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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the Jeffrey Modell Foundation through a grant from Takeda; NIH/NIAID R01AI153827 to MJB ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of the University of California Los Angeles gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript, hosted at [https://github.com/humzalikhan/CVID\_CyTOF\_PRS][1], or otherwise are available upon request. [https://github.com/humzalikhan/CVID\_CyTOF\_PRS][1] [1]: https://github.com/humzalikhan/CVID_CyTOF_PRS