Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations
Por:
Martín-Nalda A, Fortuny-Guasch 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-Otero M, Martinez-Banaclocha H, Martinez-Garcia JJ, Mensa-Vilaró A, Rabionet-Janssen R, Martin-Begue N, Rudilla F, Yagüe-Ribes J, Estivill X, García-Patos V, Pujol RM, Soler-Palacín P, Katan M, Pelegrín P, Colobran R, Vicente-Villa MA and Arostegui-Gorospe JI
Publicada:
1 oct 2020
Ahead of Print:
1 jul 2020
Resumen:
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.
Filiaciones:
Martín-Nalda A:
Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Barcelona, Spain
Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Spain
Fortuny-Guasch C:
Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Barcelona, Spain
Department of Pediatrics, Hospital Sant Joan de Deu, Esplugues, Spain
Institut de Recerca Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues, Spain
Rey L:
Department of Pediatrics, Hospital Alvaro Cunqueiro, Vigo, Spain
Bunney TD:
Institute of Structural and Molecular Biology, University College London, London, UK
Alsina L:
Institut de Recerca Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues, Spain
Department of Allergy and Clinical Immunology Clinical Immunology and Primary, Immunodeficiencies Unit, Hospital Sant Joan de Déu, Esplugues, Spain
Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic, Barcelona, Spain
Esteve-Solé A:
Institut de Recerca Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues, Spain
Department of Allergy and Clinical Immunology Clinical Immunology and Primary, Immunodeficiencies Unit, Hospital Sant Joan de Déu, Esplugues, Spain
Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic, Barcelona, Spain
Bull D:
ARUK Drug Discovery Institute, University College London, London, UK
Anton MC:
Department of Immunology-CDB (esc 4-pl 0), Hospital Clínic, Villarroel, 170, 08036, Barcelona, Spain
Basagaña M:
Allergy Section, Hospital Universitari Germans Trias i Pujol, Autonomous University of Barcelona, Badalona, Spain
Casals F:
Genomics Core Facility, Experimental and Health Sciences Department, Universitat Pompeu Fabra, Barcelona, Spain
Deyá A:
Institut de Recerca Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues, Spain
Department of Allergy and Clinical Immunology Clinical Immunology and Primary, Immunodeficiencies Unit, Hospital Sant Joan de Déu, Esplugues, Spain
Clinical Immunology Unit, Hospital Sant Joan de Déu-Hospital Clínic, Barcelona, Spain
García-Prat M:
Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Barcelona, Spain
Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Spain
Gimeno R:
Department of Immunology, Hospital del Mar, Institut Mar d'Investigacions Mèdiques, Barcelona, Spain
Juan-Otero M:
Department of Immunology-CDB (esc 4-pl 0), Hospital Clínic, Villarroel, 170, 08036, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
School of Medicine, Universitat de Barcelona, Barcelona, Spain
Martinez-Banaclocha H:
Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
Martinez-Garcia JJ:
Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
Mensa-Vilaró A:
Department of Immunology-CDB (esc 4-pl 0), Hospital Clínic, Villarroel, 170, 08036, Barcelona, Spain
Rabionet-Janssen R:
Institut de Recerca Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues, Spain
Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRJSD, CIBERER, Barcelona, Spain
Martin-Begue N:
Department of Pediatric Ophthalmology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain
Rudilla F:
Histocompatibility and Immunogenetics Laboratory, Blood and Tissue Bank, Barcelona, Spain
Transfusional Medicine Group, Vall d'Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain
Yagüe-Ribes J:
Department of Immunology-CDB (esc 4-pl 0), Hospital Clínic, Villarroel, 170, 08036, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
School of Medicine, Universitat de Barcelona, Barcelona, Spain
Estivill X:
Quantitative Genomic Medicine Laboratories (qGenomics), Esplugues del Llobregat, Barcelona, Catalonia, Spain
García-Patos V:
Department of Pediatric Dermatology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain
Pujol RM:
Department of Dermatology, Hospital del Mar, Institut Mar d'Investigacions Mèdiques, Universitat Autonoma de Barcelona, Barcelona, Spain
Soler-Palacín P:
Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Barcelona, Spain
Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Spain
Universitat Autònoma de Barcelona, Barcelona, Spain
Katan M:
Institute of Structural and Molecular Biology, University College London, London, UK
Pelegrín P:
Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
Colobran R:
Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Barcelona, Spain
Immunology Division, Department of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Barcelona, Spain
Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona, Barcelona, Spain
Vicente-Villa MA:
Department of Pediatric Dermatology, Hospital Sant Joan de Deu, Esplugues, Spain
Arostegui-Gorospe JI:
Department of Immunology-CDB (esc 4-pl 0), Hospital Clínic, Villarroel, 170, 08036, Barcelona, Spain.
Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
School of Medicine, Universitat de Barcelona, Barcelona, Spain.
Green Submitted, Green Published, hybrid
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