Molecular Pathogenesis of Common Variable Immunodeficiency

Studying genetic variants contributing to Common Variable Immunodeficiency to advance the identification of novel target therapeutics

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Full Project Name:Molecular Pathogenesis of Common Variable ImmunodeficiencyPrincipal Investigator:Denim Wang, PhD, Microbiology and ImmunologyCo-Investigator(s):James Verbsky, MD, PhD, Pediatrics
John M Routes, MD, PediatricsAward Amount:$300,000

Award Date

July2021

Project Duration:36 months

Project Summary:

Primary immune deficiencies are genetic disorders that result in a poorly functioning immune system. Common Variable Immunodeficiency (CVID) is the most common serious primary immune deficiency disease. A high proportion of these patients manifest with serious autoimmune features which negatively affect their health and survival. Previous studies have found a variety of genetic variants in lymphocyte signaling pathways, but the significance of these genetic variants is unknown. Further study of these genetic variants and the translation of these findings into a model for easier understanding is needed to advance new knowledge and identify treatment or prevention options.

Through this award, investigators aim to provide novel insights into the molecular pathogenesis of human CVID to help identify novel target therapeutics for the disease.

Outcomes & Lessons Learned:

Completed single cell (SC)RNA-seq experiments with peripheral blood mononuclear cells (PBMCs) from common variable immunodeficiency (CVID) patients that identified 10 cell populations for study that correlated with the expected subgroups of T cells
Demonstrated that patients with CVID and lung disease had larger populations of memory populations as expected, since the patient's immune systems are dysregulated and activated
Generated transgenic mice showing B cell impairment, the white blood cells that produce antibodies
Completed RNA-seq of B cells, demonstrating impaired B cell activation
Prepared one manuscript for submission based on the study findings