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.