부산대학교 도서관

Since the 1950s, the investigation of genetic causes of primary immunodeficiencies has fundamentally shaped our understanding of the immune system, and that fountain of knowledge has continued to expand explosively as we enter the genomic era with the dawn of CRISPR and personalized medicine. In this work, I describe four new monogenetic causes of primary immunodeficiency (PID) and a novel gene that may be associated with common variable immunodeficiency (CVID). The index cases were initially identified from two large PID cohorts - one based at the National Institutes of Health (NIH) in the United States and the other based at University of Cambridge in the United Kingdom. Eight individuals from four different kindreds were identified to have IL2RB deficiency due to three different loss of function IL2RB mutations, leading to either significant truncation of protein, reduced surface expression, or decreased IL-2 binding affinity. These patients all presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, and cytomegalovirus disease and had loss of regulatory T cells and "adaptive" natural killer cells. Another consanguineous kindred in the NIH cohort was found to have infantile inflammatory bowel disease associated with a rare homozygous IL37 mutation. Functional validation using cell lines and induced pluripotent stem cells (iPSCs) revealed a failure of the mutant IL-37 to be secreted extracellularly or translocated to the nucleus causing an inability to suppress pro-inflammatory cytokine production. Using a combination of whole genome sequencing and genome wide association studies to analyze the UK cohort of predominantly antibody-deficient patients, we identified PTPN2 and SOCS1 haploinsufficiency due to a combination of common and rare variants as genetic causes of CVID. These patients had loss of TC-PTP and SOCS1 protein as well as hyper-phosphorylation of STAT1. This dissertation closes with a tantalizing description of a kindred with four CVID patients with either homozygous recessive or compound heterozygous mutations in a poorly characterized gene TTC21A. Preliminary primary B cell CRISPR experiments and CRISPR knock-in mouse studies are so far inconclusive. The work presented here adds to the compendium of PID discoveries and provides insight into well-understood signaling pathways like IL-2, IL-1beta and interferon-gamma as well as attempts to elucidate the role of enigmatic genes like IL-37 and TTC21A using iPSCs and CRISPR technologies.