Complicated Common Variable Immunodeficiency is Driven by Aberrant IL-10/IL-21 Signaling and Predisposed Polygenic Risk

Background The inborn errors of immunity (IEI) that include defective antibody responses are clinically heterogenous, especially the common variable immunodeficiency (CVID) phenotype that includes low immunoglobulin levels and impaired humoral responses to antigens. Beyond recurrent infections, many with the CVID phenotype develop non-infectious complications (NICs), including autoimmunity and lymphoproliferation, that confer a high rate of morbidity and mortality. At present, it is unknown what genetic and functional factors predispose patients to NICs. Objective We aimed to discover the pathobiology underlying complicated CVID (CVIDc). Methods In a heterogenous group of 12 CVIDc patients, we conducted whole exome sequencing and high-throughput signaling assays by multiplexed phospho-mass cytometry. The immune deficiency and dysregulation activity (IDDA) score was used to determine the burden of NICs in individual patients. We integrated polygenic risk scores to determine the role of common background variants in the pathogenesis of CVIDc. Results In CVID patients with high IDDA scores, there was aberrant increased phosphorylation of STAT1 and STAT3 upon stimulation with IL-10 or IL-21. Furthermore, common variants related to high eosinophil count and allergy/eczema confer a higher likelihood of autoimmunity in CVID. Conclusion Variants in loci related to high eosinophil count/function and over-reactive IL-10 signaling are associated with the development of autoimmune disease and NICs in CVID. Clinical implications It may be possible to manage CVIDc through modulating IL-10 and IL-21 signaling pathways. Polygenic risk scoring may predict the development of autoimmune complications in CVID patients.