HLA-G in asthma and its potential as an effective therapeutic agent

Main Article Content

Jinyan Li
Yuqiu Hao
Wei Li
Xuejiao Lv
Peng Gao

Keywords

HLA-G, Asthma, Asthma Subtypes, Inflammation

Abstract

Objective: Asthma is a heterogeneous disease. Severity of asthma and sensitivity to medications vary across asthma subtypes. Human leukocyte antigen (HLA)-G has a wide range of functions in normal and pathological physiology. Due to its powerful immune function, HLA-G participates in the pathogenesis of different asthma phenotypes by regulating the activity and function of various immune cells. The mechanism of HLA-G in asthma is not fully clear, and there is no consensus on its mechanism in asthma. Further studies are needed to explore the role of HLA-G in different phenotypes of human asthma.


Methods: Observational study.


Results: HLA-G is an important immunomodulatory factor in asthma. Studies have found different levels of HLA-G in patients with different asthma subtypes and healthy controls, but other studies have come to the opposite conclusion.


Conclusion: We speculate that further study on the mechanism of HLA-G in asthma pheno-types may explain some of the contradictions in current studies. Findings should provide information regarding the potential of HLA-G as a novel target for asthma diagnosis and treatment.

Abstract 83 | PDF Downloads 57 HTML Downloads 8 XML Downloads 2

References

1. Nicolae D, Cox NJ, Lester LA, Schneider D, Tan Z, Billstrand C, et al. Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromo-some 6p21. Am J Hum Genet. 2005;76(2):349–57. 10.1086/427763

2. Ribeyre C, Carlini F, René C, Jordier F, Picard C, Chiaroni J, et al. HLA-G haplotypes are differentially associated with asthmatic features. Front Immunol. 2018;9:278. 10.3389/fimmu.2018.00278

3. Rouas-Freiss N, LeMaoult J, Moreau P, Dausset J, Carosella ED. HLA-G in transplantation: A relevant molecule for inhibition of graft rejection? Am J Transplant. 2003;3(1):11–6. 10.1034/j.1600-6143.2003.30103.x

4. Zhang JB, Wang ZY, Chen J, Wu XD, Zhou B, Yie SM. The expression of human leukocyte antigen G (HLA-G) is associated with sacroiliitis stages of ankylosing spondylitis. Immunol Lett. 2013;152(2):121–5. 10.1016/j.imlet.2013.04.006

5. Nguyen LS, Rouas-Freiss N, Funck-Brentano C, Leban M, Carosella ED, Touraine P, et al. Influence of hormones on the immunotolerogenic molecule HLA-G: A cross-sectional study in patients with congenital adrenal hyperplasia. Eur J Endocrinol. 2019;181(5):481–8. 10.1530/EJE-19-0379

6. Fainardi E, Castellazzi M, Stignani M, Morandi F, Sana G, Gonzalez R, et al. Emerging topics and new perspectives on HLA-G. Cell Mol Life Sci. 2011;68(3):433–51. 10.1007/s00018-010-0584-3

7. Reches A, Berhani O, Mandelboim O. A unique regulation region in the 3’ UTR of HLA-G with a promising potential. Int J Mol Sci. 2020;21(3):900. 10.3390/ijms21030900

8. Riteau B, Rouas-Freiss N, Menier C, Paul P, Dausset J, Carosella ED. HLA-G2,-G3, and-G4 isoforms expressed as nonmature cell surface glycoproteins inhibit NK and antigen-specific CTL cytolysis. J Immunol. 2001;166(8):5018–26. 10.4049/jimmunol.166.8.5018

9. LeMaoult J, Le Discorde M, Rouas-Freiss N, Moreau P, Menier C, McCluskey J, et al. Biology and functions of human leukocyte antigen-G in health and sickness. Tissue Antigens. 2003;62(4):273–84. 10.1034/j.1399-0039.2003.00143.x

10. Urosevic M, Kurrer MO, Kamarashev J, Mueller B, Weder W, Burg G, et al. Human leukocyte antigen G up-regulation in lung cancer associates with high-grade histology, human leukocyte antigen class I loss and interleukin-10 production. Am J Pathol. 2001;159(3):817–24. 10.1016/S0002-9440(10)61756-7

11. Curigliano G, Criscitiello C, Gelao L, Goldhirsch A. Molecular pathways: Human leukocyte antigen G (HLA-G). Clin Cancer Res. 2013;19(20):5564–71. 10.1158/1078-0432.CCR-12-3697

12. Hackmon R, Pinnaduwage L, Zhang J, Lye SJ, Geraghty DE, Dunk CE. Definitive class I human leukocyte antigen expression in gestational placentation: HLA-F, HLA-E, HLA-C, and HLA-G in extravillous trophoblast invasion on placentation, pregnancy, and parturition. Am J Reprod Immunol. 2017;77(6):e12643. 10.1111/aji.12643

13. Pabalan N, Jarjanazi H, Sun C, Iversen AC. Meta-analysis of the human leukocyte antigen-G (HLA-G) 14 bp insertion/ deletion polymorphism as a risk factor for preeclampsia. Tissue Antigens. 2015;86(3):186–94. 10.1111/tan.12627

14. Yie SM, Li LH, Xiao R, Librach CL. A single base-pair mutation in the 3’-untranslated region of HLA-G mRNA is associated with pre-eclampsia. Mol Hum Reprod. 2008;14(11):649–53. 10.1093/molehr/gan059

15. Lin A, Yan WH. Human leukocyte antigen-g (hla-g) expression in cancers: Roles in immune evasion, metastasis and target for therapy. Mol Med. 2015;21(1):782–91. 10.2119/molmed.2015.00083

16. Ozdemir C, Kucuksezer UC, Akdis M, Akdis CA. The concepts of asthma endotypes and phenotypes to guide current and novel treatment strategies. Expert Rev Respir Med. 2018;12(9):733–43. 10.1080/17476348.2018.1505507

17. Chang HS, Lee TH, Jun JA, Baek AR, Park JS, Koo SM, et al. Neutrophilic inflammation in asthma: Mechanisms and therapeutic considerations. Expert Rev Respir Med. 2017;11(1):29–40. 10.1080/17476348.2017.1268919

18. Polosa R, Thomson NC. Smoking and asthma: Dangerous liaisons. Eur Respir J. 2013;41(3):716–26. 10.1183/09031936.00073312

19. Scott HA, Gibson PG, Garg ML, Wood LG. Airway inflammation is augmented by obesity and fatty acids in asthma. Eur Respir J. 2011;38(3):594–602. 10.1183/09031936.00139810

20. Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: Identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax. 2002;57(10):875–9. 10.1136/thorax.57.10.875

21. Choi JS, Jang AS, Park JS, Park SW, Paik SH, Park JS, et al. Role of neutrophils in persistent airway obstruction due to refractory asthma. Respirology. 2012;17(2):322–9. 10.1111/j.1440-1843.2011.02097.x

22. Shaw DE, Berry MA, Hargadon B, McKenna S, Shelley MJ, Green RH, et al. Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. Chest. 2007;132(6):1871–5. 10.1378/chest.07-1047

23. Berry MA, Shaw DE, Green RH, Brightling CE, Wardlaw AJ, Pavord ID. The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: An observational study in adults with asthma. Clin Exp Allergy. 2005;35(9):1175–9. 10.1111/j.1365-2222.2005.02314.x

24. Berry M, Morgan A, Shaw DE, Parker D, Green R, Brightling C, et al. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax. 2007; 62(12):1043–9. 10.1136/thx.2006.073429

25. Wang F, He XY, Baines KJ, Gunawardhana LP, Simpson JL, Li F, et al. Different inflammatory phenotypes in adults and children with acute asthma. Eur Respir J. 2011;38(3):567–74. 10.1183/09031936.00170110

26. Ntontsi P, Loukides S, Bakakos P, Kostikas K, Papatheodorou G, Papathanassiou E, et al. Clinical, functional and inflammatory characteristics in patients with paucigranulocytic stable asthma: Comparison with different sputum phenotypes. Allergy. 2017;72(11):1761–7. 10.1111/all.13184

27. Hastie AT, Moore WC, Meyers DA, Vestal PL, Li H, Peters SP, et al. Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J Allergy Clin Immunol. 2010;125(5):1028–36.e13. 10.1016/j.jaci.2010.02.008

28. Negrini S, Contini P, Pupo F, Greco M, Murdaca G, Puppo F. Expression of membrane-bound human leucocyte antigen-G in systemic sclerosis and systemic lupus erythematosus. Hum Immunol. 2020;81(4):162–7. 10.1016/j.humimm.2019.12.004

29. Ghavimi R, Alsahebfosoul F, Salehi R, Kazemi M, Etemadifar M, Zavaran Hosseini A. High-resolution melting curve analysis of polymorphisms within CD58, CD226, HLA-G genes and association with multiple sclerosis susceptibility in a subset of Iranian population: A case-control study. Acta Neurol Belg. 2020;120(3):645–52. 10.1007/s13760-018-0992-y

30. Bae SC, Lee YH. Association of HLA-G polymorphisms with systemic lupus erythematosus and correlation between soluble HLA-G levels and the disease: A meta-analysis. Z Rheumatol. 2021;80(1):96–102. 10.1007/s00393-020-00783-6

31. Zidi I, Ben Yahia H, Bortolotti D, Mouelhi L, Laaribi AB, Ayadi S, et al. Association between sHLA-G and HLA-G 14-bp deletion/ insertion polymorphism in Crohn’s disease. Int Immunol. 2015;27(6):289–96. 10.1093/intimm/dxv002

32. Gomes RG, Brito CAA, Martinelli VF, Santos RND, Gomes F, Peixoto CA, et al. HLA-G is expressed in intestinal samples of ulcerative colitis and Crohn’s disease patients and HLA-G5 expression is differentially correlated with TNF and IL-10 cytokine expression. Hum Immunol. 2018;79(6):477–84. 10.1016/j.humimm.2018.03.006

33. Contini P, Puppo F, Canonica GW, Murdaca G, Ciprandi G. Allergen-driven HLA-G expression and secretion in peripheral blood mononuclear cells from allergic rhinitis patients. Hum Immunol. 2016;77(12):1172–8. 10.1016/j.humimm.2016.08.005

34. Negrini S, Contini P, Murdaca G, Puppo F. HLA-G in allergy: Does it play an immunoregulatory role? Front Immunol. 2021;12:789684. 10.3389/fimmu.2021.789684

35. Avelino MA, Wastowski IJ, Ferri RG, Elias TG, Lima AP, Marinho LC, et al. The human leukocyte antigen G molecule (HLA-G) expression in patients with nasal polyposis. Braz J Otorhinolaryngol. 2014;80(3):208–12. 10.1016/j.bjorl.2014.01.001

36. Ciprandi G, De Amici M, Caimmi S, Marseglia A, Marchi A, Castellazzi AM, et al. Soluble serum HLA-G in children with allergic rhinitis and asthma. J Biol Regul Homeost Agents. 2010;24(2):221–4.

37. Murdaca G, Contini P, Negrini S, Ciprandi G, Puppo F. Immunoregulatory role of hla-g in allergic diseases. J Immunol Res. 2016;2016:6865758. 10.1155/2016/6865758

38. Ciprandi G, Corsico A, Pisati P. Serum-soluble HLA-G is associated with specific IgE in patients with allergic rhinitis and asthma. Inflammation. 2014;37(5):1630–4. 10.1007/s10753-014-9890-5

39. Tahan F, Patiroglu T. Plasma soluble human leukocyte antigen G levels in asthmatic children. Int Arch Allergy Immunol. 2006;141(3):213–6. 10.1159/000095290

40. Dorling A, Monk NJ, Lechler RI. HLA-G inhibits the transendothelial migration of human NK cells. Eur J Immunol. 2000;30(2):586–93. 10.1002/1521-4141(200002)30:2<586::AID-IMMU586>3.0.CO;2-Y

41. Rajagopalan S. Endosomal signaling and a novel pathway defined by the natural killer receptor KIR2DL4 (CD158d). Traffic. 2010;11(11):1381–90. 10.1111/j.1600-0854.2010.01112.x

42. Chen XY, Yan WH, Lin A, Xu HH, Zhang JG, Wang XX. The 14 bp deletion polymorphisms in HLA-G gene play an important role in the expression of soluble HLA-G in plasma. Tissue Antigens. 2008;72(4):335–41. 10.1111/j.1399-0039.2008.01107.x

43. Jacquier A, Dumont C, Carosella ED, Rouas-Freiss N, LeMaoult J. Cytometry-based analysis of HLA-G functions according to ILT2 expression. Hum Immunol. 2020;81(4):168–77. 10.1016/j.humimm.2020.02.001

44. Melo-Lima BL, Poras I, Passos GA, Carosella ED, Donadi EA, Moreau P. The Autoimmune Regulator (Aire) transactivates HLA-G gene expression in thymic epithelial cells. Immunology. 2019;158(2):121–35. 10.1111/imm.13099

45. White SR. Human leucocyte antigen-G: Expression and function in airway allergic disease. Clin Exp Allergy. 2012; 42(2):208–17. 10.1111/j.1365-2222.2011.03881.x

46. Dumont C, Jacquier A, Verine J, Noel F, Goujon A, Wu CL, et al. CD8(+)PD-1(-)ILT2(+) T cells are an intratumoral cytotoxic population selectively inhibited by the immune-checkpoint HLA-G. Cancer Immunol Res. 2019;7(10):1619–32. 10.1158/2326-6066.CIR-18-0764

47. Bainbridge DR, Ellis SA, Sargent IL. HLA-G suppresses proliferation of CD4(+) T-lymphocytes. J Reprod Immunol. 2000;48(1): 17–26. 10.1016/S0165-0378(00)00070-X

48. Ketroussi F, Giuliani M, Bahri R, Azzarone B, Charpentier B, Durrbach A. Lymphocyte cell-cycle inhibition by HLA-G is mediated by phosphatase SHP-2 and acts on the mTOR pathway. PLoS One. 2011;6(8):e22776. 10.1371/journal.pone.0022776

49. Naji A, Durrbach A, Carosella ED, Rouas-Freiss N. Soluble HLA-G and HLA-G1 expressing antigen-presenting cells inhibit T-cell alloproliferation through ILT-2/ILT-4/FasL-mediated pathways. Hum Immunol. 2007;68(4):233–9. 10.1016/j.humimm.2006.10.017

50. Ajith A, Portik-Dobos V, Nguyen-Lefebvre AT, Callaway C, Horuzsko DD, Kapoor R, et al. HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival. FASEB J. 2019;33(4):5220–36. 10.1096/fj.201802017R

51. Pankratz S, Ruck T, Meuth SG, Wiendl H. CD4(+)HLA-G(+) regulatory T cells: Molecular signature and pathophysiological relevance. Hum Immunol. 2016;77(9):727–33. 10.1016/j.humimm.2016.01.016

52. Saurabh A, Chakraborty S, Kumar P, Mohan A, Bhatnagar AK, Rishi N, et al. Inhibiting HLA-G restores ifn-γ and tnf-α producing t cell in pleural tuberculosis. Tuberculosis. 2018;109:69–79. 10.1016/j.tube.2018.01.008

53. Morandi F, Ferretti E, Bocca P, Prigione I, Raffaghello L, Pistoia V. A novel mechanism of soluble HLA-G mediated immune modulation: Downregulation of T cell chemokine receptor expression and impairment of chemotaxis. PLoS One. 2010 Jul 23;5(7):e11763. 10.1371/journal.pone.0011763

54. Kubo M. Innate and adaptive type 2 immunity in lung allergic inflammation. Immunol Rev. 2017;278(1):162–72. 10.1111/imr.12557

55. Ciprandi G, Continia P, Fenoglio D, Sormani MP, Negrini S, Puppo F, et al. Relationship between soluble HLA-G and HLAA,-B,-C serum levels, and interferon-gamma production after sublingual immunotherapy in patients with allergic rhinitis. Hum Immunol. 2008;69(7):409–13. 10.1016/j.humimm.2008.05.009

56. Vianna P, Mondadori AG, Bauer ME, Dornfeld D, Chies JA. HLA-G and CD8+ regulatory T cells in the inflammatory environment of pre-eclampsia. Reproduction. 2016;152(6):741–51. 10.1530/REP-15-0608

57. Liang S, Ristich V, Arase H, Dausset J, Carosella ED, Horuzsko A. Modulation of dendritic cell differentiation by HLA-G and ILT4 requires the IL-6--STAT3 signaling pathway. Proc Natl Acad Sci U S A. 2008;105(24):8357–62. 10.1073/pnas.0803341105

58. Ristich V, Liang S, Zhang W, Wu J, Horuzsko A. Tolerization of dendritic cells by HLA-G. Eur J Immunol. 2005;35(4):1133–42. 10.1002/eji.200425741

59. Hazenberg MD, Otto SA, van Benthem BH, Roos MT, Coutinho RA, Lange JM, et al. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS. 2003;17(13):1881–8. 10.1097/00002030-200309050-00006

60. Zhang S, Gan J, Chen BG, Zheng D, Zhang JG, Lin RH, et al. Dynamics of peripheral immune cells and their HLA-G and receptor expressions in a patient suffering from critical COVID-19 pneumonia to convalescence. Clin Transl Immunol. 2020;9(5):e1128. 10.1002/cti2.1128

61. Zhang WQ, Xu DP, Liu D, Li YY, Ruan YY, Lin A, et al. HLA-G1 and HLA-G5 isoforms have an additive effect on NK cytolysis. Hum Immunol. 2014;75(2):182–9. 10.1016/j.humimm.2013.11.001

62. Banerjee PP, Pang L, Soldan SS, Miah SM, Eisenberg A, Maru S, et al. KIR2DL4-HLAG interaction at human NK cell-oligodendrocyte interfaces regulates IFN-γ-mediated effects. Mol Immunol. 2019;115:39–55. 10.1016/j.molimm.2018.09.027

63. Baudhuin J, Migraine J, Faivre V, Loumagne L, Lukaszewicz AC, Payen D, et al. Exocytosis acts as a modulator of the ILT4-mediated inhibition of neutrophil functions. Proc Natl Acad Sci U S A. 2013;110(44):17957–62. 10.1073/pnas.1221535110

64. Morandi F, Ferretti E, Castriconi R, Dondero A, Petretto A, Bottino C, et al. Soluble HLA-G dampens CD94/NKG2A expression and function and differentially modulates chemotaxis and cytokine and chemokine secretion in CD56bright and CD56dim NK cells. Blood. 2011;118(22):5840–50. 10.1182/blood-2011-05-352393

65. Tilburgs T, Evans JH, Crespo  C, Strominger JL. The HLA-G cycle provides for both NK tolerance and immunity at the maternal-fetal interface. Proc Natl Acad Sci U S A. 2015;112(43):13312–7. 10.1073/pnas.1517724112

66. Ishikawa M, Brooks AJ, Fernández-Rojo MA, Medina J, Chhabra Y, Minami S, et al. Growth hormone stops excessive inflammation after partial hepatectomy, allowing liver regeneration and survival through induction of h2-bl/hla-g. Hepatology. 2021;73(2):759–75. 10.1002/hep.31297

67. Lee CL, Guo Y, So KH, Vijayan M, Guo Y, Wong VH, et al. Soluble human leukocyte antigen G5 polarizes differentiation of macrophages toward a decidual macrophage-like phenotype. Hum Reprod. 2015;30(10):2263–74. 10.1093/humrep/dev196

68. Esquivel EL, Maeda A, Eguchi H, Asada M, Sugiyama M, Manabe C, et al. Suppression of human macrophage-mediated cytotoxicity by transgenic swine endothelial cell expression of HLA-G. Transpl Immunol. 2015;32(2):109–15. 10.1016/j.trim.2014.12.004

69. Melén E, Kho AT, Sharma S, Gaedigk R, Leeder JS, Mariani TJ, et al. Expression analysis of asthma candidate genes during human and murine lung development. Respir Res. 2011;12(1): 86. 10.1186/1465-9921-12-86

70. Hough KP, Curtiss ML, Blain TJ, Liu RM, Trevor J, Deshane JS, et al. Airway remodeling in asthma. Front Med. 2020;7:191. 10.3389/fmed.2020.00191

71. Schleich F, Frix AN, Paulus V, Guissard F, Sanchez CE, Henket ME, et al. Asthma: The contribution of biotherapies. Rev Med Liege. 2020;75(5–6):350–5.

72. Gauthier M, Ray A, Wenzel SE. Evolving concepts of asthma. Am J Respir Crit Care Med. 2015;192(6):660–8. 10.1164/rccm.201504-0763PP

73. Asayama K, Kobayashi T, D’Alessandro-Gabazza CN, Toda M, Yasuma T, Fujimoto H, et al. Protein S protects against allergic bronchial asthma by modulating Th1/Th2 balance. Allergy. 2020;75(9):2267–78. 10.1111/all.14261

74. Hynes G, Pavord ID. Targeted biologic therapy for asthma. Br Med Bull. 2020;133(1):16–35. 10.1093/bmb/ldaa004

75. Tanaka A, Sato H, Akimoto K, Matsunaga T, Sagara H. Spontaneous sputum discriminates inflammatory phenotypes in patients with asthma. Ann Allergy Asthma Immunol. 2021;126(1):54–60.e1. 10.1016/j.anai.2020.06.017

76. Gao P, Gibson PG, Baines KJ, Yang IA, Upham JW, Reynolds PN, et al. Anti-inflammatory deficiencies in neutrophilic asthma: Reduced galectin-3 and IL-1RA/IL-1β. Respir Res. 2015;16(1):5. 10.1186/s12931-014-0163-5

77. Zhang L, Zhang J, Gao P. The potential of interleukin-37 as an effective therapeutic agent in asthma. Respir Res. 2017;18(1):192. 10.1186/s12931-017-0675-x

78. Ober C. HLA-G: An asthma gene on chromosome 6p. Immunol Allergy Clin North Am. 2005;25(4):669–79. 10.1016/j.iac.2005.08.001

79. Nicodemus-Johnson J, Laxman B, Stern RK, Sudi J, Tierney CN, Norwick L, et al. Maternal asthma and microRNA regulation of soluble HLA-G in the airway. J Allergy Clin Immunol. 2013;131(6):1496–503. 10.1016/j.jaci.2013.01.037

80. White SR, Loisel DA, Stern R, Laxman B, Floreth T, Marroquin BA. Human leukocyte antigen-G expression in differentiated human airway epithelial cells: Lack of modulation by Th2-associated cytokines. Respir Res. 2013;14(1):4. 10.1186/1465-9921-14-4

81. Carlini F, Picard C, Garulli C, Piquemal D, Roubertoux P, Chiaroni J, et al. Bronchial epithelial cells from asthmatic patients display less functional hla-g isoform expression. Front Immunol. 2017;8:6. 10.3389/fimmu.2017.00006

82. Zheng XQ, Li CC, Xu DP, Lin A, Bao WG, Yang GS, et al. Analysis of the plasma soluble human leukocyte antigen-G and interleukin-10 levels in childhood atopic asthma. Hum Immunol. 2010;71(10):982–7. 10.1016/j.humimm.2010.06.018

83. Gregori S, Tomasoni D, Pacciani V, Scirpoli M, Battaglia M, Magnani CF, et al. Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood. 2010;116(6):935–44. 10.1182/blood-2009-07-234872

84. Mapp CE, Ferrazzoni S, Rizzo R, Miotto D, Stignani M, Boschetto P, et al. Soluble human leucocyte antigen-G and interleukin-10 levels in isocyanate-induced asthma. Clin Exp Allergy. 2009;39(6):812–9. 10.1111/j.1365-2222.2009.03215.x

85. Carosella ED, Gregori S, LeMaoult J. The tolerogenic interplay(s) among HLA-G, myeloid APCs, and regulatory cells. Blood. 2011;118(25):6499–505. 10.1182/blood-2011-07-370742

86. White SR, Nicodemus-Johnson J, Laxman B, Denner DR, Naureckas ET, Hogarth DK, et al. Elevated levels of soluble humanleukocyte antigen-G in the airways are a marker for a low-inflammatory endotype of asthma. J Allergy Clin Immunol. 2017;140(3):857–60. 10.1016/j.jaci.2017.02.031

87. Naidoo D, Wu AC, Brilliant MH, Denny J, Ingram C, Kitchner TE, et al. A polymorphism in HLA-G modifies statin benefit in asthma. Pharmacogenomics J. 2015;15(3):272–7. 10.1038/tpj.2014.55

88. Kenyon NJ, Morrissey BM, Schivo M, Albertson TE. Occupational asthma. Clin Rev Allergy Immunol. 2012;43(1–2): 3–13. 10.1007/s12016-011-8272-0