Human Genetic Dissection of Antibody Response to Pneumococcal Glycans

项目总结/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至关重要， B细胞感染患者中侵袭性肺炎球菌病（IPD）的频繁发生证明了这一点 免疫缺陷1，2.我们感兴趣的是破译三个不同的分子遗传基础 原发性免疫缺陷（PID），共有对聚糖的受损Ab应答和对IPD的易感性，（i） 普通变异型免疫缺陷（CVID），（ii）特异性抗体缺乏（SPAD）和IgG 2缺乏 （IgG 2D），和（iii）无汗性外胚叶发育不良伴免疫缺陷（EDA-ID）。EDA-ID是一种罕见的综合征 PID以多种方式表现，但在大多数（如果不是全部）中是IPD和受损抗体对聚糖反应的基础 患者3，4.大多数患者携带NEMO和NFKBIA突变，它们分别是X连锁隐性遗传的基础。 (XR)和常染色体显性（AD）形式5，6。SPAD/IgG 2D患者显示出更高的选择性， 抗体对聚糖的反应受损，这也导致IPD 7，8。它很少由IgG 29 -12突变引起。 CVID更为常见和异质，发病较晚，导致IgG水平总体下降， 在其他后果中，潜在的对聚糖和IPD的抗体应答受损13 -16。它很少是由双- ICOS 17、TACI 18、19、BAFF-R20、CD 8121、CD 1922、CD 2023或LRBA 24 -26中的等位基因突变或单等位基因突变 NFKB 227、CTLA 428、PIK 3CD 29、30、NFKB 131或IRF 2BP 232中的突变。我们假设， 遗传上无法解释的CVID、SPAD/IgG 2D或EDA-ID可能患有新的先天性免疫缺陷。我们 因此，目的在于解释B细胞和Ab介导的免疫的新的IPD诱发单基因先天性缺陷， 这些疾病患者体内的聚糖。在过去的四年里，我们发现AD IKAROS缺乏症是一种 CVID 33的新遗传病因学，以及线性泛素化复合物（LUBAC）的第一个先天性缺陷， HOIL 1和HOIP突变34，35在患有支链淀粉病和免疫缺陷（AM-ID）的患者中， 为了发现这三种相关的B细胞缺陷的新遗传病因，我们将依赖于一种 独特的患者招募（包括第1组的CVID），最近出现的下一代测序 (NGS)，包括全外显子组（WES）和全基因组测序（WGS），这是实验室中的先驱 PIDs 36 -38，以及我们开发的功能强大的预测软件39 -41。免疫学的后果， 突变等位基因将与其他PPG团队合作研究。我们的初步数据令人兴奋，因为 我们已经确定了CVID（LIG 1突变）、SPAD/IgG 2D（TIFA突变）和EDA的遗传病因， ID（定量影响NEMO的四种转录物的第一个突变）。该项目将发现新的 CVID、SPAD/IgG 2D和EDA-ID/AM-ID的原因。本研究的免疫学意义是重要的， 因为它将为人类抗体对聚糖反应的遗传控制和保护性免疫提供新的线索， 肺炎球菌临床意义同样重要，因为我们的结果将改善对 这将有助于受影响的家庭，并促进对其他PID遗传基础的调查。

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 immunodeficiencies1,2. 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 patients3,4. Most patients carry mutations in NEMO and NFKBIA, which respectively underlie X-linked recessive (XR) and autosomal dominant (AD) forms5,6. Patients with SPAD/IgG2D display a much more selective impairment of Ab response to glycans, which also leads to IPD7,8. It is rarely caused by mutations in IgG29-12. 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 consequences13-16. It is rarely caused by bi- allelic mutations in ICOS17, TACI18,19, BAFF-R20, CD8121, CD1922, CD2023, or LRBA24-26 or mono-allelic mutations in NFKB227, CTLA428, PIK3CD29,30, NFKB131, or IRF2BP232. 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 CVID33, and the first inborn errors of the linear ubiquitination complex (LUBAC), with mutations in HOIL1 and HOIP34,35 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 PIDs36-38, and our development of powerful prediction software39-41. 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.