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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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          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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            Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice.

            Understanding the immunological mechanisms of protection and pathogenesis in tuberculosis remains problematic. We have examined the extent to which tumor necrosis factor-alpha (TNF alpha) contributes to this disease using murine models in which the action of TNF alpha is inhibited. TNF alpha was neutralized in vivo by monoclonal antibody; in addition, a mouse strain with a disruption in the gene for the 55 kDa TNF receptor was used. The data from both models established that TNF alpha and the 55 kDa TNF receptor are essential for protection against tuberculosis in mice, and for reactive nitrogen production by macrophages early in infection. Granulomas were formed in equal numbers in control and experimental mice, but necrosis was observed only in mice deficient in TNF alpha or TNF receptor. TNF alpha and the 55 kDa TNF receptor are necessary conditions for protection against murine M. tuberculosis infection, but are not solely responsible for the tissue damage observed.
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              Interleukin-17 and innate immunity in infections and chronic inflammation.

              Interleukin 17 (IL-17) includes several cytokines among which IL-17A is considered as one of the major pro-inflammatory cytokine being central to the innate and adaptive immune responses. IL-17 is produced by unconventional T cells, members of innate lymphoid cells (ILCs), mast cells, as well as typical innate immune cells, such as neutrophils and macrophages located in the epithelial barriers and characterised by a rapid response to infectious agents by recruiting neutrophils as first line of defence and inducing the production of antimicrobial peptides. Th17 responses appear pivotal in chronic and acute infections by bacteria, parasites, and fungi, as well as in autoimmune and chronic inflammatory diseases, including rheumatoid arthritis, psoriasis, and psoriatic arthritis. The data discussed in this review cumulatively indicate that innate-derived IL-17 constitutes a major element in the altered immune response against self antigens or the perpetuation of inflammation, particularly at mucosal sites. New drugs targeting the IL17 pathway include brodalumab, ixekizumab, and secukinumab and their use in psoriatic disease is expected to dramatically impact our approach to this systemic condition.
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                Author and article information

                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
                : e0147814
                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.

                Article
                PONE-D-15-42296
                10.1371/journal.pone.0147814
                4740512
                26840977
                1299758b-ae19-44a9-9a51-10d6d5d65d28
                © 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.

                History
                : 24 September 2015
                : 8 January 2016
                Page count
                Figures: 0, Tables: 2, Pages: 11
                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
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                All relevant data are within the paper and its Supporting Information files.

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