Hem-1 regulates protective humoral immunity and limits autoantibody production in a B cell-specific manner.
Hem-1 regulates protective humoral immunity and limits autoantibody production in a B cell-specific manner.
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DOI：
10.1172/jci.insight.153597
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发表时间：
2022-05-09
期刊：
影响因子：
8
通讯作者：
Iritani, Brian M.
中科院分区：
文献类型：
--
作者：
Avalos, Alan;Tietsort, Jacob T.;Suwankitwat, Nutthakarn;Woods, Jonathan D.;Jackson, Shaun W.;Christodoulou, Alexandra;Morrill, Christopher;Liggitt, H. Denny;Zhu, Chengsong;Li, Quan-Zhen;Bui, Kevin K.;Park, Heon;Iritani, Brian M.
造血蛋白-1（Hem-1）是肌动蛋白调节WASp家族verprolin同系物（WAVE）复合物的成员。最近发现编码Hem-1的NCKAP 1 L基因中的功能丧失变体导致儿童原发性免疫缺陷病（PID），其特征在于特异性抗体应答差、自身抗体增加和高死亡率。然而，Hem-1缺陷如何导致PID的机制尚不清楚。在这项研究中，我们利用组成型和B细胞特异性Nckap 1 l-KO小鼠来剖析Hem-1在B细胞发育和功能中的重要性。Hem-1的B细胞特异性破坏导致再循环卵泡（FO）、边缘区（MZ）和B1 B细胞数量减少。B细胞对CXCL 12和CXCL-13的迁移反应减少。T-非依赖性抗体应答几乎被消除，导致对肺炎链球菌攻击的保护性免疫失败。相比之下，T依赖性IgM和IgG 2c、记忆B细胞和浆细胞应答相对于WT对照小鼠更稳健。B细胞特异性Hem-1缺陷小鼠针对多种自身抗原的自身抗体增加，这与高反应性BCR信号传导和与自身免疫性疾病相关的CD 11 c +T-bet+年龄相关B细胞（ABC细胞）改变的表达增加相关。这些结果表明，功能失调的B细胞可能是解释为什么功能丧失的Hem-1变体导致复发性感染和自身免疫的机制的一部分。
Hematopoietic protein-1 (Hem-1) is a member of the actin-regulatory WASp family verprolin homolog (WAVE) complex. Loss-of-function variants in the NCKAP1L gene encoding Hem-1 were recently discovered to result in primary immunodeficiency disease (PID) in children, characterized by poor specific Ab responses, increased autoantibodies, and high mortality. However, the mechanisms of how Hem-1 deficiency results in PID are unclear. In this study, we utilized constitutive and B cell–specific Nckap1l-KO mice to dissect the importance of Hem-1 in B cell development and functions. B cell–specific disruption of Hem-1 resulted in reduced numbers of recirculating follicular (FO), marginal zone (MZ), and B1 B cells. B cell migration in response to CXCL12 and -13 were reduced. T-independent Ab responses were nearly abolished, resulting in failed protective immunity to Streptococcus pneumoniae challenge. In contrast, T-dependent IgM and IgG2c, memory B cell, and plasma cell responses were more robust relative to WT control mice. B cell–specific Hem-1–deficient mice had increased autoantibodies against multiple autoantigens, and this correlated with hyperresponsive BCR signaling and increased representation of CD11c+T-bet+ age-associated B cell (ABC cells) — alterations associated with autoimmune diseases. These results suggest that dysfunctional B cells may be part of a mechanism explaining why loss-of-function Hem-1 variants result in recurring infections and autoimmunity.
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DOI：
10.1084/jem.20192275
发表时间：
2020-12-07
期刊：
The Journal of experimental medicine
影响因子：
--
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Bahram S
DOI：
10.1084/jem.20151724
发表时间：
2016-05-02
期刊：
The Journal of experimental medicine
影响因子：
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Rawlings DJ
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DOI：
10.1056/nejmoa1413462
发表时间：
2015-06-18
期刊：
The New England journal of medicine
影响因子：
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Dobbs K;Domínguez Conde C;Zhang SY;Parolini S;Audry M;Chou J;Haapaniemi E;Keles S;Bilic I;Okada S;Massaad MJ;Rounioja S;Alwahadneh AM;Serwas NK;Capuder K;Çiftçi E;Felgentreff K;Ohsumi TK;Pedergnana V;Boisson B;Haskoloğlu Ş;Ensari A;Schuster M;Moretta A;Itan Y;Patrizi O;Rozenberg F;Lebon P;Saarela J;Knip M;Petrovski S;Goldstein DB;Parrott RE;Savas B;Schambach A;Tabellini G;Bock C;Chatila TA;Comeau AM;Geha RS;Abel L;Buckley RH;İkincioğulları A;Al-Herz W;Helminen M;Doğu F;Casanova JL;Boztuğ K;Notarangelo LD
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DOI：
10.1084/jem.20091489
发表时间：
2010-04-12
期刊：
The Journal of experimental medicine
影响因子：
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通讯作者：
Tybulewicz VL
影响因子：
7.3
作者：
Bacalao MA;Satterthwaite AB
通讯作者：
Satterthwaite AB