Document Type : Original Article

Authors

• Hassan Abolhassani ^{1, 2}
• Nima Rezaei ^{1, 3, 4}
• Reza Yazdani ¹
• Somaye Aletaha ⁵
• Saied Bokaie ⁶
• Laleh Sharifi ^{1, 7}
• Abbas Mirshafiey ^{1, 5}

¹ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

² Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.

³ Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

⁴ Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Sheffield, UK.

⁵ Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

⁶ Department of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.

⁷ Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran.

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.

Keywords

• Common variable immunodeficiency
• Cytokine production
• Inborn errors of immunity
• Primary immunodeficiency
• Toll-like receptors