Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations

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...

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Authors: Martín-Nalda A, Fortuny C, Rey L, Bunney TD, Alsina L, Esteve-Solé A, Bull D, Anton MC, Basagaña M, Casals F, Deyá A, García-Prat M, Gimeno R, Juan M, Martinez-Banaclocha H, Martinez-Garcia JJ, Mensa-Vilaró A, Rabionet R, Martin-Begue N, Rudilla F, Yagüe J, Estivill X, García-Patos V, Pujol RM, Soler-Palacín P, Katan M, Pelegrín P, Colobran R, Vicente A, Arostegui JI
Format: article
Status:Published version
Publication Date:2020
Country:España
Institution:Fundació Sant Joan de Déu
Repository:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p18168
Online Access:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=18168
Access Level:Open access
Keyword:Autoinflammatory diseases
APLAID
PLC gamma 2
inflammasome
caspase-1
interleukin-1
agammaglobulinemia
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spelling Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 MutationsMartín-Nalda AFortuny CRey LBunney TDAlsina LEsteve-Solé ABull DAnton MCBasagaña MCasals FDeyá AGarcía-Prat MGimeno RJuan MMartinez-Banaclocha HMartinez-Garcia JJMensa-Vilaró ARabionet RMartin-Begue NRudilla FYagüe JEstivill XGarcía-Patos VPujol RMSoler-Palacín PKatan MPelegrín PColobran RVicente AArostegui JIAutoinflammatory diseasesAPLAIDPLC gamma 2inflammasomecaspase-1interleukin-1agammaglobulinemiaAutoinflammatory 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 PLC gamma 2 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 PLC gamma 2-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.SPRINGER/PLENUM PUBLISHERS2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=18168JOURNAL OF CLINICAL IMMUNOLOGYISSN: 02719142ISSNe: 15732592reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:fsjd.fundanetsuite.com:p181682026-05-27T12:37:41Z
dc.title.none.fl_str_mv Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations
title Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations
spellingShingle Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations
Martín-Nalda A
Autoinflammatory diseases
APLAID
PLC gamma 2
inflammasome
caspase-1
interleukin-1
agammaglobulinemia
title_short Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations
title_full Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations
title_fullStr Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations
title_full_unstemmed Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations
title_sort Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations
dc.creator.none.fl_str_mv Martín-Nalda A
Fortuny C
Rey L
Bunney TD
Alsina L
Esteve-Solé A
Bull D
Anton MC
Basagaña M
Casals F
Deyá A
García-Prat M
Gimeno R
Juan M
Martinez-Banaclocha H
Martinez-Garcia JJ
Mensa-Vilaró A
Rabionet R
Martin-Begue N
Rudilla F
Yagüe J
Estivill X
García-Patos V
Pujol RM
Soler-Palacín P
Katan M
Pelegrín P
Colobran R
Vicente A
Arostegui JI
author Martín-Nalda A
author_facet Martín-Nalda A
Fortuny C
Rey L
Bunney TD
Alsina L
Esteve-Solé A
Bull D
Anton MC
Basagaña M
Casals F
Deyá A
García-Prat M
Gimeno R
Juan M
Martinez-Banaclocha H
Martinez-Garcia JJ
Mensa-Vilaró A
Rabionet R
Martin-Begue N
Rudilla F
Yagüe J
Estivill X
García-Patos V
Pujol RM
Soler-Palacín P
Katan M
Pelegrín P
Colobran R
Vicente A
Arostegui JI
author_role author
author2 Fortuny C
Rey L
Bunney TD
Alsina L
Esteve-Solé A
Bull D
Anton MC
Basagaña M
Casals F
Deyá A
García-Prat M
Gimeno R
Juan M
Martinez-Banaclocha H
Martinez-Garcia JJ
Mensa-Vilaró A
Rabionet R
Martin-Begue N
Rudilla F
Yagüe J
Estivill X
García-Patos V
Pujol RM
Soler-Palacín P
Katan M
Pelegrín P
Colobran R
Vicente A
Arostegui JI
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Autoinflammatory diseases
APLAID
PLC gamma 2
inflammasome
caspase-1
interleukin-1
agammaglobulinemia
topic Autoinflammatory diseases
APLAID
PLC gamma 2
inflammasome
caspase-1
interleukin-1
agammaglobulinemia
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 PLC gamma 2 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 PLC gamma 2-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
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 https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=18168
url https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=18168
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv SPRINGER/PLENUM PUBLISHERS
publisher.none.fl_str_mv SPRINGER/PLENUM PUBLISHERS
dc.source.none.fl_str_mv JOURNAL OF CLINICAL IMMUNOLOGY
ISSN: 02719142
ISSNe: 15732592
reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname:Fundació Sant Joan de Déu
instname_str Fundació Sant Joan de Déu
reponame_str r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
collection r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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