largely restricted
reactivity to Rv1169c antigen in child patients with extrapulmonary infections offers the possibility of differential utility
in the serodiagnosis of tuberculosis.

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    • "Some PE_PGRS proteins are exposed at the bacterial surface, where they can interact with the host immune system (3–5). Antibodies against PE_PGRS51, PE_PGRS62, PE_PGRS33, and the PGRS domain of Wag22 (Rv1759cPE_PGRS) are present in sera from patients with tuberculosis or during experimental tuberculosis in mice (6–10). Several PE_PGRS elicit T-cell responses in humans and are recognized by major histocompatibility complex-I (MHC-I)-restricted CD8+ T cells in mice, suggesting that many members of the PE_PGRS subfamily are highly immunogenic (11, 12). "
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    ABSTRACT: The PE_PGRS33 protein is a member of the PE family, which encompasses the PE and the PE_PGRS subfamilies. Among PE_PGRS's, this protein is one of the most studied antigens and its immunomodulatory properties are influence by both PE and PGRS domains. However, the contribution of these domains to the host immune recognition of the PE_PGRS33 protein and their potential role in latent tuberculosis infection in humans is still unknown. In this study, the immunogenic properties of the complete PE_PGRS33 protein and each domain separately were evaluated in BALB/c mice and latent tuberculosis infected (LTBI) humans. In mice, PE_PGRS33 and its domains induced similar antibody production and secretion of IFN-γ. PE_PGRS33 and the PE domain stimulated higher CD4(+) and CD8(+) T-cell proliferation compared to the PGRS domain. This demonstrated that the principal difference in the immune recognition of the domains is the higher activation of T-cell subpopulations involved in the control of tuberculosis. In humans, the secretion of IFN-γ in response to PE_PGRS33 was detected in both LTBI and in non-infected vaccinated individuals. The same was observed for antibody response, which targets epitopes located in the PGRS domain but not in the PE domain. These observations suggest that T and B cell responses to PE_PGRS33 are induced by BCG vaccination and can be maintained for many years in non-infected individuals. This also indicates that the IFN-γ response detected might not be associated with latent tuberculosis infection. These results contribute to the elucidation of the role of the PE_PGRS33 protein and its PE and PGRS domains in the immune response against Mycobacterium tuberculosis.
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    • "Recombinant proteins Rv3875 and Rv3874 were purchased from Statens Serum Institute (SSI, Copenhagen, Denmark). The recombinant PPE-proteins Rv0754, Rv0978c and Rv1917c were produced by Professor K. N. Balaji, Bangalore, India [55,62-64]. A mixture of Staphylococcal Enterotoxin A and B, (SEA/SEB; 10 ng/mlSigma Aldrich, USA) was used as the positive control for T-cell reactivity. "
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    ABSTRACT: A better understanding of the quality of cellular immune responses directed against molecularly defined targets will guide the development of TB diagnostics and identification of molecularly defined, clinically relevant M.tb vaccine candidates. Recombinant proteins (n = 8) and peptide pools (n = 14) from M. tuberculosis (M.tb) targets were used to compare cellular immune responses defined by IFN-γ and IL-17 production using a Whole Blood Assay (WBA) in a cohort of 148 individuals, i.e. patients with TB + (n = 38), TB- individuals with other pulmonary diseases (n = 81) and individuals exposed to TB without evidence of clinical TB (health care workers, n = 29). M.tb antigens Rv2958c (glycosyltransferase), Rv2962c (mycolyltransferase), Rv1886c (Ag85B), Rv3804c (Ag85A), and the PPE family member Rv3347c were frequently recognized, defined by IFN-γ production, in blood from healthy individuals exposed to M.tb (health care workers). A different recognition pattern was found for IL-17 production in blood from M.tb exposed individuals responding to TB10.4 (Rv0288), Ag85B (Rv1886c) and the PPE family members Rv0978c and Rv1917c. The pattern of immune target recognition is different in regard to IFN-γ and IL-17 production to defined molecular M.tb targets in PBMCs from individuals frequently exposed to M.tb. The data represent the first mapping of cellular immune responses against M.tb targets in TB patients from Honduras.
    Full-text · Article · Mar 2013 · BMC Infectious Diseases
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    • "As compared to other members of the PE family (including PG_PGRS) or mycobacterial antigens, PE_PGR11 and PE_PGR17 have been shown to elicit stronger and differential antibody response in humans. Our laboratory has previously reported that PE_PGR11 and PE_PGR17 elicited antibodies in adult humans with active pulmonary infection, and in child patients with pulmonary or extrapulmonary TB [27], [28], [52]. Serology studies have demonstrated that antibodies reactive with a recombinant carboxyterminal fragment of the PE_PGRS protein from Rv1759c [53] or with the PGRS domain of Rv3367 [54] are present in human sera of patients infected with TB. "
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    ABSTRACT: Mycobacterium tuberculosis, a causative agent of chronic tuberculosis disease, is widespread among some animal species too. There is paucity of information on the distribution, prevalence and true disease status of tuberculosis in Asian elephants (Elephas maximus). The aim of this study was to estimate the sensitivity and specificity of serological tests to diagnose M. tuberculosis infection in captive elephants in southern India while simultaneously estimating sero-prevalence. Health assessment of 600 elephants was carried out and their sera screened with a commercially available rapid serum test. Trunk wash culture of select rapid serum test positive animals yielded no animal positive for M. tuberculosis isolation. Under Indian field conditions where the true disease status is unknown, we used a latent class model to estimate the diagnostic characteristics of an existing (rapid serum test) and new (four in-house ELISA) tests. One hundred and seventy nine sera were randomly selected for screening in the five tests. Diagnostic sensitivities of the four ELISAs were 91.3-97.6% (95% Credible Interval (CI): 74.8-99.9) and diagnostic specificity were 89.6-98.5% (95% CI: 79.4-99.9) based on the model we assumed. We estimate that 53.6% (95% CI: 44.6-62.8) of the samples tested were free from infection with M. tuberculosis and 15.9% (97.5% CI: 9.8 - to 24.0) tested positive on all five tests. Our results provide evidence for high prevalence of asymptomatic M. tuberculosis infection in Asian elephants in a captive Indian setting. Further validation of these tests would be important in formulating area-specific effective surveillance and control measures.
    Full-text · Article · Dec 2012 · PLoS ONE
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