Dysregulated lymphocyte antigen receptor signaling in common variable immunodeficiency with granulomatous lymphocytic interstitial lung disease

Abstract Purpose A subset of common variable immunodeficiency (CVID) patients either present with or develop autoimmune and lymphoproliferative complications, such as granulomatous lymphocytic interstitial lung disease (GLILD), a major cause of morbidity and mortality in CVID. While a myriad of phenotypic lymphocyte derangements has been associated with and described in GLILD, defects in T and B cell antigen receptor (TCR/BCR) signaling pathways in CVID and CVID with GLILD (CVID/GLILD) remain undefined, which hinders the discovery of biomarkers for disease monitoring, prognostic prediction, and personalized medicine approaches. Methods To identify perturbations of immune cell subsets and TCR/BCR downstream signal transduction, we applied mass cytometry analysis to peripheral blood mononuclear cells (PBMCs) from healthy control participants (HC), CVID, and CVID/GLILD patients. Results Patients with CVID, regardless of GLILD status, had increased frequency of HLADR+ CD4+ T cells, CD57+ CD8+ T cells, and CD21lo B cells when compared to healthy controls. Within these cellular populations in CVID/GLILD patients, engagement of T or B cell antigen receptors resulted in discordant downstream signaling responses compared to CVID. In CVID/GLILD patients, CD21lo B cells showed perturbed BCR-mediated protein kinase B and extracellular signal-regulated kinase activation, while HLADR+ CD4+ T cells and CD57+ CD8+ T cells displayed disrupted TCR-mediated activation of kinases most proximal to the antigen receptor. Conclusion Lymphocyte populations from CVID/GLILD patients exhibit an activated phenotype and discordant antigen receptor signaling. These findings contribute to our understanding of the mechanisms of immune dysregulation in CVID with GLILD.