Targeted Proteomics Reveals Inflammatory Pathways that Classify Immune Dysregulation in Common Variable Immunodeficiency
Berbers, Roos-Marijn; Drylewicz, Julia; Ellerbroek, Pauline M; van Montfrans, Joris M; Dalm, Virgil A S H; van Hagen, P Martin; Keller, Baerbel; Warnatz, Klaus; van de Ven, Annick; van Laar, Jaap M; Nierkens, Stefan; Leavis, Helen L
(2021) Journal of Clinical Immunology, volume 41, issue 2, pp. 362 - 373
(Article)
Abstract
Patients with common variable immunodeficiency (CVID) can develop immune dysregulation complications such as autoimmunity, lymphoproliferation, enteritis, and malignancy, which cause significant morbidity and mortality. We aimed to (i) assess the potential of serum proteomics in stratifying patients with immune dysregulation using two independent cohorts and (ii) identify cytokine and chemokine
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signaling pathways that underlie immune dysregulation in CVID. A panel of 180 markers was measured in two multicenter CVID cohorts using Olink Protein Extension Assay technology. A classification algorithm was trained to distinguish CVID with immune dysregulation (CVIDid, n = 14) from CVID with infections only (CVIDio, n = 16) in the training cohort, and validated on a second testing cohort (CVIDid n = 23, CVIDio n = 24). Differential expression in both cohorts was used to determine relevant signaling pathways. An elastic net classifier using MILR1, LILRB4, IL10, IL12RB1, and CD83 could discriminate between CVIDid and CVIDio patients with a sensitivity of 0.83, specificity of 0.75, and area under the curve of 0.73 in an independent testing cohort. Activated pathways (fold change > 1.5, FDR-adjusted p < 0.05) in CVIDid included Th1 and Th17-associated signaling, as well as IL10 and other immune regulatory markers (LAG3, TNFRSF9, CD83). Targeted serum proteomics provided an accurate and reproducible tool to discriminate between patients with CVIDid and CVIDio. Cytokine profiles provided insight into activation of Th1 and Th17 pathways and indicate a possible role for chronic inflammation and exhaustion in immune dysregulation. These findings serve as a first step towards the development of biomarkers for immune dysregulation in CVID.
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Keywords: Biomarkers, Common variable immunodeficiency (CVID), Cytokines, Immune dysregulation, Prediction, Primary immunodeficiency, Immunology and Allergy, Immunology, Journal Article
ISSN: 0271-9142
Publisher: Springer New York
Note: Funding Information: Samples for this project were obtained from the CCI-Biobank, a partner biobank of the University Medical Center Freiburg and Medical Faculty ?Center for Biobanking ? FREEZE?. Funding Information: PH reports research grants and personal fees from Shire/Takeda and CSL Behring. VD reports research grants and personal fees from Shire/Takeda, Griffols, ACtelion, Novartis and CSL Behring. JM reports personal fees from Shire/Takeda. AvdV reports personal fees from CSL Behring. HL reports research grants and personal fees from Shire/Takeda. All other authors report no potential conflict of interest. Funding Information: This study was funded by the Wilhelmina Children’s Hospital Fund. Acknowledgments Publisher Copyright: © 2020, The Author(s).
(Peer reviewed)