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      Inflammation Enhances the Risks of Stroke and Death in Chronic Chagas Disease Patients

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          Abstract

          Ischemic strokes have been implicated as a cause of death in Chagas disease patients. Inflammation has been recognized as a key component in all ischemic processes, including the intravascular events triggered by vessel interruption, brain damage and repair. In this study, we evaluated the association between inflammatory markers and the death risk (DR) and stroke risk (SR) of patients with different clinical forms of chronic Chagas disease. The mRNA expression levels of cytokines, transcription factors expressed in the adaptive immune response (Th1, Th2, Th9, Th17, Th22 and regulatory T cell), and iNOS were analyzed by real-time PCR in peripheral blood mononuclear cells of chagasic patients who exhibited the indeterminate, cardiac, digestive and cardiodigestive clinical forms of the disease, and the levels of these transcripts were correlated with the DR and SR. Cardiac patients exhibited lower mRNA expression levels of GATA-3, FoxP3, AHR, IL-4, IL-9, IL-10 and IL-22 but exhibited higher expression of IFN-γ and TNF-α compared with indeterminate patients. Digestive patients showed similar levels of GATA-3, IL-4 and IL-10 than indeterminate patients. Cardiodigestive patients exhibited higher levels of TNF-α compared with indeterminate and digestive patients. Furthermore, we demonstrated that patients with high DR and SR exhibited lower GATA-3, FoxP3, and IL-10 expression and higher IFN-γ, TNF-α and iNOS mRNA expression than patients with low DR and SR. A negative correlation was observed between Foxp3 and IL-10 mRNA expression and the DR and SR. Moreover, TNF-α and iNOS expression was positively correlated with DR and SR. Our data suggest that an inflammatory imbalance in chronic Chagas disease patients is associated with a high DR and SR. This study provides a better understanding of the stroke pathobiology in the general population and might aid the development of therapeutic strategies for controlling the morbidity and mortality of Chagas disease.

          Author Summary

          Chagas disease is caused by Trypanosoma cruzi (T. cruzi), affects 5.7 million people worldwide and causes 12,000 deaths annually. In the chronic phase of Chagas disease the main cause of death is due to heart failure (about 80%), but cerebral vascular accident or stroke (about 10%) contributes to death mechanisms. Strokes are caused by the interruption of the blood supply to the brain and can be ischemic or hemorrhagic. Stroke is the leading cause of death among adults in Latin America and the second in the world. Infectious diseases, such as Chagas disease, malaria, cysticercosis, tuberculosis, brucellosis and neurosyphilis, can also contribute to the development of immunopathogenic mechanisms leading to stroke and death. In this study, we evaluated the association between inflammatory markers (cytokines, transcription factors of the adaptive immune response and iNOS) and the death risk (DR) and stroke risk (SR) of patients with different clinical forms of chronic Chagas disease. Our data suggest that an inflammatory imbalance in chronic Chagas disease patients is correlated with a high DR and SR. The exacerbated inflammatory mechanism that leads to thrombus formation can lead to sudden death in patients with clinical indeterminate form without prior other clinical symptoms. These inflammatory mechanisms are also involved in atherosclerotic-related strokes. An improved understanding of the immunological mechanisms involved in ischemic stroke formation in Chagas disease patients may also contribute to the reduction of stroke-related mortality and morbidity in the general population and may lead to the development of prophylactic or therapeutic therapies.

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          Naturally arising CD25(+)CD4(+) regulatory T cells actively maintain immunological self-tolerance. Deficiency in or dysfunction of these cells can be a cause of autoimmune disease. A reduction in their number or function can also elicit tumor immunity, whereas their antigen-specific population expansion can establish transplantation tolerance. They are therefore a good target for designing ways to induce or abrogate immunological tolerance to self and non-self antigens.
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            Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells.

            Interleukin 22 (IL-22) is a cytokine produced by the T(H)-17 lineage of helper T cells and NK-22 subset of natural killer cells that acts on epithelial cells and keratinocytes and has been linked to skin homeostasis and inflammation. Here we characterize a population of human skin-homing memory CD4(+) T cells that expressed the chemokine receptors CCR10, CCR6 and CCR4 and produced IL-22 but neither IL-17 nor interferon-gamma (IFN-gamma). Clones isolated from this population produced IL-22 only and had low or undetectable expression of the T(H)-17 and T helper type 1 (T(H)1) transcription factors RORgammat and T-bet. The differentiation of T cells producing only IL-22 was efficiently induced in naive T cells by plasmacytoid dendritic cells in an IL-6- and tumor necrosis factor-dependent way. Our findings delineate a previously unknown subset of human CD4(+) effector T cells dedicated to skin pathophysiology.
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              Infections are a leading cause of morbidity and mortality in patients with acute CNS injury. It has recently become clear that CNS injury significantly increases susceptibility to infection by brain-specific mechanisms: CNS injury induces a disturbance of the normally well balanced interplay between the immune system and the CNS. As a result, CNS injury leads to secondary immunodeficiency - CNS injury-induced immunodepression (CIDS) - and infection. CIDS might serve as a model for the study of the mechanisms and mediators of brain control over immunity. More importantly, understanding CIDS will allow us to work on developing effective therapeutic strategies, with which the outcome after CNS damage by a host of diseases could be improved by eliminating a major determinant of poor recovery.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                26 April 2016
                April 2016
                : 10
                : 4
                : e0004669
                Affiliations
                [1 ]Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, Rio Grande do Norte, Natal, Brazil
                [2 ]Department of Biomedical Sciences, University of Rio Grande do Norte State, Rio Grande do Norte, Mossoró, Brazil
                [3 ]Department of Parasitology, Federal University of Minas Gerais, Minas Gerais, Belo Horizonte, Brazil
                [4 ]School of Medicine, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil
                [5 ]Ribeirão Preto Medical School, University of São Paulo, São Paulo, Ribeirão Preto, Brazil
                [6 ]Laboratory of Cellular Ultrastructure, Oswaldo Cruz Institute/FIOCRUZ, Rio de Janeiro, Rio de Janeiro, Brazil
                [7 ]Department of Clinical and Toxicological Analyses, Federal University of Rio Grande do Norte, Natal, Brazil
                Albert Einstein College of Medicine, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: PMMG LMdCG. Performed the experiments: PMMG CMdA DFN NdSP TBDQ MSLN ACJdC. Analyzed the data: PMMG CMdA DFN NdSP TBDQ GLLMC MSLN MADVM ACJdC LMdCG. Contributed reagents/materials/analysis tools: PMMG CMdA DFN NdSP TBDQ GLLMC MSLN MADVM ACJdC EC LMdCG. Wrote the paper: PMMG MSLN MADVM EC LMdCG.

                Article
                PNTD-D-15-01316
                10.1371/journal.pntd.0004669
                4846156
                27115869
                9f9d71ce-17d4-4a2c-bf47-74793d6062c4
                © 2016 Guedes 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
                : 29 July 2015
                : 6 April 2016
                Page count
                Figures: 5, Tables: 3, Pages: 18
                Funding
                Funded by: National Council for Scientific and Technological Development (CNPq)
                Award ID: 466698/2014-3; 470772/2012-3
                Award Recipient :
                Funded by: National Council for Scientific and Technological Development (CNPq)
                Award ID: 475572/2013-0; 404056/2012-1
                Award Recipient :
                Funded by: Coordination for the Improvement of Higher Education Personnel (CAPES)
                Award ID: 23038.005288/2011-48
                Award Recipient :
                This work was supported by the National Council for Scientific and Technological Development (CNPq/MS/SCTIE/DECIT grant no. 466698/2014-3, MCT/CNPq Grant no. 475572/2013-0, MCT/CNPq Grant no. 470772/2012-3 and MCTI/CNPq/MS-SCTIE-Decit grant no. 404056/2012-1) and the Coordination for the Improvement of Higher Education Personnel (CAPES) – National Incentive Program for Basic Parasitology, grant no. 23038.005288/2011-48. LMdCG was granted a visiting researcher fellowship by the CNPq. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Tropical Diseases
                Neglected Tropical Diseases
                Chagas Disease
                Medicine and Health Sciences
                Parasitic Diseases
                Protozoan Infections
                Chagas Disease
                Medicine and Health Sciences
                Neurology
                Cerebrovascular Diseases
                Stroke
                Medicine and Health Sciences
                Vascular Medicine
                Stroke
                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
                Medicine and Health Sciences
                Inflammatory Diseases
                Medicine and Health Sciences
                Neurology
                Cerebrovascular Diseases
                Stroke
                Ischemic Stroke
                Medicine and Health Sciences
                Vascular Medicine
                Stroke
                Ischemic Stroke
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and life sciences
                Biochemistry
                Nucleic acids
                RNA
                Messenger RNA
                Biology and life sciences
                Biochemistry
                Proteins
                DNA-binding proteins
                Transcription Factors
                Biology and Life Sciences
                Genetics
                Gene Expression
                Gene Regulation
                Transcription Factors
                Biology and Life Sciences
                Biochemistry
                Proteins
                Regulatory Proteins
                Transcription Factors
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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