Fulminant Viral Hepatitis in Two Siblings with Inherited IL-10RB Deficiency.
Fulminant Viral Hepatitis in Two Siblings with Inherited IL-10RB Deficiency.
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DOI：
10.1007/s10875-022-01376-5
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发表时间：
2023-02
影响因子：
9.1
通讯作者：
Jouanguy, Emmanuelle
中科院分区：
文献类型：
--
作者：
Korol, Cecilia B.;Belkaya, Serkan;Alsohime, Fahad;Lorenzo, Lazaro;Boisson-Dupuis, Stephanie;Brancale, Joseph;Neehus, Anna-Lena;Vilarinho, Silvia;Zobaida, Alsum;Halwani, Rabih;Al-Muhsen, Saleh;Casanova, Jean-Laurent;Jouanguy, Emmanuelle
关键词：
由甲型肝炎病毒（HAV）引起的暴发性病毒性肝炎（FVH）是一种危及生命的疾病，通常袭击健康个体。FVH的唯一已知遗传病因是遗传性IL-18 BP缺乏，其释放IL-18依赖性淋巴细胞细胞毒性和IFN-γ产生。我们研究了两名死于早发性炎症性肠病（EOIBD）和HAV引起的FVH的兄弟姐妹。所测试的同胞是先前在患有EOIBD的不相关患者中描述的IL 10 RB的W100 G变体的纯合子。我们在此显示，在其他EOIBD患者中观察到的框外IL 10 RB变体在过表达条件下和纯合细胞中破坏了对IL-10、IL-22、IL-26和IFN-λ的细胞应答。相比之下，框内致病变异的影响因病例而异。当过表达时，W100 G变体损害对IL-10的细胞应答，但不损害对IL-22、IL-26或IFN-λ1的细胞应答，而W100 G纯合细胞不应答IL-10、IL-22、IL-26或IFN-λ1。由于IL-10是吞噬细胞中IFN-γ的有效拮抗剂，因此这些发现表明，IL-18 BP或IL-10 RB缺乏患者中FVH的分子基础可能涉及HAV感染肝脏期间IFN-γ的过度活性。遗传性IL-10 RB缺乏，以及可能遗传的IL-10和IL-10 RA缺乏，赋予FVH的易感性，具有这些缺陷的患者应接种抗HAV和其他嗜肝病毒的疫苗。在线版本包含补充材料，可通过10.1007/s10875-022-01376-5获得。
Fulminant viral hepatitis (FVH) caused by hepatitis A virus (HAV) is a life-threatening disease that typically strikes otherwise healthy individuals. The only known genetic etiology of FVH is inherited IL-18BP deficiency, which unleashes IL-18-dependent lymphocyte cytotoxicity and IFN-γ production. We studied two siblings who died from a combination of early-onset inflammatory bowel disease (EOIBD) and FVH due to HAV. The sibling tested was homozygous for the W100G variant of IL10RB previously described in an unrelated patient with EOIBD. We show here that the out-of-frame IL10RB variants seen in other EOIBD patients disrupt cellular responses to IL-10, IL-22, IL-26, and IFN-λs in overexpression conditions and in homozygous cells. By contrast, the impact of in-frame disease-causing variants varies between cases. When overexpressed, the W100G variant impairs cellular responses to IL-10, but not to IL-22, IL-26, or IFN-λ1, whereas cells homozygous for W100G do not respond to IL-10, IL-22, IL-26, or IFN-λ1. As IL-10 is a potent antagonist of IFN-γ in phagocytes, these findings suggest that the molecular basis of FVH in patients with IL-18BP or IL-10RB deficiency may involve excessive IFN-γ activity during HAV infections of the liver. Inherited IL-10RB deficiency, and possibly inherited IL-10 and IL-10RA deficiencies, confer a predisposition to FVH, and patients with these deficiencies should be vaccinated against HAV and other liver-tropic viruses. The online version contains supplementary material available at 10.1007/s10875-022-01376-5.
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DOI：
10.1126/science.abj7965
发表时间：
2021-11-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Casanova JL;Abel L
通讯作者：
Abel L
DOI：
10.1084/jem.20130592
发表时间：
2013-08-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Byun M;Ma CS;Akçay A;Pedergnana V;Palendira U;Myoung J;Avery DT;Liu Y;Abhyankar A;Lorenzo L;Schmidt M;Lim HK;Cassar O;Migaud M;Rozenberg F;Canpolat N;Aydogan G;Fleckenstein B;Bustamante J;Picard C;Gessain A;Jouanguy E;Cesarman E;Olivier M;Gros P;Abel L;Croft M;Tangye SG;Casanova JL
通讯作者：
Casanova JL
影响因子：
9.8
作者：
Begue, Bernadette;Verdier, Julien;Ruemmele, Frank M.
通讯作者：
Ruemmele, Frank M.
影响因子：
4.4
作者：
Chapgier, Ariane;Wynn, Robert F.;Arkwright, Peter D.
通讯作者：
Arkwright, Peter D.
影响因子：
15.3
作者：
Belkaya, Serkan;Michailidis, Eleftherios;Casanova, Jean-Laurent
通讯作者：
Casanova, Jean-Laurent