Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations
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ORIGINAL ARTICLE
Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations Andrea Martín-Nalda 1,2 & Claudia Fortuny 3,4,1 & Lourdes Rey 5 & Tom D. Bunney 6 & Laia Alsina 4,7,8 & Ana Esteve-Solé 4,7,8 & Daniel Bull 9 & Maria Carmen Anton 10 & María Basagaña 11 & Ferran Casals 12 & Angela Deyá 4,7,8 & Marina García-Prat 1,2 & Ramon Gimeno 13 & Manel Juan 10,14,15 & Helios Martinez-Banaclocha 16 & Juan J Martinez-Garcia 16 & Anna Mensa-Vilaró 10 & Raquel Rabionet 4,17 & Nieves Martin-Begue 18 & Francesc Rudilla 19,20 & Jordi Yagüe 10,14,15 & Xavier Estivill 21 & Vicente García-Patos 22 & Ramon M. Pujol 23 & Pere Soler-Palacín 1,2,24 & Matilda Katan 6 & Pablo Pelegrín 16 & Roger Colobran 2,25,26 & Asun Vicente 27 & Juan I. Arostegui 10,14,15 Received: 10 January 2020 / Accepted: 20 May 2020 # The Author(s) 2020
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. Keywords Autoinflammatory diseases . APLAID . PLCγ2 . inflammasome . caspase-1 . interleukin-1 . agammaglobulinemia
Introduction
Andrea Martin-Nalda and Claudia Fortuny are first co-authors who contributed equally to this article. Pablo Pelegrín, Roger Colobran, Asun Vicente, and Juan I. Arostegui contributed equally to this article as senior authors. Electronic supplementary material The online version of this article (http
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