The Variation of the NK Cell Receptome in Pemphigus

摘要 天疱疮是一个广泛的术语，表示一个子集的潜在威胁生命的自身免疫性起泡皮肤病 在美国每10万成人中有5.2例患病。几种遗传变异强烈增加 PF风险，包括主要组织相容性复合体（MHC）内的变体，如人类白细胞 抗原（HLA）I类和II类基因。PI为揭示易感性遗传学做出了重大贡献 PF的变异，包括最近的全基因组关联研究。值得注意的是，基因编码的变异 天然NK受体与PF易感性密切相关，其中一些相关性是 这可以用不同的表达水平来解释。尽管有令人信服的证据表明NK细胞受体 这种自身免疫性起泡性皮肤病的变异，NK细胞在介导天疱疮风险中的精确功能， 和结果都知之甚少。总体目标是开发一个全面的序列图， 天疱疮中整个NK细胞受体组的结构变异，由大约90个基因编码， LRC（白细胞受体复合物）和NKC（自然杀伤复合物）。带来关于NK作用的新见解 疾病中的细胞，我们将表征NK受体遗传变异相关性的性质和程度 通过我们的新型高通量，高分辨率下一代测序（NGS）测定实现，并应用于 在一组不同的、已建立的、特征良好的队列中。使用最先进的方法，我们将 通过考虑疾病中的NK细胞表型，将这种基因组变异置于背景中。最后，我们将探讨 观察到的NK受体变异的功能意义，允许对影响的机制解释 为了更好地了解这些高度可变的受体在天疱疮和淋巴瘤中的作用， 理解疾病机制的基础。我们的目标是探索和发现监管 机制，我们的研究将显着扩大理解NK细胞生物学，细胞毒性， 功能我们的最终目标是揭示为推进疾病奠定基础的生物过程 通过发现NK细胞介导的免疫疗法的潜在靶点来理解和治疗。

ABSTRACT Pemphigus is a broad term denoting a subset of potentially life-threatening autoimmune blistering skin diseases with a prevalence of 5.2 cases per 100,000 adults in the United States. Several genetic variants strongly increase PF risk, including variants within the major histocompatibility complex (MHC), such as the human leukocyte antigen (HLA) class I and II genes. The PI has contributed significantly to uncovering susceptibility genetic variants in PF, including a recent genome-wide association study. Remarkably, variants in genes encoding natural NK receptors have been strongly associated with PF susceptibility, and some of these associations were explained by differential expression levels. Despite the compelling evidence for the role of NK cell receptor variation in this autoimmune blistering skin disease, the precise function of NK cells in mediating pemphigus risk and outcomes is poorly understood. The overall goal is to develop a comprehensive map of sequence and structural variation of the entire NK cell receptome in pemphigus, encoded by approximately 90 genes within the LRC (leukocyte receptor complex) and NKC (natural killer complex). To bring novel insights about the role of NK cells in disease, we will characterize the nature and extent of the association of genetic variation of NK receptors achieved via our novel high-throughput, high-resolution next-generation sequencing (NGS) assays and applied across a set of diverse, established, and well-characterized cohorts. Using state-of-art methods, we will contextualize this genomic variation by considering NK cell phenotype in disease. Finally, we will explore the functional implications of the observed NK receptor variation, allowing a mechanistic explanation of the impact of NK receptor expression to understand better the role of these highly variable receptors in pemphigus and lay the foundation for understanding disease mechanisms. As we aim to explore and uncover regulatory mechanisms, our research will significantly expand the comprehension of NK cell biology, cytotoxicity, and function. Our ultimate goal is to reveal biological processes that lay the foundation for advancing disease comprehension and treatment by discovering potential targets for NK-cell-mediated immunotherapies.