Genome-wide search for inborn errors of IL-17 immunity underlying chronic mucocutaneous candidiasis

项目摘要 慢性黏膜皮肤念珠菌病(CMC)的特征是指甲、皮肤和口腔反复发作的疾病。 和生殖器粘膜，由真菌白色念珠菌引起。CMC病(CMCD)的发病机制 长期以来，CMC的遗传形式一直难以捉摸。我们鉴定的常染色体隐性(AR)IL-17RA和 常染色体显性遗传(AD)IL-17F缺陷为AR、IL-17RC和ACT1缺陷铺平了道路 其他单纯性慢性萎缩性脑病、AR-ROR-γ缺陷和AD STAT1功能增益(GOF)患者 综合征CMCD表型较广的患者。我们发现来自IL-17RA患者的细胞，IL-17RA，IL- 此外，与IL-17RC不同，IL-17RA-和ACT1-不同于IL-17RC- 缺乏细胞，对IL-17E无反应。此外，ROR-γ缺乏症和STAT1GOF的患者显示 在体外和体外分化后，产生IL-17A/F的T细胞比例很低。我们已经报告了85 在已发表的188例CMCD病例中，有遗传病因学的患者。我们还招收了317名学生 来自来自30个国家和地区的245个家系的其他孤立或综合征性CMCD患者，我们 假设携带导致CMCD的突变。我们打算在六种已知的引起CMCD的基因中寻找突变 基因(IL17F、IL17RA、IL17RC、ACT1、RORC和STAT1)，为了描绘相关分子， 细胞、免疫学和临床表型。我们还打算继续寻找新的引起CMCD的疾病 使用全基因组(GW)方法的基因，基于GW连锁(GWL)，以及全外显子组或全外显子组 基因组测序(WES/WGS)；我们将优先考虑控制对或 IL-17A/F的生产这个项目是建立在我们在人类CMCD基因解剖方面的开创性努力的基础上 通过尖端的基因组和免疫学方法，其中一些已经在实验室开发。 我们最近取得了令人惊讶和令人兴奋的初步结果。我们发现了12名、3名和121名新患者 分别存在IL-17RA、ACT1和STAT1突变。我们还发现了三种新的遗传病因。我们 在三名患者中发现AD JNK1缺乏症，该患者来自一个患有CMCD综合征的家族，其细胞没有 对IL-17A/F的应答；这是MAPK依赖免疫的第一个先天错误。我们还发现了AR c-Rel 和ZNF341缺陷，分别来自一个和两个家系的综合征CMCD患者，他们的细胞 不产生IL-17A/F；c-Rel是NF-κB家族的成员，ZNF341是一个全新的蛋白质。这些 初步数据清楚地说明了我们方法的有效性，以及我们综合研究的潜力。我们的 该项目具有很高的创新性，但有强有力的初步证据支持。从基本的生物学观点来看， 这项研究将对皮肤粘膜免疫的机制提供大量和新的见解。 真菌，包括IL-17细胞因子的作用。这项工作也将有助于阐明CMCD的发病机制，使 它可以为患者提供分子诊断，为患者家属提供遗传咨询。这一新信息 将促进使用IL-17或其他细胞因子治疗CMC，以及抗真菌药物。

Project Summary Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent disease of the nails, skin, and oral and genital mucosae, caused by the fungus Candida albicans. The pathogenesis of CMC disease (CMCD), a genetic form of CMC, has long remained elusive. Our identification of autosomal recessive (AR) IL-17RA and autosomal dominant (AD) IL-17F deficiencies paved the way for that of AR IL-17RC and ACT1 deficiencies in other patients with isolated CMCD, and of AR ROR-γ deficiency and AD STAT1 gain-of-function (GOF) in patients with a broader phenotype of syndromic CMCD. We showed that cells from patients with IL-17RA, IL- 17RC, and ACT1 deficiencies did not respond to IL-17A/F. In addition, IL-17RA- and ACT1-, unlike IL-17RC- deficient cells, did not respond to IL-17E. Moreover, patients with ROR-γ deficiency and STAT1 GOF displayed low proportions of IL-17A/F-producing T cells, both ex vivo and after in vitro differentiation. We have reported 85 patients with a genetic etiology of CMCD, out of a total of 188 published cases. We have also enrolled 317 other patients with isolated or syndromic CMCD, from 245 kindreds, originating from 30 countries, whom we hypothesize carry CMCD-causing mutations. We intend to search for mutations in the six known CMCD-causing genes (IL17F, IL17RA, IL17RC, ACT1, RORC, and STAT1), in order to delineate the associated molecular, cellular, immunological, and clinical phenotypes. We also intend to pursue our search for novel CMCD-causing genes using genome-wide (GW) approaches, based on GW linkage (GWL), and whole-exome or whole- genome sequencing (WES/WGS); we will prioritize mutations in genes that control the response to, or the production of, IL-17A/F. This program is built on our pioneering effort in the human genetic dissection of CMCD by cutting-edge genomic and immunological methods, some of which have been developed in the laboratory. We have recently obtained surprising and exciting preliminary results. We found 12, 3, and 121 new patients with IL-17RA, ACT1, and STAT1 mutations, respectively. We also identified three novel genetic etiologies. We discovered AD JNK1 deficiency in three patients from a kindred with syndromic CMCD, whose cells do not respond to IL-17A/F; this is the first inborn error of MAPK-dependent immunity. We also discovered AR c-REL and ZNF341 deficiencies in syndromic CMCD patients from one and two kindreds, respectively, whose cells do not produce IL-17A/F; c-REL is a member of the NF-κB family and ZNF341 is a completely novel protein. These preliminary data neatly illustrate the validity of our approaches, and the potential of our integrated research. Our project is highly innovative, yet supported by strong preliminary evidence. From a basic biological standpoint, this research will provide considerable and novel insights into the mechanisms of mucocutaneous immunity to fungi, including the role of IL-17 cytokines. This work will also shed light on the pathogenesis of CMCD, making it possible to provide molecular diagnoses for patients and genetic counseling for families. This new information will facilitate the use of IL-17 or other cytokines for the treatment of CMC, in addition to antifungal agents.