Genetic and functional basis of familial hemophagocytic lymphohistiocytosis

家族性噬血细胞性淋巴组织细胞增多症的遗传和功能基础

• 批准号: 230131937
• 负责人: Professor Dr. Stephan Ehl
• 金额: --
• 依托单位: Virologisches Institut - Klinische und Molekulare Virologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/230131937?language=en
• 关键词: Genetic; functional; basis; familial; hemophagocytic

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome of impaired immune regulation. HLH is a key clinical manifestation in a number of genetic diseases, most of which are characterized by mutations in genes relevant for lymphocyte cytotoxicity. Here, we want to further elucidate the genetic and functional basis of inherited diseases predisposing to HLH. Based on a growing, clinically and immunologically well-characterized cohort of patients referred for evaluation for HLH, we will focus on patients with familial or recurrent disease, EBV triggered disease or HLH in the context of an immunodeficiency. Functional screening will identify patients with cytotoxicity and degranulation defects, particular response patterns to EBV and particular T cell differentiation patterns. Based on this phenotypic screen, we will use state of the art genetic tools including whole exome sequencing to identify novel genetic defects and characterize them in-vitro and in-vivo using cell biological and immunological approaches. The study aims to identify unknown components involved in organelle trafficking, lymphocyte cytotoxicity, and immune regulation and to improve the diagnosis and treatment options for patients with HLH.

噬血细胞性淋巴组织细胞增生症（HLH）是一种危及生命的免疫调节受损的临床综合征。HLH是许多遗传性疾病的关键临床表现，其中大多数以淋巴细胞毒性相关基因突变为特征。在这里，我们想进一步阐明遗传性疾病易感HLH的遗传和功能基础。基于越来越多的临床和免疫学特征良好的患者队列，我们将重点关注家族性或复发性疾病、EBV触发疾病或免疫缺陷背景下的HLH患者。功能性筛选将鉴定具有细胞毒性和脱颗粒缺陷的患者、对EBV的特定应答模式和特定T细胞分化模式。基于这种表型筛选，我们将使用最先进的遗传工具，包括全外显子组测序，以确定新的遗传缺陷，并使用细胞生物学和免疫学方法在体外和体内对其进行表征。该研究旨在确定参与细胞器运输，淋巴细胞毒性和免疫调节的未知成分，并改善HLH患者的诊断和治疗选择。

项目成果

Morphological alterations in two siblings with autosomal recessive congenital ichthyosis associated with CYP4F22 mutations

患有与 CYP4F22 突变相关的常染色体隐性先天性鱼鳞病的两个兄弟姐妹的形态学改变

• DOI: 10.1111/bjd.14860
• 发表时间: 2017
• 期刊: British Journal of Dermatology
• 影响因子: 10.3
• 作者: Gruber R;Rainer G;Weiss A;Udvardi A;Thiele H;Eckl KM;Schupart R;Nürnberg P;Zschocke J;Schmuth M;Volc-Platzer B;Hennies HC
• 通讯作者: Hennies HC

Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome.

• DOI: 10.1182/blood-2015-09-671636
• 发表时间: 2016-02-25
• 期刊: Blood
• 影响因子: 20.3
• 作者: Ammann S;Schulz A;Krägeloh-Mann I;Dieckmann NM;Niethammer K;Fuchs S;Eckl KM;Plank R;Werner R;Altmüller J;Thiele H;Nürnberg P;Bank J;Strauss A;von Bernuth H;Zur Stadt U;Grieve S;Griffiths GM;Lehmberg K;Hennies HC;Ehl S
• 通讯作者: Ehl S

Effective Immunological Guidance of Genetic Analyses Including Exome Sequencing in Patients Evaluated for Hemophagocytic Lymphohistiocytosis

• DOI: 10.1007/s10875-017-0443-1
• 发表时间: 2017-11-01
• 期刊: JOURNAL OF CLINICAL IMMUNOLOGY
• 影响因子: 9.1
• 作者: Ammann, Sandra;Lehmberg, Kai;Ehl, Stephan
• 通讯作者: Ehl, Stephan

The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis

• DOI: 10.3324/haematol.2014.121608
• 发表时间: 2015-06-01
• 期刊: HAEMATOLOGICA
• 影响因子: 10.1
• 作者: Bode, Sebastian F. N.;Ammann, Sandra;Ehl, Stephan
• 通讯作者: Ehl, Stephan