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      Single Nucleotide Polymorphisms in IL17A and IL6 Are Associated with Decreased Risk for Pulmonary Tuberculosis in Southern Brazilian Population

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          Abstract

          In Mycobacterium tuberculosis (MTB) infection, the complex interaction of host immune system and the mycobacteria is associated with levels of cytokines production that play a major role in determining the outcome of the disease. Several single-nucleotide polymorphisms (SNPs) in cytokine genes have been associated with tuberculosis (TB) outcome. The aim of this study was to evaluate the association between previously reported SNPs IL2–330 T>G (rs2069762); IL4–590 C>T (rs2243250); IL6–174 G>C (rs1800795); IL10–592 A>C (rs1800872); IL10–1082 G>A (rs1800896); IL17A -692 C>T (rs8193036); IL17A -197 G>A (rs2275913); TNF -238 G>A (rs361525); TNF -308 G>A (rs1800629) and IFNG +874 T>A (rs2430561) and pulmonary TB (PTB) susceptibility. We conducted a case-control study in individuals from Southern Brazil who were recruited between February 2012 and October 2013 in a high incidence TB city. We performed a multiplex genotyping assay in 191 patients with PTB and 175 healthy subjects. Our results suggest a decreased risk for PTB development associated with the IL17A -197A allele (OR = 0.29; p = 0.04), AA genotype (OR = 0.12; p = 0.04) and A carrier (AG /AA) (OR = 0.29; p = 0.004) and IL6 -174C carrier (CC/CG) (OR = 0.46; p = 0.04). We could not properly analyze IL17A -692 C>T (rs8193036) and IFNG +874T>A due to genotypic inconsistencies and found no evidence of association for the IL2, IL4, IL10 and TNF polymorphisms and PTB. In conclusion, our results show a protective effect of IL17 and IL6 polymorphisms on PTB outcome in Southern Brazilian population.

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          Most cited references 59

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          Immunology of tuberculosis.

          The resurgence of tuberculosis worldwide has intensified research efforts directed at examining the host defense and pathogenic mechanisms operative in Mycobacterium tuberculosis infection. This review summarizes our current understanding of the host immune response, with emphasis on the roles of macrophages, T cells, and the cytokine/chemokine network in engendering protective immunity. Specifically, we summarize studies addressing the ability of the organism to survive within macrophages by controlling phagolysosome fusion. The recent studies on Toll-like receptors and the impact on the innate response to M. tuberculosis are discussed. We also focus on the induction, specificity, and effector functions of CD4(+) and CD8(+) T cells, and the roles of cytokines and chemokines in the induction and effector functions of the immune response. Presentation of mycobacterial antigens by MHC class I, class II, and CD1 as well as the implications of these molecules sampling various compartments of the cell for presentation to T cells are discussed. Increased attention to this disease and the integration of animal models and human studies have afforded us a greater understanding of tuberculosis and the steps necessary to combat this infection. The pace of this research must be maintained if we are to realize an effective vaccine in the next decades.
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            The spectrum of latent tuberculosis: rethinking the biology and intervention strategies.

            Immunological tests provide evidence of latent tuberculosis in one third of the global population, which corresponds to more than two billion individuals. Latent tuberculosis is defined by the absence of clinical symptoms but carries a risk of subsequent progression to clinical disease, particularly in the context of co-infection with HIV. In this Review we discuss the biology of latent tuberculosis as part of a broad range of responses that occur following infection with Mycobacterium tuberculosis, which result in the formation of physiologically distinct granulomatous lesions that provide microenvironments with differential ability to support or suppress the persistence of viable bacteria. We then show how this model can be used to develop a rational programme to discover effective drugs for the eradication of M. tuberculosis infection.
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              IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge.

              Interferon-gamma is key in limiting Mycobacterium tuberculosis infection. Here we show that vaccination triggered an accelerated interferon-gamma response by CD4(+) T cells in the lung during subsequent M. tuberculosis infection. Interleukin 23 (IL-23) was essential for the accelerated response, for early cessation of bacterial growth and for establishment of an IL-17-producing CD4(+) T cell population in the lung. The recall response of the IL-17-producing CD4(+) T cell population occurred concurrently with expression of the chemokines CXCL9, CXCL10 and CXCL11. Depletion of IL-17 during challenge reduced the chemokine expression and accumulation of CD4(+) T cells producing interferon-gamma in the lung. We propose that vaccination induces IL-17-producing CD4(+) T cells that populate the lung and, after challenge, trigger the production of chemokines that recruit CD4(+) T cells producing interferon-gamma, which ultimately restrict bacterial growth.
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                Author and article information

                Affiliations
                [1 ]Programa de Pós-Graduação em Biologia Celular e Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
                [2 ]Centro de Desenvolvimento Científico e Tecnológico, Fundação Estadual de Produção e Pesquisa em Saúde, Porto Alegre, Rio Grande do Sul, Brazil
                [3 ]Laboratório de Hanseníase, Instituto Oswaldo Cruz Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil
                [4 ]Division of Infectious Disease and Vaccinology, University of California, Berkeley, United States of America
                [5 ]Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
                [6 ]Programa de Pós-Graduação em Clínica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
                [7 ]Hospital Sanatório Partenon, Porto Alegre, Rio Grande do Sul, Brazil
                [8 ]Universidade Luterana do Brazil, Canoas, Rio Grande do Sul, Brazil
                Public Health Research Institute at RBHS, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MM GU ERDC MLRR GM LLC. Performed the experiments: MM RR GM LLC. Analyzed the data: MOM CXC MM MD. Contributed reagents/materials/analysis tools: MD MM RR ERDC. Wrote the paper: MM MOM.

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                3 February 2016
                2016
                : 11
                : 2
                26840977 4740512 10.1371/journal.pone.0147814 PONE-D-15-42296
                © 2016 Milano et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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                Figures: 0, Tables: 2, Pages: 11
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                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Biology and Life Sciences
                Organisms
                Bacteria
                Actinobacteria
                Mycobacterium Tuberculosis
                Medicine and Health Sciences
                Infectious Diseases
                Bacterial Diseases
                Tuberculosis
                Medicine and Health Sciences
                Tropical Diseases
                Tuberculosis
                Biology and Life Sciences
                Physiology
                Immune Physiology
                Cytokines
                Medicine and Health Sciences
                Physiology
                Immune Physiology
                Cytokines
                Biology and Life Sciences
                Immunology
                Immune System
                Innate Immune System
                Cytokines
                Medicine and Health Sciences
                Immunology
                Immune System
                Innate Immune System
                Cytokines
                Biology and Life Sciences
                Developmental Biology
                Molecular Development
                Cytokines
                Biology and Life Sciences
                Genetics
                Heredity
                Genetic Mapping
                Variant Genotypes
                Biology and Life Sciences
                Computational Biology
                Genome Analysis
                Genome-Wide Association Studies
                Biology and Life Sciences
                Genetics
                Genomics
                Genome Analysis
                Genome-Wide Association Studies
                Biology and Life Sciences
                Genetics
                Human Genetics
                Genome-Wide Association Studies
                Biology and Life Sciences
                Immunology
                Immune Response
                Medicine and Health Sciences
                Immunology
                Immune Response
                Biology and Life Sciences
                Genetics
                Genetics of Disease
                Research and Analysis Methods
                Research Design
                Case-Control Studies
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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