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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 <jats:italic>PLCG2<\/jats:italic> variant in each patient (p.Ala708Pro and p.Leu845_Leu848del). A clear enhanced PLC\u03b32 activity for both variants was demonstrated by both ex vivo calcium responses of the patient\u2019s B cells to IgM stimulation and in vitro assessment of PLC activity. These data supported the autoinflammation and PLC\u03b32-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 <jats:italic>PLCG2<\/jats:italic> 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.<\/jats:p>","DOI":"10.1007\/s10875-020-00794-7","type":"journal-article","created":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T16:03:41Z","timestamp":1594829021000},"page":"987-1000","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 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Written informed consent for participation in the study was obtained from patients\u2019 parents. Blood samples from patients and unaffected relatives were collected for molecular studies, which were performed in accordance with the Declaration of Helsinki.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}