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

Year: 2020

Type: article

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.

Source: Journal of Clinical Immunology

DOI: 10.1007/s10875-020-00794-7

Institutions: Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, Institut de Recerca Sant Joan de Déu, Universitat de Barcelona, Institute of Structural and Molecular Biology, University College London, Hospital Sant Joan de Déu Barcelona, Hospital Clínic de Barcelona, Universitat Autònoma de Barcelona, Hospital Universitari Germans Trias i Pujol, Universitat Pompeu Fabra, Hospital Del Mar, Hospital del Mar Research Institute, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Instituto Murciano de Investigación Biosanitaria, Hospital Universitario Virgen de la Arrixaca, Centre for Biomedical Network Research on Rare Diseases, Institut de Biomedicina de la Universitat de Barcelona, Banc de Sang i Teixits, Quantitative Genomics Medicine Laboratories (qGenomics)

Language: English

Topic: Immunodeficiency and Autoimmune Disorders

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,860

Funders: Fundación Séneca, Ministerio de Ciencia, Innovación y Universidades, Cancer Research UK, University College London, Generalitat de Catalunya, Ministerio de Economía y Competitividad, Medical Research Council, Instituto de Salud Carlos III, European Regional Development Fund, FP7 Ideas: European Research Council

Awards: G177921026, G2186010955, G2235519674, G2365399404, Assessing new therapeutic opportunities linked to TCR signalling in mature T-cell lymphomas with unmet need, G3060490087, G341736032, G4450184886, G4679777522, G4811286969, G5869637002, G6703062027, G6847198047, Regulation of inflammatory response by extracellular ATP and P2X7 receptor signalling: through and beyond the inflammasome, Identificación de variantes genéticas causantes/moduladoras del fenotipo clínico en inmunodeficiencias primarias y con disregulación. Aplicación de la NGS.

OpenAlex ID: W3042267048