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.

自身炎症性疾病（AID）最初被描述为以看似无端的无菌性炎症反复发作为特征的临床疾病。在过去几年中，新型艾滋病的发现将其表型扩展到与血管病变、自身免疫或免疫缺陷相关的更复杂的临床表现。在此，我们描述了两名无关的患者，他们从新生儿期起就患有一种复杂的疾病，其主要特征是严重的无菌性炎症、反复的细菌感染和明显的体液免疫缺陷。全外显子组测序在每位患者中检测到一种新的从头杂合PLCG2变异（p.Ala708Pro 和 p.Leu845_Leu848del）。患者 B 细胞对 IgM 刺激的离体钙反应和 PLC 活性的体外评估都证明了两种变体的 PLCγ2 活性明显增强。这些数据支持两名患者的自身炎症和 PLCγ2 相关抗体缺陷和免疫失调 (APLAID) 诊断。免疫学评估显示免疫球蛋白和 B 细胞（尤其是类别转换记忆 B 细胞）严重减少，而 T 和 NK 细胞计数正常。对一名患者的骨髓分析显示，与对照组相比，未成熟 B 细胞比例减少。其他研究表明，两种PLCG2变体都通过替代途径而不是经典途径激活 NLRP3 炎症小体。总的来说，这里显示的证据将 APLAID 多样性扩展到比以前报道的更严重的表型，包括显性遗传性无丙种球蛋白血症，增加了有关其遗传基础的新数据，并暗示了无菌炎症基础上的替代 NLRP3-炎性体激活途径。