The shaping of immunological responses through natural selection after the Roma Diaspora
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 vasculopat...
| Autores: | , , , , , , , , , |
|---|---|
| Formato: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2020 |
| País: | España |
| Recursos: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10230/45591 |
| Acesso em linha: | http://hdl.handle.net/10230/45591 http://dx.doi.org/10.1038/s41598-020-73182-1 |
| Access Level: | acceso abierto |
| Palavra-chave: | APLAID Autoinflammatory diseases PLCγ2 Agammaglobulinemia Caspase-1 Inflammasome Interleukin-1 |
| id |
ES_d04315357fd84daa4cbe7d97ed4fea67 |
|---|---|
| oai_identifier_str |
oai:recercat.cat:10230/45591 |
| network_acronym_str |
ES |
| network_name_str |
España |
| repository_id_str |
|
| dc.title.none.fl_str_mv |
The shaping of immunological responses through natural selection after the Roma Diaspora |
| title |
The shaping of immunological responses through natural selection after the Roma Diaspora |
| spellingShingle |
The shaping of immunological responses through natural selection after the Roma Diaspora Dobón Berenguer, Begoña, 1987- APLAID Autoinflammatory diseases PLCγ2 Agammaglobulinemia Caspase-1 Inflammasome Interleukin-1 |
| title_short |
The shaping of immunological responses through natural selection after the Roma Diaspora |
| title_full |
The shaping of immunological responses through natural selection after the Roma Diaspora |
| title_fullStr |
The shaping of immunological responses through natural selection after the Roma Diaspora |
| title_full_unstemmed |
The shaping of immunological responses through natural selection after the Roma Diaspora |
| title_sort |
The shaping of immunological responses through natural selection after the Roma Diaspora |
| dc.creator.none.fl_str_mv |
Dobón Berenguer, Begoña, 1987- Ter Horst, Rob Laayouni, Hafid, 1968- Mondal, Mayukh, 1989- Bianco, Erica Comas, David, 1969- Ioana, Mihai Bosch Fusté, Elena Bertranpetit, Jaume, 1952- Netea, Mihai G. |
| author |
Dobón Berenguer, Begoña, 1987- |
| author_facet |
Dobón Berenguer, Begoña, 1987- Ter Horst, Rob Laayouni, Hafid, 1968- Mondal, Mayukh, 1989- Bianco, Erica Comas, David, 1969- Ioana, Mihai Bosch Fusté, Elena Bertranpetit, Jaume, 1952- Netea, Mihai G. |
| author_role |
author |
| author2 |
Ter Horst, Rob Laayouni, Hafid, 1968- Mondal, Mayukh, 1989- Bianco, Erica Comas, David, 1969- Ioana, Mihai Bosch Fusté, Elena Bertranpetit, Jaume, 1952- Netea, Mihai G. |
| author2_role |
author author author author author author author author author |
| dc.subject.none.fl_str_mv |
APLAID Autoinflammatory diseases PLCγ2 Agammaglobulinemia Caspase-1 Inflammasome Interleukin-1 |
| topic |
APLAID Autoinflammatory diseases PLCγ2 Agammaglobulinemia Caspase-1 Inflammasome Interleukin-1 |
| description |
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. |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 2020 2020 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10230/45591 http://dx.doi.org/10.1038/s41598-020-73182-1 |
| url |
http://hdl.handle.net/10230/45591 http://dx.doi.org/10.1038/s41598-020-73182-1 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Sci Rep. 2020; 10(1):16134 info:eu-repo/grantAgreement/ES/1PE/BFU2016-77961-P info:eu-repo/grantAgreement/ES/1PE/CGL2016-75389-P |
| dc.rights.none.fl_str_mv |
http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
http://creativecommons.org/licenses/by/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Nature Research |
| publisher.none.fl_str_mv |
Nature Research |
| dc.source.none.fl_str_mv |
reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| instname_str |
Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| reponame_str |
Recercat. Dipósit de la Recerca de Catalunya |
| collection |
Recercat. Dipósit de la Recerca de Catalunya |
| repository.name.fl_str_mv |
|
| repository.mail.fl_str_mv |
|
| _version_ |
1869420158444896256 |
| spelling |
The shaping of immunological responses through natural selection after the Roma DiasporaDobón Berenguer, Begoña, 1987-Ter Horst, RobLaayouni, Hafid, 1968-Mondal, Mayukh, 1989-Bianco, EricaComas, David, 1969-Ioana, MihaiBosch Fusté, ElenaBertranpetit, Jaume, 1952-Netea, Mihai G.APLAIDAutoinflammatory diseasesPLCγ2AgammaglobulinemiaCaspase-1InflammasomeInterleukin-1Autoinflammatory 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.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.Nature Research202020202020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/45591http://dx.doi.org/10.1038/s41598-020-73182-1reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésSci Rep. 2020; 10(1):16134info:eu-repo/grantAgreement/ES/1PE/BFU2016-77961-Pinfo:eu-repo/grantAgreement/ES/1PE/CGL2016-75389-P© 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/.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/455912026-05-29T05:05:01Z |
| score |
15.812429 |