Convergence of cytokine dysregulation and antibody deficiency in common variable immunodeficiency with inflammatory complications

Miranda L. Abyazi, Kayla A. Bell, Gavin Gyimesi, Turner S. Baker, Minji Byun, Huaibin M. Ko, Charlotte Cunningham-Rundles, Feng Feng, Paul J. Maglione

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Background: Noninfectious complications are the greatest cause of morbidity and mortality in common variable immunodeficiency (CVID), but their pathogenesis remains poorly defined. Objective: Using high-throughput approaches, we aimed to identify, correlate, and determine the significance of immunologic features of CVID with noninfectious complications (CVIDc). Methods: We simultaneously applied proteomics, RNA sequencing, and mass cytometry to a large cohort with primary antibody deficiency. Results: CVIDc is differentiated from uncomplicated CVID, other forms of primary antibody deficiency, and healthy controls by a distinct plasma proteomic profile. In addition to confirming previously reported elevations of 4-1BB, IL-6, IL-18, and IFN-γ, we found elevations of colony-stimulating factor 1, IL-12p40, IL-18R, oncostatin M, TNF, and vascular endothelial growth factor A to differentiate CVIDc. This cytokine dysregulation correlated with deficiency of LPS-specific antibodies and increased soluble CD14, suggesting microbial translocation. Indicating potential significance of reduced LPS-specific antibodies and resultant microbial-induced inflammation, CVIDc had altered LPS-induced gene expression matching plasma proteomics and corresponding with increased CD14+CD16 monocytes, memory T cells, and tissue inflammation ameliorated by T-cell–targeted therapy. Unsupervised machine learning accurately differentiated subjects with CVIDc and supported cytokine dysregulation, antibody deficit, and T-cell activation as defining and convergent features. Conclusions: Our data expand understanding of CVIDc proteomics, establish its link with deficiency of IgA and LPS-specific antibodies, and implicate altered LPS-induced gene expression and elevated monocytes and T cells in this cytokine dysregulation. This work indicates that CVIDc results when insufficient antibody neutralization of pathogen-associated molecular patterns, like LPS, occurs in those with a heightened response to these inflammatory mediators, suggesting a 2-hit model of pathogenesis requiring further exploration.

Original languageEnglish
Pages (from-to)315-326.e9
JournalJournal of Allergy and Clinical Immunology
Volume149
Issue number1
DOIs
StatePublished - Jan 2022

Keywords

  • CVID
  • Common variable immunodeficiency
  • IFN-γ
  • IL-12
  • LPS
  • T cells
  • TNF
  • lipopolysaccharide
  • monocytes
  • noninfectious complications

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