Immunomodulation of TLR2 and TLR4 by G2013 (alfa-L-Guluronic acid) in CVID Patients

Authors

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

2 Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran. AND Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran.

3 Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.

4 Department of Microbiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

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

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

7 Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

8 Department of Laboratory Medicine, Imam Hassan Mojtaba Hospital, Alborz University of Medical Sciences, Karaj, Iran.

9 Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran. AND Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.

Abstract

Background: Common variable immunodeficiency (CVID) is a primary immune disorder associated with hypogammaglobulinemia, recurrent infections and autoimmune diseases. CVID patients are frequently in contact with infectious pathogens leading to the activation of innate immunity through Toll-like receptors (TLR) affecting adaptive immunity. The aim of the present study was to test the immunomedulatory effect of small molecule G2013, a novel designed non-steroidal anti-inflammatory agent in CVID.
Materials and Methods: After blood sampling from 16 CVID patients and 16 age- and sex-matched healthy controls, peripheral blood mononuclear cells (PBMCs) were isolated and treated with/without lipopolysaccharide (LPS), lipopolyteichoic acid (LTA), and G2013. Assessing the immunomodulatory effect of G2013, flowcytometry was done for quantify the protein expression of TLR2 and TLR4. Gene expressions of signaling molecules involved in the TLR2 and TLR4 pathways were assessed by real-time PCR. ELISA performed assessing the production of IL-1b and IL-6.
Results: G2013 significantly decreased the intensity of TLR2 expression in CVID PBMCs (p=0.001) also G2013 decreased significantly the NF-kB gene expression in PBMCs of CVID patients (p=0.006).
Conclusion: These results indicated that G2013 had immunomodulatory effect at least in part via TLR2 and NF-kB expression. G2013 by decreasing MFI of TLR2 expression and NFkB gene expression provide the possibility of designing new drugs for preventing or controlling autoimmunity in CVID patients.

Keywords