Germline-activating mutations in PIK3CD compromise B cell development and function.
Germline-activating mutations in PIK3CD compromise B cell development and function.
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DOI：
10.1084/jem.20180010
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发表时间：
2018-08-06
期刊：
影响因子：
--
通讯作者：
Tangye SG
中科院分区：
文献类型：
--
作者：
Avery DT;Kane A;Nguyen T;Lau A;Nguyen A;Lenthall H;Payne K;Shi W;Brigden H;French E;Bier J;Hermes JR;Zahra D;Sewell WA;Butt D;Elliott M;Boztug K;Meyts I;Choo S;Hsu P;Wong M;Berglund LJ;Gray P;O'Sullivan M;Cole T;Holland SM;Ma CS;Burkhart C;Corcoran LM;Phan TG;Brink R;Uzel G;Deenick EK;Tangye SG
PIK 3CD突变导致免疫失调。通过研究人类和一种新的小鼠模型，我们发现这些突变本质上损害了B细胞的发育和功能。这些发现揭示了由于PIK 3CD突变导致的体液免疫受损的机制，以及恢复这些缺陷的机会。PIK 3CD中的功能获得性（GOF）突变，编码磷脂酰肌醇3-激酶（PI 3 K）的p110δ亚基，引起原发性免疫缺陷。受影响的个体在感染或免疫后显示受损的体液免疫应答。为了建立这些免疫缺陷的机制，我们研究了大量患有PIK 3CD GOF突变的患者，并使用CRISPR/Cas9介导的基因编辑建立了一种新型小鼠模型，以在Pik 3cd中引入常见的致病性突变。在这两个物种中，过度活跃的PI 3 K严重影响骨髓和外周中的B细胞发育和分化。此外，PI 3 K GOF B细胞由于活化诱导的胞苷脱氨酶（AID）的诱导受损以及未能获得浆母细胞基因特征和表型而在类别转换重组（CSR）中表现出内在缺陷。重要的是，CSR、AID表达和IG分泌的缺陷可通过leniolisib（一种特异性p110δ抑制剂）恢复。我们的研究结果揭示了平衡PI 3 K信号在B细胞发育和长期体液免疫和记忆中的关键作用，并建立了用p110δ抑制剂治疗受影响个体的有效性。
PIK3CD mutations cause immune dysregulation. By studying humans and a novel mouse model, we show these mutations intrinsically impair B-cell development and function. These findings reveal mechanisms of compromised humoral immunity due to PIK3CD mutations, and opportunities to pharmacologically restore these defects. Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd. In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.
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影响因子：
30.5
作者：
通讯作者：
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影响因子：
4.4
作者：
Andjelic, S;Hsia, C;Liou, HC
通讯作者：
Liou, HC
DOI：
10.1016/j.jaci.2016.06.021
发表时间：
2017-02
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Coulter TI;Chandra A;Bacon CM;Babar J;Curtis J;Screaton N;Goodlad JR;Farmer G;Steele CL;Leahy TR;Doffinger R;Baxendale H;Bernatoniene J;Edgar JD;Longhurst HJ;Ehl S;Speckmann C;Grimbacher B;Sediva A;Milota T;Faust SN;Williams AP;Hayman G;Kucuk ZY;Hague R;French P;Brooker R;Forsyth P;Herriot R;Cancrini C;Palma P;Ariganello P;Conlon N;Feighery C;Gavin PJ;Jones A;Imai K;Ibrahim MA;Markelj G;Abinun M;Rieux-Laucat F;Latour S;Pellier I;Fischer A;Touzot F;Casanova JL;Durandy A;Burns SO;Savic S;Kumararatne DS;Moshous D;Kracker S;Vanhaesebroeck B;Okkenhaug K;Picard C;Nejentsev S;Condliffe AM;Cant AJ
通讯作者：
Cant AJ
DOI：
10.1126/science.1243292
发表时间：
2013-11-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Angulo I;Vadas O;Garçon F;Banham-Hall E;Plagnol V;Leahy TR;Baxendale H;Coulter T;Curtis J;Wu C;Blake-Palmer K;Perisic O;Smyth D;Maes M;Fiddler C;Juss J;Cilliers D;Markelj G;Chandra A;Farmer G;Kielkowska A;Clark J;Kracker S;Debré M;Picard C;Pellier I;Jabado N;Morris JA;Barcenas-Morales G;Fischer A;Stephens L;Hawkins P;Barrett JC;Abinun M;Clatworthy M;Durandy A;Doffinger R;Chilvers ER;Cant AJ;Kumararatne D;Okkenhaug K;Williams RL;Condliffe A;Nejentsev S
通讯作者：
Nejentsev S
影响因子：
5.4
作者：
Agematsu, K;Nagumo, H;Komiyama, A
通讯作者：
Komiyama, A