Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations.
Severe Autoinflammatory Manifestations and Antibody Deficiency Due to Novel Hypermorphic PLCG2 Mutations.
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DOI：
10.1007/s10875-020-00794-7
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发表时间：
2020-10
影响因子：
9.1
通讯作者：
Arostegui JI
中科院分区：
文献类型：
--
作者：
Martín-Nalda A;Fortuny C;Rey L;Bunney TD;Alsina L;Esteve-Solé A;Bull D;Anton MC;Basagaña M;Casals F;Deyá A;García-Prat M;Gimeno R;Juan M;Martinez-Banaclocha H;Martinez-Garcia JJ;Mensa-Vilaró A;Rabionet R;Martin-Begue N;Rudilla F;Yagüe J;Estivill X;García-Patos V;Pujol RM;Soler-Palacín P;Katan M;Pelegrín P;Colobran R;Vicente A;Arostegui JI
自体炎症性疾病(AIDS)最初被描述为临床疾病，其特征是反复发作看似无缘无故的无菌炎症。在过去的几年里，对新型艾滋病的识别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图像。在此，我们描述了两名自新生儿期以来患有一种复杂疾病的无关患者，其主要特征是严重的无菌炎症、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个患者中检测到一种新的PLCG2杂合突变(p.Ala708Pro和p.Leu845_Leu848del)。通过患者B细胞对γ刺激的体外钙反应和对PLC活性的体外评估，这两个变异体的PLC IgM 2活性都明显增强。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的诊断。免疫学检测显示免疫球蛋白和B细胞严重减少，尤其是类转换记忆B细胞，T和NK细胞计数正常。一名患者的骨髓分析显示，与对照组相比，未成熟B细胞比例降低。进一步的研究表明，这两个PLCG2变异体都通过替代途径而不是典型途径激活NLRP3-炎症体。总而言之，这些证据将APLAID多样性扩展到比先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，增加了关于其遗传基础的新数据，并在无菌炎症的基础上暗示了替代的NLRP3-炎症体激活途径。本文的在线版本(10.1007/s10875-020-00794-7)包含向授权用户提供的补充材料。
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. The online version of this article (10.1007/s10875-020-00794-7) contains supplementary material, which is available to authorized users.
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DOI：
10.1056/nejmoa1312625
发表时间：
2014-08-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Liu Y;Jesus AA;Marrero B;Yang D;Ramsey SE;Sanchez GAM;Tenbrock K;Wittkowski H;Jones OY;Kuehn HS;Lee CR;DiMattia MA;Cowen EW;Gonzalez B;Palmer I;DiGiovanna JJ;Biancotto A;Kim H;Tsai WL;Trier AM;Huang Y;Stone DL;Hill S;Kim HJ;St Hilaire C;Gurprasad S;Plass N;Chapelle D;Horkayne-Szakaly I;Foell D;Barysenka A;Candotti F;Holland SM;Hughes JD;Mehmet H;Issekutz AC;Raffeld M;McElwee J;Fontana JR;Minniti CP;Moir S;Kastner DL;Gadina M;Steven AC;Wingfield PT;Brooks SR;Rosenzweig SD;Fleisher TA;Deng Z;Boehm M;Paller AS;Goldbach-Mansky R
通讯作者：
Goldbach-Mansky R
DOI：
10.1056/nejmoa1102140
发表时间：
2012-01-26
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ombrello MJ;Remmers EF;Sun G;Freeman AF;Datta S;Torabi-Parizi P;Subramanian N;Bunney TD;Baxendale RW;Martins MS;Romberg N;Komarow H;Aksentijevich I;Kim HS;Ho J;Cruse G;Jung MY;Gilfillan AM;Metcalfe DD;Nelson C;O'Brien M;Wisch L;Stone K;Douek DC;Gandhi C;Wanderer AA;Lee H;Nelson SF;Shianna KV;Cirulli ET;Goldstein DB;Long EO;Moir S;Meffre E;Holland SM;Kastner DL;Katan M;Hoffman HM;Milner JD
通讯作者：
Milner JD
影响因子：
20.3
作者：
Liu, Ta-Ming;Woyach, Jennifer A.;Johnson, Amy J.
通讯作者：
Johnson, Amy J.
影响因子：
9.8
作者：
Zhou, Qing;Lee, Geun-Shik;Aksentijevich, Ivona
通讯作者：
Aksentijevich, Ivona
影响因子：
1.5
作者：
Torrelo, Antonio;Vera, Angel;Zambrano, Antonio
通讯作者：
Zambrano, Antonio