Toll-like Receptor 2 Signaling Abnormalities Are Associated with Clinical Manifestations in Common Variable...

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.

To assess aberrations in TLR2 signaling among patients with CVID and to explore their associations with clinical manifestations and immunological parameters.

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.

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.

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.