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Toll-like receptors pathway in common variable immune deficiency (CVID) and X-linked agammaglobulinemia (XLA)

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Abstract

Common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) are two major humoral immunodeficiencies, causing a high rate of early age mortality in children. In order to identifiy the possible factors involved in the pathogenesis of CVID and XLA, recent studies have focused on Toll-like receptors (TLRs) and demonstrate the defects in different TLR pathways in immune cells of CVID and XLA patients. Herein, we measured TLR-4 and TLR-9 RNA levels and consequently TNF-α and IFN-α production in peripheral blood mononuclear cells (PBMCs) of patients with CVID and XLA. Contrary to healthy individuals, TLR-9 expression was not significantly increased after ligand stimulation, whereas ligand-induced TLR-4 expression was not significantly different from that in healthy control PBMCs. Lipopolysaccharide (LPS)-stimulated TNF-α production was significantly reduced in patients compared to controls, whereas IFN-α production was increased in all groups after CpG stimulation without any significant inter-group difference. Our data suggest that defects in TLR-9 activated pathways may be a result of the decreased TLR-9 expression, although TLR-9 is not the only modulator of IFN-α production in these patients. On the other hand, impaired signaling in TLR-4 activated pathways which results in significant reduction in TNF-α production are not related to a defect in TLR-4 expression.

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References

  1. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010; 11(5): 373–84.

    Article  CAS  PubMed  Google Scholar 

  2. Kono H, Rock KL. How dying cells alert the immune system to danger. Nat Rev Immunol 2008; 8(4): 279–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fillatreau S, Manz RA. Tolls for B cells. Eur J Immunol 2006; 36(4): 798–801.

    Article  CAS  PubMed  Google Scholar 

  4. Bernasconi NL, Onai N, Lanzavecchia A. A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. Blood 2003; 101(11): 4500–4.

    Article  CAS  PubMed  Google Scholar 

  5. Sharifi L, Mirshafiey A, Rezaei N, et al. The role of toll-like receptors in B-cell development and immunopathogenesis of common variable immunodeficiency. Expert Rev Clin Immunol 2016; 12(2): 195–207.

    Article  CAS  PubMed  Google Scholar 

  6. Rezaei NA, Notarangelo L. Primary immunodeficiency diseases, definition, diagnosis and management. Berlin, Heidelberg: Springer-Verlag Berlin Heidelberg, 2017.

    Book  Google Scholar 

  7. Yu JE, Knight AK, Radigan L, et al. Toll-like receptor 7 and 9 defects in common variable immunodeficiency. J Allergy Clin Immunol 2009; 124(2): 349–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Branda RF, Moore AL, Hong R, McCormack JJ, Zon G, Cunningham-Rundles C. B-cell proliferation and differentiation in common variable immunodeficiency patients produced by an anti-sense oligomer to the rev gene of HIV-1. Clin Immunol Immunopathol 1996; 79(2): 115–21.

    Article  CAS  PubMed  Google Scholar 

  9. Cunningham-Rundles C, Radigan L, Knight AK, Zhang L, Bauer L, Nakazawa A. TLR9 activation is defective in common variable immune deficiency. J Immunol 2006; 176(3): 1978–87.

    Article  CAS  PubMed  Google Scholar 

  10. Escobar D, Pons J, Clemente A, et al. Defective B cell response to TLR9 ligand (CpG-ODN). Streptococcus pneumoniae and Haemophilus influenzae extracts in common variable immunodeficiency patients}. Cell Immunol 2010; 262(2): 105–11.

    Article  CAS  PubMed  Google Scholar 

  11. Trujillo CM, Muskus C, Arango J, Patino PJ, Montoya CJ. Quantitative and functional evaluation of innate immune responses in patients with common variable immunodeficiency. J Investig Allergol Clin Immunol 2011; 21(3): 207–15.

    CAS  PubMed  Google Scholar 

  12. Gonzalez-Serrano ME, Estrada-Garcia I, Mogica-Martinez D, et al. Increased pro-inflammatory cytokine production after lipopolysaccharide stimulation in patients with X-linked agammaglobulinemia. J Clin Immunol 2012; 32(5): 967–74.

    Article  CAS  PubMed  Google Scholar 

  13. Horwood NJ, Mahon T, McDaid JP, et al. Bruton’s tyrosine kinase is required for lipopolysaccharide-induced tumor necrosis factor alpha production. J Exp Med 2003; 197(12): 1603–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Horwood NJ, Page TH, McDaid JP, et al. Bruton’s tyrosine kinase is required for TLR2 and TLR4-induced TNF, but not IL-6, production. J Immunol 2006; 176(6): 3635–41.

    Article  CAS  PubMed  Google Scholar 

  15. Taneichi H, Kanegane H, Sira M M, et al. Toll-like receptor signaling is impaired in dendritic cells from patients with X-linked agammaglobulinemia. Clin Immunol 2008; 126(2): 148–54.

    Article  CAS  PubMed  Google Scholar 

  16. Marron TU, Yu JE, Cunningham-Rundles C. Toll-like receptor function in primary B cell defects. Front Biosci 2012; 4: 1853–63.

    Article  Google Scholar 

  17. Morbach H, Schickel JN, Cunningham-Rundles C, et al. CD19 controls Toll-like receptor 9 responses in human B cells. J Allergy Clin Immunol 2016; 137(3): 889–98.e6.

    Article  CAS  PubMed  Google Scholar 

  18. Lougaris V, Baronio M, Vitali M, et al. B cell responses to CpG correlate with CXCL16 expression levels in common variable immunodeficiency. Sci World J 2012; 2012: 960219.

    Article  CAS  Google Scholar 

  19. Lougaris V, Baronio M, Vitali M, et al. Bruton tyrosine kinase mediates TLR9-dependent human dendritic cell activation. J Allergy Clin Immunol 2014; 133(6): 1644–50.e4.

    Article  CAS  PubMed  Google Scholar 

  20. Lollo C, de Moraes Vasconcelos D, Oliveira L, et al. Chemokine, cytokine and type I interferon production induced by Toll-like receptor activation in common variable immune deficiency. Clin Immunol 2016; 169: 121–7.

    Article  CAS  PubMed  Google Scholar 

  21. Gray P, Dunne A, Brikos C, Jefferies CA, Doyle SL, O’Neill LA. MyD88 adapter-like (Mal) is phosphorylated by Bruton’s tyrosine kinase during TLR2 and TLR4 signal transduction. J Biol Chem 2006; 281(15): 10489–95.

    Article  CAS  PubMed  Google Scholar 

  22. Jefferies CA, Doyle S, Brunner C, et al. Bruton’s tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. J Biol Chem 2003; 278(28): 26258–64.

    Article  CAS  PubMed  Google Scholar 

  23. Sochorova K, Horvath R, Rozkova D, et al. Impaired Toll-like receptor 8-mediated IL-6 and TNF-alpha production in antigen-presenting cells from patients with X-linked agammaglobulinemia. Blood 2007; 109(6): 2553–6.

    Article  CAS  PubMed  Google Scholar 

  24. Marron TU, Martinez-Gallo M, Yu JE, Cunningham-Rundles C. Toll-like receptor 4-, 7-, and 8-activated myeloid cells from patients with X-linked agammaglobulinemia produce enhanced inflammatory cytokines. J Allergy Clin Immunol 2012; 129(1): 184–90.e1–4.

    Article  CAS  PubMed  Google Scholar 

  25. Taraldsrud E, Fevang B, Aukrust P, et al. Common variable immunodeficiency revisited: normal generation of naturally occurring dendritic cells that respond to Toll-like receptors 7 and 9. Clin Exp Immunol 2014; 175(3): 439–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Nima Rezaei.

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Tavasolian, P., Sharifi, L., Aghamohammadi, A. et al. Toll-like receptors pathway in common variable immune deficiency (CVID) and X-linked agammaglobulinemia (XLA). Eur Cytokine Netw 29, 153–158 (2018). https://doi.org/10.1684/ecn.2018.0420

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  • DOI: https://doi.org/10.1684/ecn.2018.0420

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