Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

Co-inhibitory receptors in female asthmatic patients: Correlation with IL-17 and IL-26

1 Unit Research 12SP15 “Homeostasis and Molecular Dysfunction in the lung” Abderrahman Mami Hospital, Pavillon B, Ariana, Tunisia
2 Université de Tunis El Manar, Faculty of Medicine of Tunis, Tunisia
3 Division of Paediatric Respiratory Diseases, Pavillon B, A. Mami Hospital, Ariana, Tunisia

Topical Section: Cytokine function

Background: Asthma is an immunological disorder in which T helper 2 (Th2)-type cells and inflammatory cytokines have a prominent role in its pathogenesis. B- and T-lymphocyte attenuator (BTLA), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) are co-inhibitory receptors that regulate T cell activation. Objective: In the present study of asthmatic patients we measured the soluble isoforms of BTLA (sBTLA), CTLA-4 (sCTLA-4) and PD-1 (sPD-1) in induced sputum fluid with the aim to evaluate their utility as responsible for exacerbation. Methods: Eighty patients with asthma and 30 healthy controls (HC) were included in the study. Sputum fluid concentrations of sBTLA, sCTLA-4 and sPD-1 were measured with ELISA. Comparisons were made with Mann-Whitney U test and correlations with IL-17, IL-26 levels and FEV1 (%) were assessed with Spearman’s Rank correlation test. Results: sBTLA levels were significantly higher in the severe and moderate asthmatic patients compared to healthy controls. Significant differences were observed between severe and moderate asthmatics (p < 0.0001). No significant differences were found between mild asthmatics and healthy controls (p = 0.799). Soluble PD-1 levels were higher in severe and moderate asthmatic patients compared to HC and no significant difference was observed between these two asthmatic groups (p = 0.124). Mild asthmatics and control subjects expressed similar sPD-1 levels (p = 0.856). Soluble CTLA-4 was exclusively expressed in certain severe asthmatic patients. IL-17 inflammatory cytokine was significantly correlated with BTLA and sPD-1. IL-17 and IL-26 cytokines were highly expressed in sputum asthmatic groups compared to sputum from HC. Severe asthmatic group was characterized by the highest levels of both IL-17 and IL-26 mediators. Soluble BTLA correlates positively with IL-17 (r = 0.817; p < 0.0001) and IL-26 (r = 0.805; p < 0.0001) inflammatory cytokines. IL-17 and IL-26 levels were associated with the asthma clinical severity from severe to mild asthma (p < 0.0001). The inflammatory cytokines IL-17 and IL-26 were positively correlated with the percentages of macrophages, PNN and FEV1 (%). Conclusion: Here, we provide the first report on the increased expression of sBTLA and sPD-1 in induced sputum of severe asthmatics. IL-26 and IL-17 appeared as a novel proinflammatory axis. Both sBTLA and sPD-1 might be involved in the pathogenesis of asthma and were associated with a poor prognosis.
  Article Metrics

Keywords severe asthma; induced sputum; sBTLA; sCTLA4; sPD-1; IL-17; IL-26

Citation: Sabrine Louhaichi, Mariem Salhi, Anissa Berraïes, Besma Hamdi, Jamel Ammar, Kamel Hamzaoui, Agnès Hamzaoui. Co-inhibitory receptors in female asthmatic patients: Correlation with IL-17 and IL-26. AIMS Allergy and Immunology, 2018, 2(1): 10-23. doi: 10.3934/Allergy.2018.1.10


  • 1. Cosmi L, Liotta F, Maggi L, et al. (2017) Role of Type 2 innate lymphoid cellsin allergic diseases. Curr Allergy Asthm R 17: 66–72.    
  • 2. Galowitz S, Chang C (2015) Immunobiology of critical pediatric asthma. Clin Rev Allerg Immu 48: 84–96.    
  • 3. Charrad R, Berraïes A, Hamdi B, et al. (2016) Anti-inflammatory activity of IL-37 in asthmatic children: Correlation with inflammatory cytokines TNF-α, IL-β, IL-6 and IL-17A. Immunobiology 221: 182–187.    
  • 4. Bernard A, Lamy AL, Alberti I (2002) The two-signal model of T-cell activation after 30 years. Transplantation 73: S31–S35.    
  • 5. Boulougouris G, Mcleod JD, Patel YI, et al. (1998) Positive and negative regulation of human T cell activation mediated by the CTLA-4/CD28 ligand CD80. J Immunol 161: 3919–3924.
  • 6. Freeman GJ, Long AJ, Iwai Y, et al. (2000) Engagement of the PD-1immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192: 1027–1034.    
  • 7. Wang XF, Chen YJ, Wang Q, et al. (2007) Distinct expression and inhibitory function of B and T lymphocyte attenuator on human T cells. HLA 69: 145–153.
  • 8. Waterhouse P, Penninger JM, Timms E, et al. (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270: 985–988.    
  • 9. Boomer JS, Jennifer SS, Hotchkiss RS, et al. (2012) A prospective analysis of lymphocyte phenotypeand function over the course of acute sepsis. Crit Care 16: R112.    
  • 10. Van WC, Bateman ED, Bousquet J, et al. (2008) Asthma management pocket reference 2008. Allergy 63: 997–1004.    
  • 11. Berraïes A, Hamdi B, Ammar J, et al. (2016) Increased Expression of Thymic Stromal Lymphopoietin in induced sputum from asthmatic children. Immunol Lett 178: 85–91.    
  • 12. Moermans C, Heinen V, Nguyen M, et al. (2011) Local and systemic cellular inflammation and cytokine release in chronic obstructive pulmonary disease. Cytokine 56: 298–304.    
  • 13. Delvaux M, Henket M, Lau L, et al. (2004) Nebulised salbutamol administered during sputum induction improves bronchoprotection in patients with asthma. Thorax 59: 111–115.    
  • 14. Kaabachi W, Berraïes A, Dhifallh IB, et al. (2017) Interleukin-26 is overexpressed in Behçet's disease and enhances Th17 related -cytokines. Immunol Lett 190: 177–184.    
  • 15. Wang X, Zhu G, Huang Z, et al. (2012) Application of monoclonal antibodies in a sandwich enzyme-linked immunosorbent assay for identification and detection of soluble human B and T lymphocyte attenuator. Hybridoma 31: 417–423.    
  • 16. Cai G, Freeman GJ (2009) The CD160, BTLA, LIGHT/HVEM pathway: a bidirectional switch regulating T-cell activation. Immunol Rev 229: 244–258.    
  • 17. Oaks MK, Hallett KM, Penwell RT, et al. (2000) A native soluble form of CTLA-4. Cell Immunol 201: 144–153.    
  • 18. Nielsen C, Ohm-Laursen L, Barington T, et al. (2005) Alternative splice variants of the human PD-1 gene. Cell Immunol 235: 109–116.    
  • 19. Magistrelli G, Jeannin P, Herbault N, et al. (1999) A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells. Eur J Immunol 29: 3596–3602.    
  • 20. Chesné J, Braza F, Mahay G, et al. (2014) IL-17 in severe asthma. Where do we stand? Am J Respir Crit Care Med 190: 1094–1101.
  • 21. Bullens DM, Truyen E, Coteur L, et al. (2006) IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Resp Res 7: 135.    
  • 22. Wu H, Miao M, Zhang G, et al. (2009) Soluble PD-1 isassociated with aberrant regulation of T cells activation in aplasticanemia. Immunol Invest 38: 408–421.    
  • 23. Song MY, Park SH, Nam HJ, et al. (2011) Enhancementof vaccine-induced primary and memory CD8(+) T-cell responsesby soluble PD-1. J Immunother 34: 297–306.    
  • 24. Kuipers H, Muskens F, Willart M, et al. (2006) Contribution of the PD-1 ligands/PD-1 signaling pathway to dendritic cell-mediated CD4+ T cell activation. Eur J Immunol 36: 2472–2482.    
  • 25. Hasegawa T, Uga H, Mori A, et al. (2017) Increased serum IL-17A and Th2 cytokinelevels in patients with severe uncontrolled asthma. Eur Cytokine Netw 28: 8–18.
  • 26. Pyle CJ, Uwadiae FI, Swieboda DP, et al. (2017) Early IL-6 signalling promotesIL-27 dependent maturation of regulatory T cells in the lungs and resolution ofviral immunopathology. PLoS Pathog 13: e1006640.    
  • 27. Maalmi H, Beraies A, Charad R, et al. (2014) IL-17A and IL-17F genes variants and susceptibility to childhood asthma in Tunisia. J Asthma 51: 348–354.    
  • 28. Charrad R, Kaabachi W, Berraies A, et al. (2017) IL-33 gene variants and protein expression in pediatric Tunisian asthmatic patients. Cytokine 11: 32.
  • 29. Chen JH, Qin L, Shi YY, et al. (2016) IL-17 protein levels in both induced sputum and plasma are increased in stable but not acute asthma individuals with obesity. Resp Med 121: 48–58.    
  • 30. Lindén A, Dahlén B (2014) Interleukin-17 cytokine signalling in patients with asthma. Eur Respir J 44: 1319–1331.    
  • 31. Ricciardolo FL, Sorbello V, Folino A, et al. (2017) Identification of IL-17F/frequent exacerbator endotype in asthma. J Allergy Clin Immunol 140: 395–406.    
  • 32. Griffiths KL, Khader SA (2014) Bringing in the cavalry: IL-26 mediates neutrophil recruitment to the lungs. Am J Respir Crit Care Med 190: 1079–1080.    
  • 33. Ohnuma K, Hatano R, Aune TM, et al. (2015). Regulation of pulmonary graft-versus-host disease by IL- 26+CD26+CD4 T lymphocytes. J Immunol 194: 3697–3712.    
  • 34. Burlingham WJ, Love RB, Jankowskagan E, et al. (2007) IL-17-dependent cellular immunity to collagen Type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest 117: 3498–3506.    
  • 35. Che KF, Tengvall S, Levanen B, et al. (2014) Interleukin-26 in antibacterial host defense of human lungs. Effects on neutrophil mobilization. Am J Respir Crit Care Med 190: 1022–1031.    
  • 36. Elgaili AA, Nzungize L, Duan X, et al. (2016) Interleukin-10 family and tuberculosis: Old story renewed. Int J Biol Sci 12: 710–717.    
  • 37. Charrad R, Kaabachi W, Rafrafi A, et al. (2017) IL-8 gene variants and expression in childhood asthma. Lung 195: 1–9.    


This article has been cited by

  • 1. Mariem Salhi, Oussama Lahmar, Marwa Ouled Salah, Ivana Banić, Bao Binghao, Waqar Malik, Kamel Hamzaoui, Mirjana Turkalj, Agnes Hamzaoui, GLCCI1 and STIP1 Variants are Associated with Asthma Susceptibility and Inhaled Corticosteroid Response in a Tunisian Population, Journal of Asthma, 2019, 1, 10.1080/02770903.2019.1666867
  • 2. Mariem Salhi, Kalthoum Tizaoui, Sabrine Louhaichi, Oussama Lahmar, Kamel Hamzaoui, Agnes Hamzaoui, IL-26 gene variants and protein expression in Tunisian asthmatic patients, Cytokine, 2020, 134, 155206, 10.1016/j.cyto.2020.155206

Reader Comments

your name: *   your email: *  

© 2018 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Copyright © AIMS Press All Rights Reserved