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      The X chromosome and sex-specific effects in infectious disease susceptibility

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          Abstract

          The X chromosome and X-linked variants have largely been ignored in genome-wide and candidate association studies of infectious diseases due to the complexity of statistical analysis of the X chromosome. This exclusion is significant, since the X chromosome contains a high density of immune-related genes and regulatory elements that are extensively involved in both the innate and adaptive immune responses. Many diseases present with a clear sex bias, and apart from the influence of sex hormones and socioeconomic and behavioural factors, the X chromosome, X-linked genes and X chromosome inactivation mechanisms contribute to this difference. Females are functional mosaics for X-linked genes due to X chromosome inactivation and this, combined with other X chromosome inactivation mechanisms such as genes that escape silencing and skewed inactivation, could contribute to an immunological advantage for females in many infections. In this review, we discuss the involvement of the X chromosome and X inactivation in immunity and address its role in sexual dimorphism of infectious diseases using tuberculosis susceptibility as an example, in which male sex bias is clear, yet not fully explored.

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          Most cited references80

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          Gene action in the X-chromosome of the mouse (Mus musculus L.).

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            TLR signaling.

            The Toll-like receptor (TLR) family plays an instructive role in innate immune responses against microbial pathogens, as well as the subsequent induction of adaptive immune responses. TLRs recognize specific molecular patterns found in a broad range of microbial pathogens such as bacteria and viruses, triggering inflammatory and antiviral responses and dendritic cell maturation, which result in the eradication of invading pathogens. Individual TLRs interact with different combinations of adapter proteins and activate various transcription factors such as nuclear factor (NF)-kappaB, activating protein-1 and interferon regulatory factors, driving a specific immune response. This review outlines the recent advances in our understanding of TLR-signaling pathways and their roles in immune responses. Further, we also discuss a new concept of TLR-independent mechanisms for recognition of microbial pathogens.
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              The X-files in immunity: sex-based differences predispose immune responses

              Sex-based differences in immune responses can influence the susceptibility to autoimmune and infectious diseases and the efficacy of therapeutic drugs. In this Perspective, Eleanor Fish discusses factors, such as X-linked genes, hormones and societal context, that underlie disparate immune responses in men and women.
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                Author and article information

                Contributors
                haiko@sun.ac.za
                Muneeb.Salie@STJUDE.ORG
                gctromp@sun.ac.za
                egvh@sun.ac.za
                gkin@sun.ac.za
                marlom@sun.ac.za
                Journal
                Hum Genomics
                Hum. Genomics
                Human Genomics
                BioMed Central (London )
                1473-9542
                1479-7364
                8 January 2019
                8 January 2019
                2019
                : 13
                : 2
                Affiliations
                [1 ]ISNI 0000 0001 2214 904X, GRID grid.11956.3a, DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, , Stellenbosch University, ; Cape Town, South Africa
                [2 ]ISNI 0000 0001 0224 711X, GRID grid.240871.8, Department of Genetics, , St. Jude Children’s Research Hospital, ; Memphis, TN 38105 USA
                [3 ]ISNI 0000 0001 2214 904X, GRID grid.11956.3a, South African Tuberculosis Bioinformatics Initiative (SATBBI), Faculty of Medicine and Health Sciences, , Stellenbosch University, ; Cape Town, South Africa
                Author information
                http://orcid.org/0000-0002-0009-3409
                Article
                185
                10.1186/s40246-018-0185-z
                6325731
                30621780
                ef2b6f4e-4bd2-4ab0-8569-a47285b522dc
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 13 August 2018
                : 30 November 2018
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Genetics
                tuberculosis,sex bias,x chromosome,host genetics,susceptibility
                Genetics
                tuberculosis, sex bias, x chromosome, host genetics, susceptibility

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