Targeted Proteomics Reveals Inflammatory Pathways that Classify Immune Dysregulation in Common Variable...

Area of Science:

• Immunology
• Proteomics
• Biomarker Discovery

Background:

• Common variable immunodeficiency (CVID) is associated with immune dysregulation, leading to autoimmunity, lymphoproliferation, enteritis, and malignancy.
• These complications significantly increase morbidity and mortality in CVID patients.

Purpose of the Study:

• To evaluate serum proteomics for stratifying CVID patients with immune dysregulation.
• To identify cytokine and chemokine signaling pathways implicated in CVID immune dysregulation.

Main Methods:

• Utilized Olink Protein Extension Assay to measure 180 markers in two independent CVID cohorts.
• Trained and validated a classification algorithm to differentiate CVID with immune dysregulation (CVIDid) from CVID with infections only (CVIDio).
• Analyzed differential protein expression to identify relevant signaling pathways.

Main Results:

• An elastic net classifier accurately discriminated CVIDid from CVIDio patients (AUC=0.73) in an independent cohort.
• Activated pathways in CVIDid included Th1 and Th17 signaling, IL10, and other immune regulatory markers.
• Targeted serum proteomics proved effective for stratifying CVID patients.

Conclusions:

• Serum proteomics offers a reproducible method for distinguishing CVID patients with immune dysregulation.
• Cytokine profiles suggest Th1/Th17 pathway activation and a role for chronic inflammation in CVID immune dysregulation.
• Findings represent a preliminary step toward developing biomarkers for CVID immune dysregulation.