Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.
Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.
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DOI：
10.1016/j.jaci.2015.05.036
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Tangye SG
中科院分区：
文献类型：
--
作者：
Ma CS;Wong N;Rao G;Avery DT;Torpy J;Hambridge T;Bustamante J;Okada S;Stoddard JL;Deenick EK;Pelham SJ;Payne K;Boisson-Dupuis S;Puel A;Kobayashi M;Arkwright PD;Kilic SS;El Baghdadi J;Nonoyama S;Minegishi Y;Mahdaviani SA;Mansouri D;Bousfiha A;Blincoe AK;French MA;Hsu P;Campbell DE;Stormon MO;Wong M;Adelstein S;Smart JM;Fulcher DA;Cook MC;Phan TG;Stepensky P;Boztug K;Kansu A;İkincioğullari A;Baumann U;Beier R;Roscioli T;Ziegler JB;Gray P;Picard C;Grimbacher B;Warnatz K;Holland SM;Casanova JL;Uzel G;Tangye SG
T滤泡辅助细胞（Tfh）是T细胞依赖性体液免疫和大多数疫苗成功的基础。Tfh细胞也有助于人类免疫紊乱，如自身免疫、免疫缺陷和恶性肿瘤。了解Tfh细胞产生和功能的分子需求将为靶向这些细胞以调节其在这些免疫异常情况下的行为提供策略。确定人类Tfh细胞发育和功能所需的信号通路和细胞相互作用。由单基因突变引起的人类原发性免疫缺陷（pid）提供了一个独特的机会来评估调节人类淋巴细胞功能对特定分子的需求。在健康对照以及由STAT3、STAT1、TYK2、IL21、IL21R、IL10R、IFNGR1/2、IL12RB1、CD40LG、NEMO、ICOS或BTK突变引起的PIDs患者中，对循环Tfh （cTfh）细胞亚群、记忆B细胞和血清Ig水平进行了量化和功能评估。STAT3、IL10R、CD40LG、NEMO、ICOS或BTK中的功能丧失（LOF）突变降低了cTfh的频率。STAT3、IL21/R LOF和STAT1获得性功能突变使cTfh分化向过度表达IFNγ和程序性死亡-1 （PD-1）的表型倾斜。IFNγ在体外和体内抑制cTfh功能，IFNGR1/2、STAT1和IL12RB1 LOF突变患者的高γ球蛋白血症证实了这一点。特异性突变影响cTfh细胞的数量和质量，强调需要通过多种标准评估患者的Tfh细胞，包括表型和功能。此外，IFNγ在体内还能抑制tfh诱导的B细胞分化。这些发现为Tfh生物学及其产生、维持和效应功能所需的综合信号通路提供了新的视角，并解释了一些pid中体液免疫受损的原因。
T follicular helper (Tfh) cells underpin T-cell dependent humoral immunity and the success of most vaccines. Tfh cells also contribute to human immune disorders such as autoimmunity, immunodeficiency and malignancy. Understanding the molecular requirements for the generation and function of Tfh cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunological abnormalities. To determine the signaling pathways and cellular interactions required for the development and function of Tfh cells in humans. Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating Tfh (cTfh) cell subsets, memory B cells and serum Ig levels were quantified and functionally assessed in healthy controls as well as patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS or BTK. Loss-of function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS or BTK reduced cTfh frequencies. STAT3, IL21/R LOF and STAT1 gain-of function mutations skewed cTfh differentiation towards a phenotype characterized by over-expression of IFNγ and programmed death -1 (PD-1). IFNγ inhibited cTfh function in vitro and in vivo, corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1 and IL12RB1 LOF mutations. Specific mutations impact the quantity and quality of cTfh cells, highlighting the need to assess Tfh cells in patients by multiple criteria, including phenotype and function. Furthermore, IFNγ functions in vivo to restrain Tfh-induced B cell differentiation. These findings shed new light on Tfh biology and the integrated signaling pathways required for their generation, maintenance and effector function, and explain compromised humoral immunity in some PIDs.
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影响因子：
30.5
作者：
Butler, Noah S.;Moebius, Jacqueline;Pewe, Lecia L.;Traore, Boubacar;Doumbo, Ogobara K.;Tygrett, Lorraine T.;Waldschmidt, Thomas J.;Crompton, Peter D.;Harty, John T.
通讯作者：
Harty, John T.
DOI：
10.1038/nrrheum.2012.58
发表时间：
2012-05-01
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
通讯作者：
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DOI：
10.1084/jem.20070663
发表时间：
2007-08-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Annunziato F;Cosmi L;Santarlasci V;Maggi L;Liotta F;Mazzinghi B;Parente E;Filì L;Ferri S;Frosali F;Giudici F;Romagnani P;Parronchi P;Tonelli F;Maggi E;Romagnani S
通讯作者：
Romagnani S
影响因子：
7.3
作者：
Al-Herz W;Bousfiha A;Casanova JL;Chatila T;Conley ME;Cunningham-Rundles C;Etzioni A;Franco JL;Gaspar HB;Holland SM;Klein C;Nonoyama S;Ochs HD;Oksenhendler E;Picard C;Puck JM;Sullivan K;Tang ML
通讯作者：
Tang ML
影响因子：
82.9
作者：
通讯作者：
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