Defining New Human Immunodeficiency and Immunodysregulation Disorders

定义新的人类免疫缺陷和免疫失调疾病

• 批准号: 10927825
• 负责人: Helen Su
• 金额: $ 157.07万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10927825
• 关键词: Apoptosis; Autoimmune; Autoimmunity; B-Lymphocytes; Bacterial Infections; Biochemical; CASP8 gene; CTLA4 gene; Candidate Disease Gene; Clinical; Common Variable Immunodeficiency; Defect; Diagnosis; Disease; Epstein-Barr Virus Infections; Evaluation; Evans Syndrome; Genes; Genetic; Genomics; Human; Human Herpesvirus 4; Hybridization Array; Hypersensitivity; Immune System Diseases; Immune system; Immunologic Deficiency Syndromes; In Vitro; Infiltration; Intake; Job' s Syndrome; Link; Lymphocyte; Lymphocyte Activation; Lymphoid; Magnesium; Molecular; Mutation; Mycoses; NF-kappa B; Natural History; Natural Immunity; Neoplasms; Organ; Pathogenesis; Patients; Predisposition; Publications; Publishing; Reporting; Respiratory syncytial virus; Rhinovirus; STAT3 gene; System; T cell anergy; T-Lymphocyte; Technology; Testing; Variant; Virus Diseases; Work; autoimmune lymphoproliferative syndrome; comparative genomic hybridization; exome sequencing; experimental study; gain of function; genome sequencing; improved; influenzavirus; lymphadenopathy; optimal treatments; patient subsets; respiratory virus; screening; senescence; transcriptome sequencing; whole genome

Besides unique patients with immunodeficiency and immunodysregulation disorders lacking known diagnoses, our intake includes patients with combined immunodeficiency, common variable immunodeficiency (CVID), variants of hyper-IgE syndrome or autoimmune lymphoproliferative syndrome (ALPS), Evans syndrome, caspase-8-deficiency state (CEDS), B cell expansion with NF-kB and T cell anergy (BENTA) disease, X-linked Magnesium defect with EBV infection and Neoplasia (XMEN), PASLI (p110 delta activation mutation causing senescent T cells, lymphadenopathy, and immunodeficiency) disease, and CHAI (CTLA4 haploinsufficiency with autoimmune infiltration) disease. Patients with susceptibility to EBV, rhinovirus, influenza virus, respiratory syncytial virus, and other respiratory viruses are also being investigated. Our evaluation includes functional screening and gene sequencing, and a subset of patients is also being intensively studied using biochemical analyses, RNA-seq with PAR-CLIP, flow cytometric analyses, in vitro functional tests, and other technologies. These experiments have provided leads for sequencing of new candidate genes not previously associated with disease. Additionally, we are using comparative genomic hybridization (CGH) arrays, whole exome sequencing, whole genome sequencing, and other technologies to determine genetic causes of new immunological diseases in an unbiased manner. In FY2023, we continued our work on investigating the molecular pathogenesis of several as yet undescribed immunodeficiency-immunodysregulation disorders, as well as the natural history and optimal treatment of previously reported rare immunological disorders. We completed additional work on two new immunodysregulation disorders that were submitted for publication. We also contributed to several other studies that were published in FY2023, namely further characterization of molecular effects in BENTA disease and natural history of patients with STAT3 gain-of-function disease.

除了缺乏已知诊断的免疫缺陷和免疫失调疾病的独特患者外，我们的纳入包括患有联合免疫缺陷、常见变异型免疫缺陷（CVID）、高IgE综合征或自身免疫性淋巴增生综合征（ALPS）变体、Evans综合征、半胱天冬酶-8缺陷状态（CEDS）、B细胞扩增伴NF-κ B和T细胞无反应性（BENTA）疾病的患者，X连锁镁缺陷伴EBV感染和瘤形成（XMEN）、PASLI（p110 δ激活突变导致T细胞衰老、淋巴结病和免疫缺陷）疾病和CHAI（CTLA 4单倍不足伴自身免疫浸润）疾病。对EB病毒、鼻病毒、流感病毒、呼吸道合胞病毒和其他呼吸道病毒易感的患者也正在接受调查。我们的评估包括功能筛选和基因测序，并且还使用生化分析、RNA测序与PAR-CLIP、流式细胞术分析、体外功能测试和其他技术对一部分患者进行了深入研究。这些实验为以前与疾病无关的新候选基因的测序提供了线索。此外，我们正在使用比较基因组杂交（CGH）阵列，全外显子组测序，全基因组测序和其他技术，以公正的方式确定新的免疫性疾病的遗传原因。 在2023财年，我们继续研究几种尚未描述的免疫缺陷-免疫失调疾病的分子发病机制，以及之前报道的罕见免疫疾病的自然史和最佳治疗方法。我们完成了两个新的免疫失调疾病的额外工作，提交出版。我们还参与了2023财年发表的其他几项研究，即进一步表征BENTA病的分子效应和STAT 3功能获得性疾病患者的自然史。

项目成果

Designs for massively parallel sequencing approaches to identify causal mutations in human immune disorders.

设计大规模并行测序方法来识别人类免疫疾病的因果突变。

• DOI: 10.1007/978-1-62703-290-2_14
• 发表时间: 2013
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Zhang,Yu;Su,HelenC
• 通讯作者: Su,HelenC

Cutaneous manifestations of DOCK8 deficiency syndrome.

• DOI: 10.1001/archdermatol.2011.262
• 发表时间: 2012-01
• 期刊: ARCHIVES OF DERMATOLOGY
• 作者: Chu, Emily Y.;Freeman, Alexandra F.;Jing, Huie;Cowen, Edward W.;Davis, Joie;Su, Helen C.;Holland, Steven M.;Turner, Maria L. Chanco
• 通讯作者: Turner, Maria L. Chanco

Subcutaneous panniculitis-like T-cell lymphoma in two unrelated individuals with BENTA disease.

两名不相关的 BENTA 患者出现皮下脂膜炎样 T 细胞淋巴瘤。

• DOI: 10.1016/j.clim.2023.109732
• 发表时间: 2023
• 期刊: Clinical immunology (Orlando, Fla.)
• 作者: Bauman,BradlyM;Dorjbal,Batsukh;Pittaluga,Stefania;Zhang,Yu;Niemela,JulieE;Stoddard,JenniferL;Rosenzweig,SergioD;Anderson,Ronald;Guilcher,GregoryMT;Auer,Iwona;Perrier,Renee;Campbell,Martin;Bhandal,SamarjeetK;Alba,Camille

Gastrointestinal: Adult presentation of intestinal malrotation.

胃肠道：成人肠旋转不良的表现。

• DOI: 10.1111/jgh.13401
• 发表时间: 2016
• 期刊: Journal of gastroenterology and hepatology
• 影响因子: 4.1
• 作者: Eccleston,JL;Su,H;Ling,A;Heller,T;Koh,C
• 通讯作者: Koh,C

Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity.

• DOI: 10.3389/fimmu.2023.1172004
• 发表时间: 2023
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Beers, Breanna J. J.;Similuk, Morgan N. N.;Ghosh, Rajarshi;Seifert, Bryce A. A.;Jamal, Leila;Kamen, Michael;Setzer, Michael R. R.;Jodarski, Colleen;Duncan, Rylee;Hunt, Devin;Mixer, Madison;Cao, Wenjia;Bi, Weimin;Veltri, Daniel;Karlins, Eric;Zhang, Lingwen;Li, Zhiwen;Oler, Andrew J. J.;Jevtich, Kathleen;Yu, Yunting;Hullfish, Haley;Bielekova, Bibiana;Frischmeyer-Guerrerio, Pamela;Dang Do, An;Huryn, Laryssa A. D. A.;Olivier, Kenneth N. N.;Su, Helen C. C.;Lyons, Jonathan J. J.;Zerbe, Christa S. S.;Rao, V. Koneti;Keller, Michael D.;Freeman, Alexandra F. F.;Holland, Steven M. M.;Franco, Luis M. M.;Walkiewicz, Magdalena A. A.;Yan, Jia
• 通讯作者: Yan, Jia