The shaping of immunological responses through natural selection after the Roma Diaspora

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• dc.contributor.author Dobón Berenguer, Begoña, 1987-
• dc.contributor.author Ter Horst, Rob
• dc.contributor.author Laayouni, Hafid, 1968-
• dc.contributor.author Mondal, Mayukh, 1989-
• dc.contributor.author Bianco, Erica
• dc.contributor.author Comas, David, 1969-
• dc.contributor.author Ioana, Mihai
• dc.contributor.author Bosch Fusté, Elena
• dc.contributor.author Bertranpetit, Jaume, 1952-
• dc.contributor.author Netea, Mihai G
• dc.date.accessioned 2020-10-28T07:01:10Z
• dc.date.available 2020-10-28T07:01:10Z
• dc.date.issued 2020
• dc.description.abstract Autoinflammatory diseases (AIDs) were first described as clinical disorders characterized by recurrent episodes of seemingly unprovoked sterile inflammation. In the past few years, the identification of novel AIDs expanded their phenotypes toward more complex clinical pictures associating vasculopathy, autoimmunity, or immunodeficiency. Herein, we describe two unrelated patients suffering since the neonatal period from a complex disease mainly characterized by severe sterile inflammation, recurrent bacterial infections, and marked humoral immunodeficiency. Whole-exome sequencing detected a novel, de novo heterozygous PLCG2 variant in each patient (p.Ala708Pro and p.Leu845_Leu848del). A clear enhanced PLCγ2 activity for both variants was demonstrated by both ex vivo calcium responses of the patient's B cells to IgM stimulation and in vitro assessment of PLC activity. These data supported the autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID) diagnosis in both patients. Immunological evaluation revealed a severe decrease of immunoglobulins and B cells, especially class-switched memory B cells, with normal T and NK cell counts. Analysis of bone marrow of one patient revealed a reduced immature B cell fraction compared with controls. Additional investigations showed that both PLCG2 variants activate the NLRP3-inflammasome through the alternative pathway instead of the canonical pathway. Collectively, the evidences here shown expand APLAID diversity toward more severe phenotypes than previously reported including dominantly inherited agammaglobulinemia, add novel data about its genetic basis, and implicate the alternative NLRP3-inflammasome activation pathway in the basis of sterile inflammation.
• dc.description.sponsorship This work has been partially funded by the following: CERCA Programme/Generalitat de Catalunya (JIA), SAF2015-68472-C2-1-R grant from the Spanish Ministry of Economy and Competitiveness co-financed by European Regional Development Fund (ERDF) (JIA), RTI2018-096824-B-C21 grant from the Spanish Ministry of Science, Innovation and Universities co-financed by ERDF (JIA), AC15/00027 grant from the Instituto de Salud Carlos III/Transnational Research Projects on Rare Diseases (JIA), PI14/00405 grant from the Instituto de Salud Carlos III co-financed by ERDF (RC), PI13/00174 grant from the Spanish Ministry of Economy and Competitiveness co-financed by ERDF (PP), SAF2017-88276-R grant from the Spanish Ministry of Economy, Industry and Competitiveness co-financed by ERDF (PP), ERC-2013-CoG project 614578 from the European Research Council (PP), 20859/PI/18 grant from Fundación Séneca (PP), SAF2015-68472-C2-2-R grant from the Spanish Ministry of Economy and Competitiveness co-financed by ERDF (FC) and RTI2018-096824-B-C22 grant from the Spanish Ministry of Science, Innovation and Universities co-financed by ERDF (FC). MK acknowledges support from CRUK (A16567) and MRC (P028160). H M-B is a Rio Hortega fellowship from Instituto de Salud Carlos III (CM14/00008) and DB acknowledges support from the UCL Impact Studentship.
• dc.format.mimetype application/pdf
• dc.identifier.citation Dobon B, Ter Horst R, Laayouni H, Mondal M, Bianco E, Comas D, Ioana M, Bosch E, Bertranpetit J, Netea MG. The shaping of immunological responses through natural selection after the Roma Diaspora. Sci Rep. 2020; 10(1):16134. DOI: 10.1038/s41598-020-73182-1
• dc.identifier.doi http://dx.doi.org/10.1038/s41598-020-73182-1
• dc.identifier.issn 2045-2322
• dc.identifier.uri http://hdl.handle.net/10230/45591
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Sci Rep. 2020; 10(1):16134
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-77961-P
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/CGL2016-75389-P
• dc.rights © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword APLAID
• dc.subject.keyword Autoinflammatory diseases
• dc.subject.keyword PLCγ2
• dc.subject.keyword Agammaglobulinemia
• dc.subject.keyword Caspase-1
• dc.subject.keyword Inflammasome
• dc.subject.keyword Interleukin-1
• dc.title The shaping of immunological responses through natural selection after the Roma Diaspora
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion