Mechanisms of a Novel Combined Immunodeficiency Caused by a Homozygous Mutation in COPG1

COPG1 纯合突变引起的新型联合免疫缺陷的机制

• 批准号: 10493663
• 负责人: RAIF SALIM GEHA
• 金额: $ 5.27万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-03 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10493663
• 关键词: ADP-Ribosylation Factors; Age; Antibody Response; Apoptosis; Arginine; B cell differentiation; B-Lymphocytes; Bacteria; Bacterial Infections; Binding; Birth; CD4 Positive T Lymphocytes; CDC42 gene; Capsid Proteins; Cell Count; Cell Survival; Cell physiology; Cells; Coat Protein Complex I; Complex; Coupling; Cytomegalovirus; Cytosol; Data; Defect; Disease; Disease model; Encapsulated; Endoplasmic Reticulum; Ensure; Family; Fibroblasts; GTPase-Activating Proteins; Golgi Apparatus; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Human Herpesvirus 4; Immunity; Immunoglobulin G; Immunoglobulins; Immunologic Deficiency Syndromes; Impairment; In Vitro; Integral Membrane Protein; Interleukin-4; KDEL receptor; Link; Lung infections; Lymphocytic choriomeningitis virus; Lymphopenia; Lysine; Mediating; Membrane; Molecular Chaperones; Monomeric GTP-Binding Proteins; Mus; Mutant Strains Mice; Mutation; Outcome Study; Patients; Pharmaceutical Preparations; Pneumococcal Infections; Preclinical Testing; Predisposition; Production; Proteins; Recurrence; Retrieval; Role; Secondary to; Siblings; Side; System; T-Lymphocyte; Testing; Transcript; Treatment Efficacy; Vesicle; Viremia; Virus Diseases; chronic infection; consanguineous family; endoplasmic reticulum stress; hypogammaglobulinemia; in vivo; inhibitor; lysyl-aspartyl-glutamyl-leucine; man; mutant; mutant mouse model; novel; preclinical efficacy; protein folding; protein transport; receptor; receptor binding; recruit; response; retrograde transport; tauroursodeoxycholic acid; trafficking; vesicle transport

We identified a biallelic K652E mutation in the γ1-COP subunit of the heptameric coat protein I (COPI) complex in 5 Omani siblings, suffering from recurrent pulmonary infections with encapsulated bacteria, CMV and EBV viremia. The four older siblings presented with severe CD4+ T cell lymphopenia and increased T cell apoptosis; the youngest had normal T cell numbers shortly after birth, but developed CMV viremia and CD4+ T cell lymphopenia at 6 mo. Coat proteins deform membranes to generate transport vesicles. They also bind to cargo proteins to properly sort them into these vesicles, and ensure their transport to specific intracellular compartments. In the early secretory system, the COPII complex transports cargo from the endoplasmic reticulum (ER) to the Golgi, while the COPI complex transports select cargo in the other direction, from the Golgi to the ER, and additionally mediates CDC42-dependent transport through the Golgi. Specific sequences on cargo proteins recognized by COPI include the di-lysine and the di-arginine motifs. Coat proteins can also bind indirectly to COPI through transmembrane proteins that act as cargo receptors. These include the KDEL receptor (KDELR), which links COPI (residing on the cytosolic side of Golgi membrane) to soluble proteins within the Golgi (lumenal side) that have a KDEL sequence. KDEL proteins are abundant ER proteins involved in protein folding (chaperones). A fraction of KDEL proteins leak from the ER, and are retrieved from the Golgi to the ER through the KDELR and COPI. Defect in this retrieval leads to the loss of ER chaperones, which has been found to induce ER stress. Preliminary data show that fibroblasts from patients, and mice homozygous for the K652E γ1-COP mutation, express the mutant protein, but demonstrate defective COPI-mediated trafficking, and that the mutation disrupts the binding of the mutant COPI complex to KDELR. Mutant mice have severe hypogammaglobulinemia and poor antibody responses. Their B cells had increased ER stress and impaired immunoglobulin (Ig) secretion that was rescued by the ER stress inhibitor TUDCA. T cells from the mutant were normal in numbers, but had increased ER stress, and displayed increased apoptosis and diminished IL-4 production following sustained activation in vitro. We propose to test the hypothesis that the γ1-COP mutation disrupts COPI-mediated trafficking causing increased ER stress that impairs B and T cell function, increases susceptibility to bacterial and viral infection, and results in CD4+ T cell lymphopenia secondary to persistent viral infection. The studies proposed will elucidate the mechanisms by which a novel monogenic defect that impairs COPI-mediated trafficking leads to CID with CD4+ T cell lymphopenia, and will test pre-clinically the therapeutic efficacy of ER stress relieving drugs in this disease.

我们在七聚体外壳蛋白 I (COPI) 的 γ1-COP 亚基中发现了双等位基因 K652E 突变 5 名阿曼兄弟姐妹患有复发性肺部包膜细菌感染、巨细胞病毒 (CMV) 感染 四个哥哥姐姐出现严重的 CD4+ T 细胞淋巴细胞减少症和 T 细胞增多。 细胞凋亡；最小的孩子出生后不久 T 细胞数量正常，但出现 CMV 病毒血症和 CD4+ T 6个月时细胞淋巴细胞减少。 外壳蛋白使膜变形以产生运输囊泡，它们还与货物蛋白结合。 将它们正确分类到这些囊泡中，并确保它们运输到特定的细胞内区室。 早期分泌系统，COPII复合体将货物从内质网（ER）运输到高尔基体， 而 COPI 复合体向另一个方向运输选定的货物，从高尔基体到 ER，并且 此外，还介导通过高尔基体的 CDC42 依赖性转运。货物蛋白上的特定序列。 COPI 识别的二赖氨酸和二精氨酸基序也可以间接结合。 COPI 通过充当货物受体的跨膜蛋白，其中包括 KDEL 受体。 (KDELR)，它将 COPI（位于高尔基膜的胞质侧）与细胞内的可溶性蛋白质连接起来 具有KDEL序列的高尔基体（腔侧）是参与蛋白质的丰富的ER蛋白。 折叠（分子伴侣）的一部分 KDEL 蛋白从 ER 泄漏，并从高尔基体回收到 ER。 通过 KDELR 和 COPI，该检索中的缺陷导致 ER 伴侣的丢失，这已被证实。 发现诱发 ER 应激。 初步数据显示，来自患者和小鼠的成纤维细胞具有 K652E γ1-COP 纯合子 突变，表达突变蛋白，但表现出 COPI 介导的运输有缺陷，并且 突变破坏了突变 COPI 复合物与 KDELR 的结合，突变小鼠患有严重的疾病。 低丙种球蛋白血症和抗体反应较差，他们的 B 细胞增加了 ER 应激并受损。 突变体 T 细胞中的 ER 应激抑制剂 TUDCA 可以恢复免疫球蛋白 (Ig) 的分泌。 数量正常，但 ER 应激增加，细胞凋亡增加，IL-4 减少 体外持续激活后产生。 我们建议检验 γ1-COP 突变破坏 COPI 介导的贩运的假设 内质网应激增加，损害 B 细胞和 T 细胞功能，增加对细菌的易感性 和病毒感染，并导致继发于持续病毒感染的 CD4+ T 细胞淋巴细胞减少。 拟议的研究将阐明一种新的单基因缺陷损害的机制 COPI 介导的贩运导致 CI​​D 并伴有 CD4+ T 细胞淋巴细胞减少，并将在临床前测试治疗方法 ER应激缓解药物在此疾病中的疗效。

项目成果

Rethinking newborn screening for severe combined immunodeficiency: Lessons from an international partnership for patients with primary immunodeficiencies in Pakistan.

重新思考新生儿严重联合免疫缺陷筛查：巴基斯坦原发性免疫缺陷患者国际合作伙伴关系的经验教训。

• 发表时间: 2019
• 作者: Wallace, Jacqueline G;Tipu, Hamid Nawaz;Stafstrom, Kelsey;Alosaimi, Mohammed F;Massaad, Michel J;Bainter, Wayne;Geha, Raif S;Chou, Janet
• 通讯作者: Chou, Janet

T-cell mitochondrial dysfunction and lymphopenia in DOCK2-deficient patients.

DOCK2 缺陷患者的 T 细胞线粒体功能障碍和淋巴细胞减少。

• 发表时间: 2019
• 作者: Alosaimi, Mohammed F;Shendi, Hiba;Beano, Abdallah;Stafstrom, Kelsey;El Hawary, Rabab;Meshaal, Safa;Galal, Nermeen;Pai, Sung;El;Geha, Raif S;Chou, Janet
• 通讯作者: Chou, Janet

A novel truncating mutation in MYD88 in a patient with BCG adenitis, neutropenia and delayed umbilical cord separation.

患有 BCG 腺炎、中性粒细胞减少症和脐带分离延迟的患者中 MYD88 的新型截短突变。

• 发表时间: 2019
• 作者: Platt, Craig D;Zaman, Fatima;Wallace, Jacqueline G;Seleman, Michael;Chou, Janet;Al Sukaiti, Nashat;Geha, Raif S
• 通讯作者: Geha, Raif S

Successful hematopoietic stem cell transplantation in a 4-1BB deficient patient with EBV-induced lymphoproliferation.

成功对一名 4-1BB 缺陷且 EB 病毒诱导淋巴增殖的患者进行造血干细胞移植。

• 发表时间: 2021
• 作者: Wildermann, Christine;Alosaimi, Mohammed;Liebenehm, Sophie;Jacobsen, Eva;Barth, Thomas F E;Möller, Peter;Debatin, Klaus;Schulz, Ansgar;Sirin, Mehtap;Abosoudah, Ibraheem F;Alkuraya, Fowzan S;Geha, Raif S;Hönig, Manfred
• 通讯作者: Hönig, Manfred

Immunologic reconstitution following hematopoietic stem cell transplantation despite lymph node paucity in NF-κB-inducing kinase deficiency.

尽管淋巴结缺乏 NF-κB 诱导激酶缺陷，但造血干细胞移植后的免疫重建。

• 发表时间: 2019
• 作者: Ben Farhat, Khaoula;Alosaimi, Mohammed F;Shendi, Hiba;Al;Jones, Jennifer;Schwarz, Klaus;Schulz, Ansgar;Alawdah, Laila S;Burchett, Sandra;Albuhairi, Sultan;Whangbo, Jennifer;Kwatra, Neha;Shamseldin, Hanan E;Alkuraya, Fowzan S
• 通讯作者: Alkuraya, Fowzan S