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Evaluation of the TLR negative regulatory network in CVID patients

Genes & Immunity volume 20, pages 198–206 (2019)Cite this article

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Abstract

Common variable immunodeficiency (CVID), a clinically symptomatic primary immunodeficiency disease (PID), is characterized by hypogammaglobulinemia leading to recurrent infections and various complications. Recently, some defects in the signaling of TLRs have been identified in CVID patients which led us to investigate the expression of TLR4 and 9 negative regulatory molecules and their upregulation status following their activation. Using TaqMan real-time PCR, SOCS1, TNFAIP3, RFN216, and IRAK-M transcripts among peripheral blood mononuclear cells (PBMCs) were measured with/without TLR4 and 9 activations. TLR4 and 9 were activated by lipopolysaccharide (LPS) and unmethylated CpG-oligodeoxynucleotide (CpG-ODN), respectively. Production of IFN-α and TNF-α cytokines, as a part of the functional response of mentioned TLRs, was also measured using ELISA. Deficient transcripts of IRAK-M and TNFAIP3 in unstimulated PBMCs and lower production of TNF-α and IFN-α after treatments were observed. Upregulation of RFN216 and TNFAIP3 after TLR9 activation was abnormal compared to healthy individuals. Significant correlations were found between abnormal IRAK-M and TNFAIP3 transcripts, and lymphadenopathy and inflammatory scenarios in patients, respectively. It seems that the transcriptional status of some negative regulatory molecules is disturbed in CVID patients, and this could be caused by the underlying pathogenesis of CVID and could involve complications like autoimmunity and inflammatory responses.

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References

  1. Aghamohammadi A, Abolhassani H, Latif A, Tabassomi F, Shokuhfar T, Torabi Sagvand B, et al. Long-term evaluation of a historical cohort of Iranian common variable immunodeficiency patients. Expert Rev Clin Immunol. 2014;10:1405–17.

    Article  CAS  Google Scholar 

  2. Mokhtari M, Shakeri A, Mirminachi B, Abolhassani H, Yazdani R, Grimbacher B, et al. Important factors influencing severity of common variable immunodeficiency. Arch Iran Med. 2016;19:544–50.

    PubMed  Google Scholar 

  3. Azizi G, Abolhassani H, Asgardoon MH, Alinia T, Yazdani R, Mohammadi J, et al. Autoimmunity in common variable immunodeficiency: epidemiology, pathophysiology and management. Expert Rev Clin Immunol. 2017;13:101–15.

    Article  CAS  Google Scholar 

  4. Yazdani R, Heydari A, Azizi G, Abolhassani H, Aghamohammadi A. Asthma and allergic diseases in a selected group of patients with common variable immunodeficiency. J Investig Allergol Clin Immunol. 2016;26:209–11.

    Article  CAS  Google Scholar 

  5. Yazdani R, Abolhassani H, Rezaei N, Azizi G, Hammarstrom L, Aghamohammadi A. Evaluation of known defective signaling-associated molecules in patients who primarily diagnosed as common variable immunodeficiency. Int Rev Immunol. 2016;35:7–24.

    Article  CAS  Google Scholar 

  6. Yazdani R, Seify R, Ganjalikhani-Hakemi M, Abolhassani H, Eskandari N, Golsaz-Shirazi F, et al. Comparison of various classifications for patients with common variable immunodeficiency (CVID) using measurement of B-cell subsets. Allergol Immunopathol. 2017;45:183–92.

    Article  CAS  Google Scholar 

  7. Yazdani R, Ganjalikhani-Hakemi M, Esmaeili M, Abolhassani H, Vaeli S, Rezaei A, et al. Impaired Akt phosphorylation in B-cells of patients with common variable immunodeficiency. Clin Immunol. 2017;175:124–32.

    Article  CAS  Google Scholar 

  8. Azizi G, Rezaei N, Kiaee F, Tavakolinia N, Yazdani R, Mirshafiey A, et al. T-cell abnormalities in common variable immunodeficiency. J Investig Allergol Clin Immunol. 2016;26:233–43.

    Article  CAS  Google Scholar 

  9. Pegu A, Qin S, Fallert Junecko BA, Nisato RE, Pepper MS, Reinhart TA. Human lymphatic endothelial cells express multiple functional TLRs. J Immunol. 2008;180:3399–405.

    Article  CAS  Google Scholar 

  10. Sharifi L, Mirshafiey A, Rezaei N, Azizi G, Magaji Hamid K, Amirzargar AA, et al. The role of Toll-like receptors in B-cell development and immunopathogenesis of common variable immunodeficiency. Expert Rev Clin Immunol. 2016;12:195–207.

    Article  CAS  Google Scholar 

  11. Chen JQ, Szodoray P, Zeher M. Toll-like receptor pathways in autoimmune diseases. Clin Rev Allergy Immunol. 2016;50:1–17.

    Article  CAS  Google Scholar 

  12. Hanagata N. CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies. Int J Nanomed. 2017;12:515–31.

    Article  CAS  Google Scholar 

  13. Gay NJ, Symmons MF, Gangloff M, Bryant CE. Assembly and localization of Toll-like receptor signalling complexes. Nat Rev Immunol. 2014;14:546–58.

    Article  CAS  Google Scholar 

  14. Leifer CA, Medvedev AE. Molecular mechanisms of regulation of Toll-like receptor signaling. J Leukoc Biol. 2016;100:927–41.

    Article  CAS  Google Scholar 

  15. Liew FY, Xu D, Brint EK, O’Neill LAJ. Negative regulation of Toll-like receptor-mediated immune responses. Nat Rev Immunol. 2005;5:446–58.

    Article  CAS  Google Scholar 

  16. Kobayashi K, Hernandez LD, Galan JE, Janeway CA Jr., Medzhitov R, Flavell RA. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell. 2002;110:191–202.

    Article  CAS  Google Scholar 

  17. Hubbard LL, Moore BB. IRAK-M regulation and function in host defense and immune homeostasis. Infect Dis Rep. 2010;2:e9.

    Article  Google Scholar 

  18. Kobayashi K, Hernandez LD, Galán JE, Janeway CA, Medzhitov R, Flavell RA. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell. 2002;110:191–202.

    Article  CAS  Google Scholar 

  19. del Fresno C, Gomez-Garcia L, Caveda L, Escoll P, Arnalich F, Zamora R, et al. Nitric oxide activates the expression of IRAK-M via the release of TNF-alpha in human monocytes. Nitric Oxide. 2004;10:213–20.

    Article  Google Scholar 

  20. van ‘t Veer C, van den Pangaart PS, van Zoelen MA, de Kruif M, Birjmohun RS, Stroes ES, et al. Induction of IRAK-M is associated with lipopolysaccharide tolerance in a human endotoxemia model. J Immunol. 2007;179:7110–20.

    Article  Google Scholar 

  21. Fukao T, Koyasu S. PI3K and negative regulation of TLR signaling. Trends Immunol. 2003;24:358–63.

    Article  CAS  Google Scholar 

  22. Su J, Zhang T, Tyson J, Li L. The interleukin-1 receptor-associated kinase M selectively inhibits the alternative, instead of the classical NFκB pathway. J Innate Immun. 2009;1:164–74.

    Article  CAS  Google Scholar 

  23. Verstrepen L, Verhelst K, Van Loo G, Carpentier I, Ley SC, Beyaert R. Expression, biological activities and mechanisms of action of A20 (TNFAIP3). Biochem Pharmacol. 2010;80:2009–20.

    Article  CAS  Google Scholar 

  24. Luo H, Liu Y, Li Q, Liao L, Sun R, Liu X, et al. A20 regulates IL-1-induced tolerant production of CXC chemokines in human mesangial cells via inhibition of MAPK signaling. Sci Rep. 2015;5:5.

    Google Scholar 

  25. Keller B, Cseresnyes Z, Stumpf I, Wehr C, Fliegauf M, Bulashevska A, et al. Disturbed canonical nuclear factor of kappa light chain signaling in B cells of patients with common variable immunodeficiency. J Allergy Clin Immunol. 2017;139:220–31.e8.

    Article  CAS  Google Scholar 

  26. Fliegauf M, Bryant VL, Frede N, Slade C, Woon ST, Lehnert K, et al. Haploinsufficiency of the NF-kappaB1 subunit p50 in common variable immunodeficiency. Am J Hum Genet. 2015;97:389–403.

    Article  CAS  Google Scholar 

  27. Taraldsrud E, Aukrust P, Jørgensen S, Lingjærde OC, Olweus J, Myklebust JH, et al. Patterns of constitutively phosphorylated kinases in B cells are associated with disease severity in common variable immunodeficiency. Clin Immunol. 2017;175(Supplement C):69–74.

    Article  CAS  Google Scholar 

  28. Xuan NT, Wang X, Nishanth G, Waisman A, Borucki K, Isermann B, et al. A20 expression in dendritic cells protects mice from LPS-induced mortality. Eur J Immunol. 2015;45:818–28.

    Article  Google Scholar 

  29. Kool M, van Loo G, Waelput W, De Prijck S, Muskens F, Sze M, et al. The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity. Immunity. 2011;35:82–96.

    Article  CAS  Google Scholar 

  30. Turer EE, Tavares RM, Mortier E, Hitotsumatsu O, Advincula R, Lee B, et al. Homeostatic MyD88-dependent signals cause lethal inflammation in the absence of A20. J Exp Med. 2008;205:451–64.

    Article  CAS  Google Scholar 

  31. Wertz IE, O’rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling. Nature. 2004;430:694–9.

    Article  CAS  Google Scholar 

  32. Murakami K, Suzuki C, Kobayashi F, Nakano A, Fujii A, Sakai K, et al. Intravenous immunoglobulin preparation attenuates LPS-induced production of pro-inflammatory cytokines in human monocytic cells by modulating TLR4-mediated signaling pathways. Naunyn Schmiede Arch Pharmacol. 2012;385:891–8.

    Article  CAS  Google Scholar 

  33. Barbosa RR, Silva SP, Silva SL, Tendeiro R, Melo AC, Pedro E, et al. Monocyte activation is a feature of common variable immunodeficiency irrespective of plasma lipopolysaccharide levels. Clin Exp Immunol. 2012;169:263–72.

    Article  CAS  Google Scholar 

  34. Litzman J, Nechvátalová J, Xu J, Tichá O, Vlková M, Hel Z. Chronic immune activation in common variable immunodeficiency (CVID) is associated with elevated serum levels of soluble CD14 and CD25 but not endotoxaemia. Clin & Exp Immunol. 2012;170:321–32.

    Article  CAS  Google Scholar 

  35. Perreau M, Vigano S, Bellanger F, Pellaton C, Buss G, Comte D, et al. Exhaustion of bacteria-specific CD4 T cells and microbial translocation in common variable immunodeficiency disorders. J Exp Med. 2014;211:2033–45.

    Article  CAS  Google Scholar 

  36. Musone SL, Taylor KE, Lu TT, Nititham J, Ferreira RC, Ortmann W, et al. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat Genet. 2008;40:1062–4.

    Article  CAS  Google Scholar 

  37. Walle LV, Van Opdenbosch N, Jacques P, Fossoul A, Verheugen E, Vogel P, et al. Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis. Nature. 2014;512:69–73.

    Article  CAS  Google Scholar 

  38. Weersma RK, Oostenbrug LE, Nolte IM, Van Der Steege G, Oosterom E, Van Dullemen HM, et al. Association of interleukin-1 receptor-associated kinase M (IRAK-M) and inflammatory bowel diseases. Scand J Gastroenterol. 2007;42:827–33.

    Article  CAS  Google Scholar 

  39. Palumbo R, Sampaolesi M, De Marchis F, Tonlorenzi R, Colombetti S, Mondino A, et al. Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation. J Cell Biol. 2004;164:441–9.

    Article  CAS  Google Scholar 

  40. O’Neill LA. How Toll-like receptors signal: what we know and what we don’t know. Curr Opin Immunol. 2006;18:3–9.

    Article  Google Scholar 

  41. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4:499–511.

    Article  CAS  Google Scholar 

  42. Fearns C, Pan Q, Mathison JC, Chuang T-H. Triad3A regulates ubiquitination and proteasomal degradation of RIP1 following disruption of Hsp90 binding. J Biol Chem. 2006;281:34592–600.

    Article  CAS  Google Scholar 

  43. McGettrick AF, O’Neill LAJ. Localisation and trafficking of Toll-like receptors: an important mode of regulation. Curr Opin Immunol. 2010;22:20–7.

    Article  CAS  Google Scholar 

  44. 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;176:1978–87.

    Article  CAS  Google Scholar 

  45. Joyce EY, Knight AK, Radigan L, Marron TU, Zhang L, Sanchez-Ramón S, et al. Toll-like receptor 7 and 9 defects in common variable immunodeficiency. J Allergy Clin Immunol. 2009;124:349–56. e3.

    Article  Google Scholar 

  46. Joyce EY, Zhang L, Radigan L, Sanchez-Ramon S, Cunningham-Rundles C. TLR-mediated B cell defects and IFN-α in common variable immunodeficiency. J Clin Immunol. 2012;32:50–60.

    Article  Google Scholar 

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Acknowledgements

This work has been supported by a grant from Iran University of Medical Sciences to fulfill first authors’ Master of Sciences degree (grant no. 25709). The authors have no conflicts of interest.

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Authors and Affiliations

  1. Immunology Research Center (IRC), Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran

    Roozbeh Sanaei, Ali-Akbar Delbandi & Nader Tajik

  2. Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

    Nima Rezaei, Asghar Aghamohammadi, Reza Yazdani, Parsova Tavasolian & Fatemeh Kiaee

  3. Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

    Nima Rezaei

  4. Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran

    Nima Rezaei & Asghar Aghamohammadi

  5. Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran

    Shahram Teimourian

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  1. Roozbeh Sanaei
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Sanaei, R., Rezaei, N., Aghamohammadi, A. et al. Evaluation of the TLR negative regulatory network in CVID patients. Genes Immun 20, 198–206 (2019). https://doi.org/10.1038/s41435-018-0022-3

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