Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations
Por:
Martin-Nalda, A, Fortuny, C, Rey, L, Bunney, TD, Alsina, L, Esteve-Sole, A, Bull, D, Anton, MC, Basagana, M, Casals, F, Deya, A, Garcia-Prat, M, Gimeno, R, Juan, M, Martinez-Banaclocha, H, Martinez-Garcia, JJ, Mensa-Vilaro, A, Rabionet, R, Martin-Begue, N, Rudilla, F, Yague, J, Estivill, X, Garcia-Patos, V, Pujol, RM, Soler-Palacin, P, Katan, M, Pelegrin, P, Colobran, R, Vicente, A and Arostegui, 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:
Martin-Nalda, A:
Hosp Univ Vall dHebron, Vall dHebron Inst Recerca, Pediat Infect Dis & Immunodeficiencies Unit, Barcelona, Spain
Jeffrey Modell Diagnost & Res Ctr Primary Immunod, Barcelona, Spain
Fortuny, C:
Hosp Univ Vall dHebron, Vall dHebron Inst Recerca, Pediat Infect Dis & Immunodeficiencies Unit, Barcelona, Spain
Hosp St Joan de Deu, Dept Pediat, Esplugues, Spain
Univ Barcelona, Inst Recerca Hosp St Joan de Deu, Esplugues, Spain
Rey, L:
Hosp Alvaro Cunqueiro, Dept Pediat, Vigo, Spain
Bunney, TD:
UCL, Inst Struct & Mol Biol, London, England
Alsina, L:
Univ Barcelona, Inst Recerca Hosp St Joan de Deu, Esplugues, Spain
Hosp St Joan de Deu, Dept Allergy & Clin Immunol Clin Immunol & Primar, Immunodeficiencies Unit, Esplugues, Spain
Hosp St Joan de Deu, Clin Immunol Unit, Hosp Clin, Barcelona, Spain
Esteve-Sole, A:
Univ Barcelona, Inst Recerca Hosp St Joan de Deu, Esplugues, Spain
Hosp St Joan de Deu, Dept Allergy & Clin Immunol Clin Immunol & Primar, Immunodeficiencies Unit, Esplugues, Spain
Hosp St Joan de Deu, Clin Immunol Unit, Hosp Clin, Barcelona, Spain
Bull, D:
UCL, ARUK Drug Discovery Inst, London, England
Anton, MC:
Hosp Clin Barcelona, Dept Immunol CDB, Esc 4 Pl 0,Villarroel 170, Barcelona, Spain
:
Autonomous Univ Barcelona, Hosp Univ Germans Trias & Pujol, Allergy Sect, Badalona, Spain
Casals, F:
Univ Pompeu Fabra, Expt & Hlth Sci Dept, Genom Core Facil, Barcelona, Spain
Deya, A:
Univ Barcelona, Inst Recerca Hosp St Joan de Deu, Esplugues, Spain
Hosp St Joan de Deu, Dept Allergy & Clin Immunol Clin Immunol & Primar, Immunodeficiencies Unit, Esplugues, Spain
Hosp St Joan de Deu, Clin Immunol Unit, Hosp Clin, Barcelona, Spain
Garcia-Prat, M:
Hosp Univ Vall dHebron, Vall dHebron Inst Recerca, Pediat Infect Dis & Immunodeficiencies Unit, Barcelona, Spain
Jeffrey Modell Diagnost & Res Ctr Primary Immunod, Barcelona, Spain
Gimeno, R:
Hosp del Mar, Inst Mar Invest Med, Dept Immunol, Barcelona, Spain
Juan, M:
Hosp Clin Barcelona, Dept Immunol CDB, Esc 4 Pl 0,Villarroel 170, Barcelona, Spain
Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain
Univ Barcelona, Sch Med, Barcelona, Spain
Martinez-Banaclocha, H:
Hosp Clin Univ Virgen de la Arrixaca, Inst Murciano Invest Biosanitaria IMIB Arrixaca, Murcia, Spain
Martinez-Garcia, JJ:
Hosp Clin Univ Virgen de la Arrixaca, Inst Murciano Invest Biosanitaria IMIB Arrixaca, Murcia, Spain
Mensa-Vilaro, A:
Hosp Clin Barcelona, Dept Immunol CDB, Esc 4 Pl 0,Villarroel 170, Barcelona, Spain
Rabionet, R:
Univ Barcelona, Inst Recerca Hosp St Joan de Deu, Esplugues, Spain
Univ Barcelona, Fac Biol, Dept Genet Microbiol & Stat, IBUB,CIBERER,IRJSD, Barcelona, Spain
Martin-Begue, N:
Hosp Univ Vall dHebron, Vall dHebron Inst Recerca, Dept Pediat Ophthalmol, Barcelona, Spain
Rudilla, F:
Blood & Tissue Bank, Histocompatibil & Immunogenet Lab, Barcelona, Spain
Autonomous Univ Barcelona, Vall dHebron Res Inst, Transfus Med Grp, Barcelona, Spain
Yague, J:
Hosp Clin Barcelona, Dept Immunol CDB, Esc 4 Pl 0,Villarroel 170, Barcelona, Spain
Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain
Univ Barcelona, Sch Med, Barcelona, Spain
Estivill, X:
Quantitat Genom Med Labs qGenom, Barcelona, Spain
Garcia-Patos, V:
Hosp Univ Vall dHebron, Vall dHebron Inst Recerca, Dept Pediat Dermatol, Barcelona, Spain
Pujol, RM:
Univ Autonoma Barcelona, Hosp del Mar, Inst Mar Invest Med, Dept Dermatol, Barcelona, Spain
Soler-Palacin, P:
Hosp Univ Vall dHebron, Vall dHebron Inst Recerca, Pediat Infect Dis & Immunodeficiencies Unit, Barcelona, Spain
Jeffrey Modell Diagnost & Res Ctr Primary Immunod, Barcelona, Spain
Univ Autonoma Barcelona, Barcelona, Spain
Katan, M:
UCL, Inst Struct & Mol Biol, London, England
Pelegrin, P:
Hosp Clin Univ Virgen de la Arrixaca, Inst Murciano Invest Biosanitaria IMIB Arrixaca, Murcia, Spain
Colobran, R:
Jeffrey Modell Diagnost & Res Ctr Primary Immunod, Barcelona, Spain
Hosp Univ Vall dHebron, Vall dHebron Res Inst, Dept Clin & Mol Genet, Immunol Div, Barcelona, Spain
Autonomous Univ Barcelona, Dept Cell Biol Physiol & Immunol, Barcelona, Spain
Vicente, A:
Hosp St Joan de Deu, Dept Pediat Dermatol, Esplugues, Spain
Arostegui, JI:
Hosp Clin Barcelona, Dept Immunol CDB, Esc 4 Pl 0,Villarroel 170, Barcelona, Spain
Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain
Univ Barcelona, Sch Med, Barcelona, Spain
Green Published, hybrid
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