Human Genetic Dissection of Antibody Response to Pneumococcal Glycans

对肺炎球菌聚糖抗体反应的人类基因剖析

• 批准号: 10218005
• 负责人: Jean-Laurent Casanova
• 金额: $ 44.81万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218005
• 关键词: Accounting; Address; Affect; Agammaglobulinemia; Alleles; Anhidrotic Ectodermal Dysplasia; Antibodies; Antibody Response; Antibody-mediated protection; B-Cell Development; B-Lymphocytes; CD19 gene; CD81 gene; CTLA4 gene; Child; Clinical; Code; Collaborations; Common Variable Immunodeficiency; Complex; Computer software; Coupled; Data; Defect; Development; Disease; Dissection; Ectodermal Dysplasia; Elements; Etiology; Family; Genes; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Glycogen Storage Disease Type IV; Hereditary Disease; Human; Human Genetics; IRAK1 gene; IRAK4 gene; IgG2; Immunity; Immunoglobulin G; Immunologic Deficiency Syndromes; Immunologics; Impairment; International; Investigation; Laboratories; Lead; Ligase; Light; Link; MS4A1 gene; MYD88 deficiency; Mediating; Memory; Meningitis; Molecular; Molecular Genetics; Mucous Membrane; Mutate; Mutation; Mutation Detection; NFKB2 gene; NFKBIA gene; Patient Recruitments; Patients; Phenotype; Pneumococcal Infections; Polysaccharides; Predisposition; Proteins; RNA; Recurrence; Role; STAT3 gene; Septicemia; Serum; Signal Pathway; Signal Transduction; Specific antibody deficiency; Streptococcus pneumoniae; Structure; Syndrome; TIRAP gene; Therapeutic Intervention; Transcript; Ubiquitination; Validation; Variant; base; congenital immunodeficiency; exome; genetic disorder diagnosis; genetic technology; genome sequencing; genome-wide; humoral immunity deficiency; improved; interest; kindred; mutant; next generation sequencing; novel; rare condition; recruit

Project Summary/Abstract Antibody (Ab)-mediated opsonization is essential for protective immunity to pneumococcus in humans, as attested by the frequent occurrence of invasive pneumococcal disease (IPD) in patients with B cell immunodeficiencies. We are interested in deciphering the molecular genetic basis of three otherwise distinct primary immunodeficiencies (PIDs) sharing an impaired Ab response to glycans and predisposition to IPD, (i) common variable immunodeficiency (CVID), (ii) specific antibody deficiency (SPAD) and IgG2 deficiency (IgG2D), and (iii) anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). EDA-ID is a rare syndromic PID that manifests in multiple ways, yet underlies IPD and impaired Ab response to glycans in most, if not all patients. Most patients carry mutations in NEMO and NFKBIA, which respectively underlie X-linked recessive (XR) and autosomal dominant (AD) forms. Patients with SPAD/IgG2D display a much more selective impairment of Ab response to glycans, which also leads to IPD. It is rarely caused by mutations in IgG2. CVID is more common and heterogeneous, of later onset, and results in a global decrease of IgG levels, underlying impaired Ab response to glycans and IPD among other consequences. It is rarely caused by bi- allelic mutations in ICOS, TACI, BAFF-R, CD81, CD19, CD20, or LRBA or mono-allelic mutations in NFKB2, CTLA4, PIK3CD, NFKB1, or IRF2BP2. We hypothesize that patients with genetically unexplained CVID, SPAD/IgG2D, or EDA-ID may suffer from novel inborn errors of immunity. We thus aim to decipher novel IPD-predisposing single-gene inborn errors of B cell- and Ab-mediated immunity to glycans in patients with these conditions. In the last four years, we discovered AD IKAROS deficiency as a novel genetic etiology of CVID, and the first inborn errors of the linear ubiquitination complex (LUBAC), with mutations in HOIL1 and HOIP in patients with amylopectinosis and immunodeficiency (AM-ID), which is related to EDA-ID. To discover new genetic etiologies of these three related B cell deficiencies, we will rely on a unique recruitment of patients (including CVID from team 1), the recent advent of next-generation sequencing (NGS), including whole-exome (WES) and -genome sequencing (WGS), which have been pioneered in the lab for PIDs, and our development of powerful prediction software. The immunological consequences of the mutant alleles will be studied in collaboration with the other PPG teams. Our preliminary data are exciting, as we have identified genetic etiologies of CVID (mutations in LIG1), SPAD/IgG2D (mutations in TIFA), and EDA- ID (the first mutation impacting quantitatively the four transcripts of NEMO). This project will discover new causes of CVID, SPAD/IgG2D, and EDA-ID/AM-ID. The immunological implications of this study are important, as it will shed new light onto the genetic control of human Ab responses to glycans and protective immunity to pneumococcus. The clinical implications are equally important, as our results will improve the management of affected families and facilitate the investigation of the genetic basis of other PIDs.

项目摘要/摘要 抗体(Ab)介导的调理作用对于人类对肺炎球菌的保护性免疫是必不可少的，因为 侵袭性肺炎球菌病(IPD)在B细胞患者中的频繁发生证明 免疫缺陷。我们对破译三种截然不同的基因的分子遗传学基础很感兴趣 原发免疫缺陷(PID)具有对多糖的抗体反应受损和IPD的易感性，(I) 常见可变型免疫缺陷(CVID)、(Ii)特异性抗体缺陷(SPAD)和IgG2缺陷 (3)无汗性外胚层发育不良伴免疫缺陷(EDA-ID)。EDA-ID是一种罕见的综合征 以多种方式表现的PID，但大多数(如果不是全部)是IPD和对多糖的抗体反应受损的基础 病人。大多数患者携带NEMO和NFKBIA突变，这两个突变分别是X连锁隐性遗传的基础 (XR)和常染色体显性遗传型(AD)。SPAD/IgG2D患者表现出更多的选择性 抗体对多糖的反应受损，也会导致IPD。它很少由IgG2的突变引起。 CVID更为常见和异质性，发病较晚，并导致全球免疫球蛋白水平下降， 对多糖和IPD的潜在抗体反应受损，以及其他后果。它很少由胆汁淤积症引起 ICOS、TACI、BAFF-R、CD81、CD19、CD20或LRBA等位基因突变或单等位基因 NFKB2、CTLA4、PIK3CD、NFKB1或IRF2BP2的突变。我们假设患有这种疾病的患者 遗传上无法解释的CVID、SPAD/IgG2D或EDA-ID可能患有新的先天性免疫错误。我们 因此，旨在破译新的IPD-易感B细胞的单基因先天错误和抗体介导的免疫 患有这些疾病的患者体内的葡聚糖。在过去的四年里，我们发现AD IKAROS缺陷是一种 CVID的新遗传病因学，以及线性泛素化复合体(LUBAC)的第一个先天性错误，与 支链淀粉增多症和免疫缺陷(AM-ID)患者HOIL1和HOIP基因突变 与EDA-ID相关。为了发现这三种相关B细胞缺陷的新的遗传病因，我们将依赖于 独特的患者招募(包括团队1中的CVID)，最近出现的下一代测序 (NGS)，包括实验室首创的全外显子组(WES)和全基因组测序(WGS) 以及我们开发的功能强大的预测软件。病毒感染的免疫学后果 突变的等位基因将与其他PPG团队合作进行研究。我们的初步数据令人兴奋，因为 我们已经确定了CVID(LIG1突变)、SPAD/IgG2D(TIFA突变)和EDA-1的遗传病因。 ID(第一个定量影响NEMO四个转录本的突变)。这个项目将发现新的 CVID、SPAD/IgG2D和EDA-ID/AM-ID的原因。这项研究的免疫学意义是重要的， 因为这将为人类抗体对多糖的反应和保护性免疫的基因控制提供新的线索 肺炎球菌。临床意义同样重要，因为我们的结果将改善对 此外，儿童基金会还将继续向受影响的家庭提供援助，并协助调查其他艾滋病患者的遗传基础。