Understanding Genetic and Immune Cellular-Signaling Defects in Common Variable Immunodeficiency with Granulomatous Lymphocytic Interstitial Lung Disease

Abstract

Abstract Common Variable Immunodeficiency (CVID) is a heterogenous disorder characterized by hypogammaglobulinemia, failure to mount vaccine responses, recurrent sinopulmonary infections. Furthermore, a subset of CVID patients develop various autoimmune and lymphoproliferative complications, highlighting the dysregulated immune mechanisms underlying the disorder. One such autoimmune complication is granulomatous lymphocytic interstitial lung disease (GLILD) which is a major cause of mortality in CVID. The clinical heterogeneity of CVID indicate that it is a collection of disorders with monogenic and polygenic defects. Due to the genetic and phenotypic complexity of CVID, our understanding of the immunopathogenesis of CVID and the development of its complications is limited. Our goal is to elucidate relationships between genetic variants and their downstream phenotypic and signaling defects in CVID patients with GLILD. We hypothesize that specific genetic variants will result in unique immune cellular (and signaling) signatures in CVID with GLILD. To identify these cellular and molecular signatures, we integrate whole exome sequencing and mass cytometry data. We examined cellular subsets affected by perturbed T and B cell receptor signaling pathways via mass cytometry, and then correlate these signatures with specific genetic variants identified through whole exome sequencing. These results will reveal mechanisms of immune dysregulation in CVID with GLILD. In CVID patients with GLILD, we find expansion of CD57+ CD8+ T cells, which may represent a class of senescent cells. We also find enrichment of CD21-low B cells within CVID patients, regardless of GLILD status.