Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/171007
Title: | Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations |
Author: | Martín Nalda, Andrea Fortuny Guasch, Claudia Rey, Lourdes Bunney, Tom D. Alsina, Laia Esteve Solé, Ana Bull, Daniel Anton, Maria Carmen Basagaña, Maria Casals López, Ferran Deyá, Angela García Prat, Marina Gimeno, Ramon Juan, Manel Martinez Banaclocha, Helios Martinez Garcia, Juan J. Mensa Vilaró, Anna Rabionet Janssen, Raquel Martin Begue, Nieves Rudilla, Francesc Yagüe, Jordi Estivill, Xavier, 1955- García Patos, Vicente Pujol, Ramon M. Soler Palacín, Pere Katan, Matilda Pelegrín, Pablo Colobran, Roger Vicente, Asun Aróstegui Gorospe, Juan Ignacio |
Keywords: | Síndromes de deficiència immunitària Gammaglobulines Immunological deficiency syndromes Gamma globulins |
Issue Date: | 15-Jul-2020 |
Publisher: | Springer Verlag |
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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1007/s10875-020-00794-7 |
It is part of: | Journal of Clinical Immunology, 2020, num. 40, p. 987-1000 |
URI: | http://hdl.handle.net/2445/171007 |
Related resource: | https://doi.org/10.1007/s10875-020-00794-7 |
ISSN: | 0271-9142 |
Appears in Collections: | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) Articles publicats en revistes (Cirurgia i Especialitats Medicoquirúrgiques) Articles publicats en revistes (Institut de Biomedicina (IBUB)) Articles publicats en revistes (Genètica, Microbiologia i Estadística) |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
703483.pdf | 1.95 MB | Adobe PDF | View/Open |
This item is licensed under a Creative Commons License