Toll-Like Receptor 2 Signaling Abnormalities Are Associated With Clinical Manifestations in Common Variable Immunodeficiency Pubmed



Abolhassani H ; Rezaei N ; Yazdani R ; Aletaha S ; Bokaie S ; Sharifi L ; Mirshafiey A
Source: Iranian Journal of Immunology Published:2025

Abstract

Background: Common Variable Immunodeficiency (CVID) is an inborn error of immunity characterized by a defect in terminal B cell differentiation, resulting in hypogammaglobulinemia, and impaired production of specific antibodies. Stimulation via Toll-like receptors (TLRs) has been shown to promote the differentiation and functional maturation of late-stage B cells. Objective: To assess aberrations in TLR2 signaling among patients with CVID and to explore their associations with clinical manifestations and immunological parameters. Methods: Sixteen CVID patients and 16 healthy controls were recruited for this individual-matched case-control study Genetic variants in patients had been previously identified through whole-exome sequencing. TLR2 and TLR4 downstream gene expression were analyzed using qRT-PCR, while cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA). Statistical associations between clinical features and laboratory parameters were analyzed using SPSS software. Results: downstream gene expression following TLR2 stimulation was significantly reduced in 25% of CVID patients, while the TLR4 signaling pathway remained largely unaffected. Patients exhibiting TLR2 overexpression demonstrated a later disease onset, presenting with autoimmunity, lymphoproliferation, and atopic manifestations. A consistent immunologic feature among patients with defective TLR2 signaling was the reduction in marginal zone and switched memory B cell populations. Furthermore, Levels of IL-6 and IL-1β following agonist stimulation were significantly lower in CVID patients compared to healthy controls. Conclusion: This study demonstrates that functional impairment of TLR2 signaling influences the clinical presentation, immunologic profile, and cytokine production in patients with CVID. These findings suggest a potential underlying etiology in a subset of patients with unidentified monogenic defects. © 2025 Elsevier B.V., All rights reserved.