Plasma protein profiling reflects T_H1-driven immune dysregulation in common variable immunodeficiency

Area of Science:

• Immunology
• Clinical Medicine
• Proteomics

Background:

• Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by antibody deficiency.
• A significant portion of CVID patients experience immune dysregulation, leading to increased illness and death.
• The underlying causes of CVID pathogenesis remain largely unknown.

Purpose of the Study:

• To investigate the association between plasma protein profiles in CVID patients and their clinical features.
• To explore the relationship between plasma protein signatures and lymphocyte abnormalities in CVID.
• To correlate protein signatures with the severity of immune dysregulation.

Main Methods:

• Utilized a proximity extension assay for targeted profiling of 145 plasma proteins in 29 CVID patients.
• Employed flow cytometry for peripheral lymphocyte phenotyping.
• Correlated proteomic and flow cytometry findings with the extent of immune dysregulation.

Main Results:

• Unsupervised clustering identified two distinct CVID patient groups based on plasma protein profiles.
• These groups differed significantly in immune dysregulation complications and activated B- and T-cell frequencies.
• Pathway analysis implicated IFN-γ and IL-1β as key upstream regulators of immune dysregulation, with elevated CXCL13 levels observed.

Conclusions:

• Plasma protein profiling delineated a CVID subgroup with activated T cells and clinical immune dysregulation.
• Findings suggest CVID-associated immune dysregulation is a T_H1-mediated inflammatory process.
• The IFN-γ pathway appears to be a critical driver of this inflammation in CVID.