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      Autoimmunity and allergy control in adults submitted to complete thymectomy early in infancy

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          Abstract

          The contribution of the decline in thymic activity for the emergence of autoimmunity is still debatable. Immune-competent adults submitted to complete thymectomy early in life provide a unique model to address this question. We applied here strict criteria to identify adults lacking thymic activity based on sjTREC levels, to exclude thymic rebound and/or ectopic thymuses. In agreement, they featured severe naïve CD4 T-cell depletion and contraction of T-cell receptor diversity. Notwithstanding this, there was neither increased incidence of autoimmune disease in comparison with age-matched controls nor significant changes in their IgG/IgA/IgM/IgE autoreactivity profiles, as assessed through extensive arrays. We reasoned that the observed relative preservation of the regulatory T-cell compartment, including maintenance of naïve regulatory CD4 T-cells, may contribute to limit the emergence of autoimmunity upon thymectomy. Our findings have implications in other clinical settings with impaired thymic activity, and are particularly relevant to studies of autoimmunity in ageing.

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          Most cited references26

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          International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods.

          The aetiology of asthma and allergic disease remains poorly understood, despite considerable research. The International Study of Asthma and Allergies in Childhood (ISAAC), was founded to maximize the value of epidemiological research into asthma and allergic disease, by establishing a standardized methodology and facilitating international collaboration. Its specific aims are: 1) to describe the prevalence and severity of asthma, rhinitis and eczema in children living in different centres, and to make comparisons within and between countries; 2) to obtain baseline measures for assessment of future trends in the prevalence and severity of these diseases; and 3) to provide a framework for further aetiological research into genetic, lifestyle, environmental, and medical care factors affecting these diseases. The ISAAC design comprises three phases. Phase 1 uses core questionnaires designed to assess the prevalence and severity of asthma and allergic disease in defined populations. Phase 2 will investigate possible aetiological factors, particularly those suggested by the findings of Phase 1. Phase 3 will be a repetition of Phase 1 to assess trends in prevalence.
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            Regulatory T Cell Specificity Directs Tolerance versus Allergy against Aeroantigens in Humans.

            FOXP3+ regulatory T cells (Tregs) maintain tolerance against self-antigens and innocuous environmental antigens. However, it is still unknown whether Treg-mediated tolerance is antigen specific and how Treg specificity contributes to the selective loss of tolerance, as observed in human immunopathologies such as allergies. Here, we used antigen-reactive T cell enrichment to identify antigen-specific human Tregs. We demonstrate dominant Treg-mediated tolerance against particulate aeroallergens, such as pollen, house dust mites, and fungal spores. Surprisingly, we found no evidence of functional impairment of Treg responses in allergic donors. Rather, major allergenic proteins, known to rapidly dissociate from inhaled allergenic particles, have a generally reduced capability to generate Treg responses. Most strikingly, in individual allergic donors, Th2 cells and Tregs always target disparate proteins. Thus, our data highlight the importance of Treg antigen-specificity for tolerance in humans and identify antigen-specific escape from Treg control as an important mechanism enabling antigen-specific loss of tolerance in human allergy.
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              Autoimmune diseases - connecting risk alleles with molecular traits of the immune system.

              Genome-wide strategies have driven the discovery of more than 300 susceptibility loci for autoimmune diseases. However, for almost all loci, understanding of the mechanisms leading to autoimmunity remains limited, and most variants that are likely to be causal are in non-coding regions of the genome. A critical next step will be to identify the in vivo and ex vivo immunophenotypes that are affected by risk variants. To do this, key cell types and cell states that are implicated in autoimmune diseases will need to be defined. Functional genomic annotations from these cell types and states can then be used to resolve candidate genes and causal variants. Together with longitudinal studies, this approach may yield pivotal insights into how autoimmunity is triggered.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Investigation
                Role: Formal analysisRole: SoftwareRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: Formal analysisRole: Writing – original draft
                Role: Investigation
                Role: ConceptualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                7 July 2017
                2017
                : 12
                : 7
                : e0180385
                Affiliations
                [1 ]Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa. Lisboa, Portugal
                [2 ]Clinica Universitária de Imunoalergologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte. Lisboa, Portugal
                [3 ]Microarray Core Facility, University of Texas Southwestern Medical Center, Dallas, United States of America
                [4 ]Clinica Universitária de Medicina 2, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte. Lisboa, Portugal
                [5 ]Cytokines and Viral Infections, Immunology Infection and Inflammation department, Institut Cochin, INSERM, U1016, Paris, France
                [6 ]Centre National de la Recherche Scientifique, UMR8104, Paris, France
                [7 ]Université Paris Descartes, Paris, France
                Universite Paris-Sud, FRANCE
                Author notes

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

                Author information
                http://orcid.org/0000-0002-4618-9799
                Article
                PONE-D-17-10638
                10.1371/journal.pone.0180385
                5501530
                28686710
                1dbf5623-803e-41ce-a903-1d4299d81217
                © 2017 Silva 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
                : 17 March 2017
                : 14 June 2017
                Page count
                Figures: 4, Tables: 1, Pages: 13
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001871, Fundação para a Ciência e a Tecnologia;
                Award ID: POCI2010/IC/83068/2007
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001871, Fundação para a Ciência e a Tecnologia;
                Award ID: PTDC/SAU-MIC/109786/2009
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100005635, Fundação Calouste Gulbenkian;
                Award ID: P132532/2013
                Award Recipient :
                This work was supported by Fundação para a Ciência e Tecnologia (FCT; POCI2010/IC/83068/2007 to RMMV; PTDC/SAU-MIC/109786/2009 to AES), and Gulbenkian Foundation (P132532/2013 to AES). SLS, ASA and AJA received FCT scholarships. AJA was supported by an EMBO long-term fellowship (ALT-33-2010) and a Marie Curie European Integration Grant (PERG-GA-2009-256595).
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                Autoantibodies
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