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

Journal of Clinical Immunology
Andrea Martín-NaldaJuan I Aróstegui

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 immat...Continue Reading

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Citations

Feb 2, 2021·Journal of Alzheimer's Disease : JAD·Fan ChenGuiyou Liu
Sep 24, 2020·Progress in Lipid Research·Matilda Katan, Shamshad Cockcroft
May 27, 2021·Nature Reviews. Rheumatology·Ivona Aksentijevich, Oskar Schnappauf
Jun 23, 2021·The Journal of Biological Chemistry·Jacob T JacksonSeth L Masters
Sep 10, 2021·Nature·Rasa ElmentaiteSarah A Teichmann
Sep 19, 2021·The FEBS Journal·Akhouri Kishore RaghawanGhanshyam Swarup

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Methods Mentioned

BETA
PCR
flow cytometry
transfection
transfections
cesarean section

Software Mentioned

BWA
FLICA
GATK Unified Genotyper
CellQuest
Morpheus
gnomAD

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