Investigation of a Novel Inborn Error of Immunity with B Cell Deficiency

Project Summary Inborn errors of immunity (IEI) are genetic disorders of the immune system that can manifest with a wide variety of presentations, including susceptibility to infection, lymphoproliferation, autoimmunity, and malignancy. Investigating IEI is critical not only to develop targeted molecular therapies for patients, but also to enhance our understanding of the human immune system. Indeed, fundamental advances of the human immune response have stemmed from studying patients with IEI. The long-term goal of this research is to investigate genetic mechanisms of novel IEI to enhance our understanding of the human immune system and improve patient care through the application of targeted molecular therapies. Here we propose to investigate patients with an autosomal dominant antibody deficiency and defect in memory B cells. These patients suffer from recurrent and severe infections due to an inability to mount appropriate antibody responses. Our preliminary studies have identified a defect in B cell maturation associated with increased proliferation. In Aim 1 of this application we will test B cell signaling and in vitro maturation in an effort to pinpoint important pathways that are altered and disease-causing. In Aim 2 of this application we focus on a genomic finding of a region of duplicated DNA with overexpression of a gene that we hypothesize leads to the altered B cell phenotype. We will use genomic and genome engineering approaches to better define this genetic change and determine whether it is responsible for disease in these patients. Results from these studies have the potential to molecularly define a new IEI and provide insight into novel genetic mechanisms of human disease.