Immunopathogenesis of Chronic Rhinosinusitis and Nasal Polyposis

Annual Review of Pathology: Mechanisms of Disease

Volumn 12, Issue , 2017, Pages 331-357

  Schleimer, Robert P ^a  

^a NORTHWESTERN UNIVERSITY   (United States)

Author keywords

Acantholysis; Acanthosis; Allergy; Chronic rhinosinusitis; Eosinophilic inflammation; Epithelial barrier; Epithelial to mesenchymal transition (EMT); Glandular hyperplasia; Nasal polyp; Sinus disease

Indexed keywords

ENDOTOXIN; LACTOFERRIN; LYSOZYME; POLYPEPTIDE ANTIBIOTIC AGENT; TOLL LIKE RECEPTOR;

ADAPTIVE IMMUNITY; BITTER TASTE; CELL DAMAGE; CELL REGENERATION; CHRONIC RHINOSINUSITIS; CILIATED EPITHELIUM; CLINICAL EFFECTIVENESS; DISEASE COURSE; EOSINOPHILIA; EPITHELIAL MESENCHYMAL TRANSITION; GENOTYPE ENVIRONMENT INTERACTION; HEALTH CARE COST; HEALTH CARE NEED; HUMAN; IMMUNE RESPONSE; IMMUNOPATHOGENESIS; INFLAMMATION; INNATE IMMUNITY; MICROBIOME; NASAL MICROBIOME; NONHUMAN; NOSE; NOSE EPITHELIUM; NOSE POLYP; PARANASAL SINUS; PATHOLOGICAL ANATOMY; PRIORITY JOURNAL; RACE; REVIEW; TASTE BUD; ADULT; CHRONIC DISEASE; IMMUNOLOGY; PATHOLOGY; RHINITIS; SINUSITIS;

ADULT; CHRONIC DISEASE; HUMANS; NASAL POLYPS; RHINITIS; SINUSITIS;

EID: 85011286238     PISSN: 15534006     EISSN: 15534014     Source Type: Book Series    
DOI: 10.1146/annurev-pathol-052016-100401     Document Type: Review

References (186)

1. Meltzer EO, Hamilos DL, Hadley JA, Lanza DC, Marple BF, et al. 2004. Rhinosinusitis: establishing definitions for clinical research and patient care. J. Allergy Clin. Immunol. 114(6 Suppl):155-212
2. Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, et al. 2012. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 50(1):1-12
3. Senior BA,KennedyDW,Tanabodee J,KrogerH,HassabM, et al. 1998. Long-term results of functional endoscopic sinus surgery. Laryngoscope 108(2):151-57
4. Laidlaw TM, Boyce JA. 2016. Aspirin-exacerbated respiratory disease-new prime suspects. N. Engl. J. Med. 374(5):484-88
5. Bhattacharyya N, Orlandi RR, Grebner J, Martinson M. 2011. Cost burden of chronic rhinosinusitis: a claims-based study. Otolaryngol. Head Neck Surg. 144(3):440-45
6. TanBK, Kern RC, Schleimer RP, SchwartzBS. 2013. Chronic rhinosinusitis: the unrecognized epidemic. Am. J. Respir. Crit. Care Med. 188(11):1275-77
7. Stevens WW, Peters AT, Suh L, Norton JE, Kern RC, et al. 2015. A retrospective, cross-sectional study reveals that women with CRSwNP have more severe disease than men. Immun. Inflamm. Dis. 3(1):14-22
8. Sahin-Yilmaz A, Naclerio RM. 2011. Anatomy and physiology of the upper airway. Proc. Am. Thorac. Soc. 8(1):31-39
9. Kato A,Hulse KE, Tan BK, Schleimer RP. 2013. B-lymphocyte lineage cells and the respiratory system. J. Allergy Clin. Immunol. 131(4):933-57
10. Avila PC, Schleimer RP. 2008. Airway epithelium. In Allergy and Allergic Diseases, Vol. 1, ed. AB Kay, AP Kaplan, J Bousquet, PG Holt, pp. 366-97. Hoboken, NJ: Wiley-Blackwell. 2nd ed
11. Hopkins C, Browne JP, Slack R, Lund V, Brown P. 2007. The Lund-Mackay staging system for chronic rhinosinusitis: How is it used and what does it predict? Otolaryngol. Head Neck Surg. 137(4):555-61
12. Tos M, Larsen PL, Larsen K, Caye-Thomasen P. 2010. Pathogenesis and pathophysiology of nasal polyps. In Nasal Polyposis, ed. TM Onerci, BJ Ferguson, pp. 53-63. Berlin: Springer-Verlag
13. Akdis CA, Bachert C, Cingi C, Dykewicz MS, Hellings PW, et al. 2013. Endotypes and phenotypes of chronic rhinosinusitis: a PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma &Immunology. J. Allergy Clin. Immunol. 131(6):1479-90
14. Tomassen P, Vandeplas G, Van Zele T, Cardell LO, Arebro J, et al. 2016. Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers. J. Allergy Clin. Immunol. 137(5):1449-56
15. Kountakis SE, Arango P, Bradley D, Wade ZK, Borish L. 2004. Molecular and cellular staging for the severity of chronic rhinosinusitis. Laryngoscope 114(11):1895-905
16. Van Bruaene N, Bachert C. 2011. Tissue remodeling in chronic rhinosinusitis. Curr. Opin. Allergy Clin. Immunol. 11(1):8-11
17. Shi LL, Xiong P, Zhang L, Cao PP, Liao B, et al. 2013. Features of airway remodeling in different types of Chinese chronic rhinosinusitis are associated with inflammation patterns. Allergy 68(1):101-9
18. Kim DK, Jin HR, Eun KM, Mutusamy S, Cho SH, et al. 2015. Non-eosinophilic nasal polyps shows increased epithelial proliferation and localized disease pattern in the early stage. PLOS ONE 10(10):e0139945
19. Watelet JB, Bachert C, Claeys C, Van Cauwenberge P. 2004. Matrix metalloproteinases MMP-7, MMP-9 and their tissue inhibitor TIMP-1: expression in chronic sinusitis versus nasal polyposis. Allergy 59(1):54-60
20. Nielsen LF, Moe D, Kirkeby S, Garbarsch C. 1998. Sirius red and acid fuchsin staining mechanisms. Biotech Histochem. 73(2):71-77
21. Eyibilen A, Cayli S, Aladag I, Koc S, Gurbuzler L, et al. 2011. Distribution of matrix metalloproteinases MMP-1, MMP-2, MMP-8 and tissue inhibitor of matrix metalloproteinases-2 in nasal polyposis and chronic rhinosinusitis. Histol. Histopathol. 26(5):615-21
22. Kostamo K, Tervahartiala T, Sorsa T, Richardson M, Toskala E. 2007. Metalloproteinase function in chronic rhinosinusitis with nasal polyposis. Laryngoscope 117(4):638-43
23. Lechapt-Zalcman E, Coste A, d'Ortho MP, Frisdal E, Harf A, et al. 2001. Increased expression of matrix metalloproteinase-9 in nasal polyps. J. Pathol. 193(2):233-41
24. Wang LF, Chien CY, Tai CF, Kuo WR, Hsi E, et al. 2010. Matrix metalloproteinase-9 gene polymorphisms in nasal polyposis. BMC Med. Genet. 11:85
25. Meng J, Zhou P, Liu Y, Liu F, Yi X, et al. 2013. The development of nasal polyp disease involves early nasal mucosal inflammation and remodelling. PLOS ONE 8(12):e82373
26. Carroll WW, O'Connell BP, Schlosser RJ, Gudis DA, Karnezis TT, et al. 2016. Fibroblast levels are increased in chronic rhinosinusitis with nasal polyps and are associated with worse subjective disease severity. Int. Forum Allergy Rhinol. 6(2):162-68
27. YoshikawaM,Wada K, Yoshimura T, Asaka D, Okada N, et al. 2013. Increased CXCL10 expression in nasal fibroblasts from patients with refractory chronic rhinosinusitis and asthma. Allergol. Int. 62(4):495-502
28. Takabayashi T, Kato A, Peters AT, Hulse KE, Suh LA, et al. 2013. Excessive fibrin deposition in nasal polyps caused by fibrinolytic impairment through reduction of tissue plasminogen activator expression. Am. J. Respir. Crit. Care Med. 187(1):49-57
29. Takabayashi T, Kato A, Peters AT, Hulse KE, Suh LA, et al. 2013. Increased expression of factor XIII-A in patients with chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 132(3):584-592
30. HulseKE, StevensWW,Tan BK, Schleimer RP. 2015. Pathogenesis of nasal polyposis. Clin. Exp. Allergy 45(2):328-46
31. Lee H, Kim SR, Oh Y, Cho SH, Schleimer RP, et al. 2014. Targeting insulin-like growth factor-I and insulin-like growth factor-binding protein-3 signaling pathways. A novel therapeutic approach for asthma. Am. J. Respir. Cell Mol. Biol. 50(4):667-77
32. NiessenCM.2007. Tight junctions/adherens junctions: basic structure and function. J. Investig.Dermatol. 127(11):2525-32
33. Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, et al. 2011. Tight junction defects in patients with atopic dermatitis. J. Allergy Clin. Immunol. 127(3):773-86
34. Barmeyer C, Schulzke JD, Fromm M. 2015. Claudin-related intestinal diseases. Semin. Cell Dev. Biol. 42:30-38
35. Hackett TL. 2012. Epithelial-mesenchymal transition in the pathophysiology of airway remodelling in asthma. Curr. Opin. Allergy Clin. Immunol. 12(1):53-59
36. Holgate ST. 2011. The sentinel role of the airway epithelium in asthma pathogenesis. Immunol. Rev. 242(1):205-19
37. Kalluri R, Weinberg RA. 2009. The basics of epithelial-mesenchymal transition. J. Clin. Investig. 119(6):1420-28
38. Pain M, BermudezO,Lacoste P,Royer PJ,Botturi K, et al. 2014. Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype. Eur. Respir. Rev. 23(131):118-30
39. Yang J, Weinberg RA. 2008. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell. 14(6):818-29
40. Taniguchi K,Wu LW, Grivennikov SI, de Jong PR, Lian I, et al. 2015. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 519(7541):57-62
41. Lee SN, Lee DH, Sohn MH, Yoon JH. 2013. Overexpressed proprotein convertase 1/3 induces an epithelial-mesenchymal transition in airway epithelium. Eur. Respir. J. 42(5):1379-90
42. Sidhu SS, Yuan S, Innes AL, Kerr S, Woodruff PG, et al. 2010. Roles of epithelial cell-derived periostin in TGF-βactivation, collagen production, and collagen gel elasticity in asthma. PNAS 107(32):14170-75
43. Bernstein JM, Gorfien J, Noble B, Yankaskas JR. 1997. Nasal polyposis: immunohistochemistry and bioelectrical findings (a hypothesis for the development of nasal polyps). J. Allergy Clin. Immunol. 99(2):165-75
44. Dejima K, Randell SH, Stutts MJ, Senior BA, BoucherRC. 2006. Potential role of abnormal ion transport in the pathogenesis of chronic sinusitis. Arch. Otolaryngol. Head Neck Surg. 132(12):1352-62
45. Soyka MB, Wawrzyniak P, Eiwegger T, Holzmann D, Treis A, et al. 2012. Defective epithelial barrier in chronic rhinosinusitis: the regulation of tight junctions by IFN-γand IL-4. J. Allergy Clin. Immunol. 130(5):1087-96
46. Zhang N, Van Crombruggen K, Gevaert E, Bachert C. 2016. Barrier function of the nasal mucosa in health and type-2 biased airway diseases. Allergy 71(3):295-307
47. Jang YJ, Kim HG, Koo TW, Chung PS. 2002. Localization of ZO-1 and E-cadherin in the nasal polyp epithelium. Eur. Arch. Otorhinolaryngol. 259(9):465-69
48. Shahana S, Jaunmuktane Z, Asplund MS, RoomansGM. 2006. Ultrastructural investigation of epithelial damage in asthmatic and non-asthmatic nasal polyps. Respir. Med. 100(11):2018-28
49. Rogers GA, Den Beste K, Parkos CA, Nusrat A, Delgaudio JM, et al. 2011. Epithelial tight junction alterations in nasal polyposis. Int. Forum Allergy Rhinol. 1(1):50-54
50. Hupin C, Gohy S, Bouzin C, Lecocq M, Polette M, et al. 2014. Features of mesenchymal transition in the airway epithelium from chronic rhinosinusitis. Allergy 69(11):1540-49
51. Johnson JR, Roos A, Berg T, Nord M, Fuxe J. 2011. Chronic respiratory aeroallergen exposure in mice induces epithelial-mesenchymal transition in the large airways. PLOS ONE 6(1):e16175
52. Steelant B, Farre R, Wawrzyniak P, Belmans J, Dekimpe E, et al. 2016. Impaired barrier function in patients with house dust mite-induced allergic rhinitis is accompanied by decreased occludin and zonula occludens-1 expression. J. Allergy Clin. Immunol. 137(4):1043-53
53. Wan H,Winton HL, Soeller C, Tovey ER, Gruenert DC, et al. 1999. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J. Clin. Investig. 104(1):123-33
54. Richer SL,Truong-Tran AQ,ConleyDB, Carter R,VermylenD, et al. 2008. Epithelial genes in chronic rhinosinusitis with and without nasal polyps. Am. J. Rhinol. 22(3):228-34
55. Tieu DD, Kern RC, Schleimer RP. 2009. Alterations in epithelial barrier function and host defense responses in chronic rhinosinusitis. J. Allergy Clin. Immunol. 124(1):37-42
56. Heijink IH, Postma DS, Noordhoek JA, Broekema M, Kapus A. 2010. House dust mite-promoted epithelial-to-mesenchymal transition in human bronchial epithelium. Am. J. Respir. Cell Mol. Biol. 42(1):69-79
57. ShinHW, ChoK, KimDW,Han DH,Khalmuratova R, et al. 2012. Hypoxia-inducible factor 1mediates nasal polypogenesis by inducing epithelial-to-mesenchymal transition. Am. J. Respir. Crit. Care. Med. 185(9):944-54
58. Shaykhiev R, Crystal RG. 2014. Early events in the pathogenesis of chronic obstructive pulmonary disease. Smoking-induced reprogramming of airway epithelial basal progenitor cells. Ann. Am. Thorac. Soc. 11(Suppl 5):S252-8
59. Gevaert P, Van BruaeneN, CattaertT, Van Steen K, Van Zele T, et al. 2011. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J. Allergy Clin. Immunol. 128(5):989-95
60. Flood-Page P, Menzies-Gow A, Phipps S, Ying S, Wangoo A, et al. 2003. Anti-IL-5 treatment reduces deposition ofECMproteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J. Clin. Investig. 112(7):1029-36
61. Lee RCN. 2016. Physiology of the nose and paranasal sinuses. In Otolaryngology Head and Neck Surgery, ed. C deSouza et al. New Delhi: Jaypee Publishers. In press. 2nd ed
62. Chen B, Shaari J, Claire SE, Palmer JN, Chiu AG, et al. 2006. Altered sinonasal ciliary dynamics in chronic rhinosinusitis. Am. J. Rhinol. 20(3):325-29
63. GudisD, Zhao KQ, CohenNA. 2012. Acquired cilia dysfunction in chronic rhinosinusitis. Am. J. Rhinol. Allergy 26(1):1-6
64. Li YY, Li CW, Chao SS, Yu FG, Yu XM, et al. 2014. Impairment of cilia architecture and ciliogenesis in hyperplastic nasal epithelium from nasal polyps. J. Allergy Clin. Immunol. 134(6):1282-92
65. Hamilos DL. 2014. Host-microbial interactions in patients with chronic rhinosinusitis. J. Allergy Clin. Immunol. 133(3):640-53
66. Stevens WW, Lee RJ, Schleimer RP, Cohen NA. 2015. Chronic rhinosinusitis pathogenesis. J. Allergy Clin. Immunol. 136(6):1442-53
67. Van Crombruggen K, Jacob F, Zhang N, Bachert C. 2013. Damage-associated molecular patterns and their receptors in upper airway pathologies. Cell Mol. Life Sci. 70(22):4307-21
68. Claeys S, de Belder T, Holtappels G, Gevaert P, Verhasselt B, et al. 2003. Human β-defensins and toll-like receptors in the upper airway. Allergy 58(8):748-53
69. Sha Q, Truong-Tran AQ, Plitt JR, Beck LA, Schleimer RP. 2004. Activation of airway epithelial cells by toll-like receptor agonists. Am. J. Respir. Cell Mol. Biol. 31(3):358-64
70. Vandermeer J, Sha Q, Lane AP, Schleimer RP. 2004. Innate immunity of the sinonasal cavity: expression of messenger RNA for complement cascade components and toll-like receptors. Arch. Otolaryngol. Head Neck Surg. 130(12):1374-80
71. Hirschberg A, Kiss M, Kadocsa E, Polyanka H, Szabo K, et al. 2015. Different activations of toll-like receptors and antimicrobial peptides in chronic rhinosinusitis with or without nasal polyposis. Eur. Arch. Otorhinolaryngol. 273:1779-88
72. Lane AP, Truong-Tran QA, Myers A, Bickel C, Schleimer RP. 2006. Serum amyloid A, properdin, complement 3, and toll-like receptors are expressed locally in human sinonasal tissue. Am. J. Rhinol. 20(1):117-23
73. Sun Y, Zhou B, Wang C, Huang Q, Zhang Q, et al. 2012. Biofilm formation and Toll-like receptor 2, Toll-like receptor 4, and NF-κB expression in sinus tissues of patients with chronic rhinosinusitis. Am. J. Rhinol. Allergy 26(2):104-9
74. Ramanathan M Jr., Lee WK, Dubin MG, Lin S, Spannhake EW, et al. 2007. Sinonasal epithelial cell expression of Toll-like receptor 9 is decreased in chronic rhinosinusitis with polyps. Am. J. Rhinol. 21(1):110-16
75. Zhang Q,Wang CS, Han DM, Sy C, Huang Q, et al. 2013. Differential expression of Toll-like receptor pathway genes in chronic rhinosinusitis with or without nasal polyps. Acta Otolaryngol. 133(2):165-73
76. Park CS, Cho JH, Park YJ. 2011. Toll-like receptor 2 gene polymorphisms in a Korean population: association with chronic rhinosinusitis. Otolaryngol. Head Neck Surg. 144(1):96-100
77. Lee RJ, Xiong G, Kofonow JM, Chen B, Lysenko A, et al. 2012. T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection. J. Clin. Investig. 122(11):4145-59
78. Lee RJ, Cohen NA. 2015. Role of the bitter taste receptor T2R38 in upper respiratory infection and chronic rhinosinusitis. Curr. Opin. Allergy Clin. Immunol. 15(1):14-20
79. Lee RJ, Kofonow JM, Rosen PL, Siebert AP, Chen B, et al. 2014. Bitter and sweet taste receptors regulate human upper respiratory innate immunity. J. Clin. Investig. 124(3):1393-405
80. Adappa ND, Workman AD, Hadjiliadis D, Dorgan DJ, Frame D, et al. 2016. T2R38 genotype is correlated with sinonasal quality of life in homozygous F508 cystic fibrosis patients. Int. Forum Allergy Rhinol. 6(4):356-61
81. Adappa ND, Zhang Z, Palmer JN, Kennedy DW, Doghramji L, et al. 2014. The bitter taste receptor T2R38 is an independent risk factor for chronic rhinosinusitis requiring sinus surgery. Int. Forum Allergy Rhinol. 4(1):3-7
82. Mfuna-Endam L, Zhang Y, Desrosiers MY. 2011. Genetics of rhinosinusitis. Curr. Allergy Asthma Rep. 11(3):236-46
83. Wiener A, Shudler M, Levit A, Niv MY. 2012. BitterDB: a database of bitter compounds. Nucleic Acids Res. 40(Database issue):D413-19
84. Zhang Z, Adappa ND, Lautenbach E, Chiu AG, Doghramji L, et al. 2014. The effect of diabetes mellitus on chronic rhinosinusitis and sinus surgery outcome. Int. Forum Allergy Rhinol. 4(4):315-20
85. Bingle CD, Craven CJ. 2002. PLUNC: a novel family of candidate host defence proteins expressed in the upper airways and nasopharynx. Hum. Mol. Genet. 11(8):937-43
86. Min-man W, Hong S, Zhi-qiang X, Xue-ping F, Chang-qi L, et al. 2009. Differential proteomic analysis of nasal polyps, chronic sinusitis, and normal nasal mucosa tissues. Otolaryngol. Head Neck Surg. 141(3):364-68
87. Ghafouri B, Kihlstrom E, Stahlbom B, Tagesson C, Lindahl M. 2003. PLUNC (palate, lung and nasal epithelial clone) proteins in human nasal lavage fluid. Biochem. Soc. Trans. 31(Pt 4):810-14
88. Seshadri S, Lin DC, Rosati M, Carter RG, Norton JE, et al. 2012. Reduced expression of antimicrobial PLUNC proteins in nasal polyp tissues of patients with chronic rhinosinusitis. Allergy 67(7):920-28
89. Wei Y, Xia W, Ye X, Fan Y, Shi J, et al. 2014. The antimicrobial protein short palate, lung, and nasal epithelium clone 1 (SPLUNC1) is differentially modulated in eosinophilic and noneosinophilic chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 133(2):420-28
90. Tsou YA, Peng MT, Wu YF, Lai CH, Lin CD, et al. 2014. Decreased PLUNC expression in nasal polyps is associated with multibacterial colonization in chronic rhinosinusitis patients. Eur. Arch. Otorhinolaryngol. 271(2):299-304
91. Thaikoottathil JV, Martin RJ, Di PY, Minor M, Case S, et al. 2012. SPLUNC1 deficiency enhances airway eosinophilic inflammation in mice. Am. J. Respir. Cell Mol. Biol. 47(2):253-60
92. Barnes KC, Grant A, Gao P, Baltadjieva D, Berg T, et al. 2006. Polymorphisms in the novel gene acyloxyacyl hydroxylase (AOAH) are associated with asthma and associated phenotypes. J. Allergy Clin. Immunol. 118(1):70-77
93. Zhang Y, Endam LM, Filali-Mouhim A, Zhao L, Desrosiers M, et al. 2012. Polymorphisms in RYBP and AOAH genes are associated with chronic rhinosinusitis in a Chinese population: a replication study. PLOS ONE 7(6):e39247
94. Bryborn M, Adner M, Cardell LO. 2005. Psoriasin, one of several new proteins identified in nasal lavage fluid from allergic and non-allergic individuals using 2-dimensional gel electrophoresis and mass spectrometry. Respir. Res. 6:118
95. Tieu DD, Peters AT, Carter RG, Suh L, Conley DB, et al. 2010. Evidence for diminished levels of epithelial psoriasin and calprotectin in chronic rhinosinusitis. J. Allergy Clin. Immunol. 125(3):667-75
96. Kvarnhammar AM, Rydberg C, Jarnkrants M, Eriksson M, Uddman R, et al. 2012. Diminished levels of nasal S100A7 (psoriasin) in seasonal allergic rhinitis: an effect mediated by Th2 cytokines. Respir. Res. 13:2
97. Van Crombruggen K, Vogl T, Perez-Novo C, Holtappels G, Bachert C. 2016. Differential release and deposition of S100A8/A9 proteins in inflamed upper airway tissue. Eur. Respir. J. 47(1):264-74
98. Cho SH, Hong SJ, Han B, Lee SH, Suh L, et al. 2012. Age-related differences in the pathogenesis of chronic rhinosinusitis. J. Allergy Clin. Immunol. 129(3):858-60
99. Dong D, Yulin Z, Yan X,Hongyan Z, Shitao Z, et al. 2014. Enhanced expressions of lysozyme, SLPI and glycoprotein 340 in biofilm-associated chronic rhinosinusitis. Eur. Arch. Otorhinolaryngol. 271(6):1563-71
100. Ishida M, Matsunaga T, Uda H. 1984. An immunohistological study of nasal and paranasal mucosa of patients with relapsing chronic sinusitis. Rhinology 22(2):115-18
101. JeneyEV, RaphaelGD,Meredith SD, KalinerMA.1990. Abnormal nasal glandular secretion in recurrent sinusitis. J. Allergy Clin. Immunol. 86(1):10-18
102. Psaltis AJ, Wormald PJ, Ha KR, Tan LW. 2008. Reduced levels of lactoferrin in biofilm-associated chronic rhinosinusitis. Laryngoscope 118(5):895-901
103. Tewfik MA, Latterich M, DiFalco MR, SamahaM. 2007. Proteomics of nasal mucus in chronic rhinosinusitis. Am. J. Rhinol. 21(6):680-85
104. GaunsbaekMQ, Lange B, Kjeldsen AD, Svane-Knudsen V, Skjoedt K, et al. 2012. Complement defects in patients with chronic rhinosinusitis. PLOS ONE 7(11): e47383
105. Hamilos DL. 2015. Drivers of chronic rhinosinusitis: inflammation versus infection. J. Allergy Clin. Immunol. 136(6):1454-59
106. Liu T, Li TL, Zhao F, Xie C, Liu AM, et al. 2011. Role of thymic stromal lymphopoietin in the pathogenesis of nasal polyposis. Am. J. Med. Sci. 341(1):40-47
107. Miljkovic D, Bassiouni A, Cooksley C, Ou J, Hauben E, et al. 2014. Association between group 2 innate lymphoid cells enrichment, nasal polyps and allergy in chronic rhinosinusitis. Allergy 69(9):1154-61
108. Nagarkar DR, Poposki JA, Tan BK, Comeau MR, Peters AT, et al. 2013. Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis. J. Allergy Clin. Immunol. 132(3):593-600
109. Lund S, WalfordHH,DohertyTA. 2013. Type 2 innate lymphoid cells in allergic disease. Curr. Immunol. Rev. 9(4):214-21
110. McKenzie AN, Spits H, Eberl G. 2014. Innate lymphoid cells in inflammation and immunity. Immunity 41(3):366-74
111. Stevens WW, Ocampo CJ, Berdnikovs S, Sakashita M, Mahdavinia M, et al. 2015. Cytokines in chronic rhinosinusitis. Role in eosinophilia and aspirin-exacerbated respiratory disease. Am. J. Respir. Crit. Care. Med. 192(6):682-94
112. Ho J, Bailey M, Zaunders J, Mrad N, Sacks R, et al. 2015. Group 2 innate lymphoid cells (ILC2s) are increased in chronic rhinosinusitis with nasal polyps or eosinophilia. Clin. Exp. Allergy 45(2):394-403
113. Mjosberg JM, Trifari S, Crellin NK, Peters CP, van Drunen CM, et al. 2011. Human IL-25-and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat. Immunol. 12(11):1055-62
114. Shaw JL, Fakhri S, Citardi MJ, Porter PC, Corry DB, et al. 2013. IL-33-responsive innate lymphoid cells are an important source of IL-13 in chronic rhinosinusitis with nasal polyps. Am. J. Respir. Crit. Care. Med. 188(4):432-39
115. ZaissDM, GauseWC, Osborne LC, Artis D. 2015. Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity 42(2):216-26
116. Pothoven KL, Norton JE, Hulse KE, Suh LA, Carter RG, et al. 2015. Oncostatin M promotes mucosal epithelial barrier dysfunction, and its expression is increased in patientswith eosinophilic mucosal disease. J. Allergy Clin. Immunol. 136(3):737-46
117. Homma T, Kato A,Masafumi S,Norton J, Suh L, et al. 2015. Involvement of EGFR ligands and MMP-1 in pathogenesis of CRS. Am. J. Respir. Crit. Care Med. 191:A1377 (Abstr.)
118. Gevaert P, Holtappels G, Johansson SG, Cuvelier C, Cauwenberge P, et al. 2005. Organization of secondary lymphoid tissue and local IgE formation to Staphylococcus aureus enterotoxins in nasal polyp tissue. Allergy 60(1):71-79
119. Hulse KE, Norton JE, Suh L, Zhong Q, Mahdavinia M, et al. 2013. Chronic rhinosinusitis with nasal polyps is characterized by B-cell inflammation and EBV-induced protein 2 expression. J. Allergy Clin. Immunol. 131(4):1075-83
120. Mechtcheriakova D, Sobanov Y, Holtappels G, Bajna E, Svoboda M, et al. 2011. Activation-induced cytidine deaminase (AID)-associated multigene signature to assess impact of AID in etiology of diseases with inflammatory component. PLOS ONE 6(10):e25611
121. Bachert C, Zhang N, Holtappels G, De Lobel L, van Cauwenberge P, et al. 2010. Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma. J. Allergy Clin. Immunol. 126(5):962-68
122. TanBK, Li QZ, Suh L, KatoA,ConleyDB, et al. 2011. Evidence for intranasal antinuclear autoantibodies in patients with chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 128(6):1198-206
123. Jeffe JS, Seshadri S, Hamill KJ, Huang JH, Carter R, et al. 2013. A role for anti-BP180 autoantibodies in chronic rhinosinusitis. Laryngoscope 123(9):2104-11
124. Van Roey GA, Vanison C, Huang H, Kern R, Chandra R, et al. 2015. Complement activation in nasal tissue of patients with chronic rhinosinusitis. J. Allergy Clin. Immunol. 135(2):AB237
125. Kato A, Peters A, Suh L, Carter R,Harris KE, et al. 2008. Evidence of a role for B cell-activating factor of the TNF family in the pathogenesis of chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 121(6):1385-92
126. Bachert C, Mannent L, Naclerio RM, Mullol J, Ferguson BJ, et al. 2016. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA 315(5):469-79
127. Bochner BS, Schleimer RP. 2001. Mast cells, basophils, and eosinophils: distinct but overlapping pathways for recruitment. Immunol. Rev. 179:5-15
128. Poposki JA, Uzzaman A, Nagarkar DR, Chustz RT, Peters AT, et al. 2011. Increased expression of the chemokine CCL23 in eosinophilic chronic rhinosinusitis with nasal polyps. J. Allergy Clin. Immunol. 128(1):73-81
129. Cao PP, Li HB,Wang BF, Wang SB, You XJ, et al. 2009. Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese. J. Allergy Clin. Immunol. 124(3):478-84
130. Saitoh T, Kusunoki T, YaoT, KawanoK,Kojima Y, et al. 2010. Role of interleukin-17A in the eosinophil accumulation and mucosal remodeling in chronic rhinosinusitis with nasal polyps associated with asthma. Int. Arch. Allergy Immunol. 151(1):8-16
131. Shen Y, Pan CK, Tang XY, Yang YC, Ke X, et al. 2011. Significance of interleukin-17A in patients with nasal polyposis. Asian Pac. J. Allergy Immunol. 29(2):169-75
132. Cao PP, Zhang YN, Liao B, Ma J, Wang BF, et al. 2014. Increased local IgE production induced by common aeroallergens and phenotypic alteration of mast cells in Chinese eosinophilic, but not noneosinophilic, chronic rhinosinusitis with nasal polyps. Clin. Exp. Allergy 44(5):690-700
133. Ho J, Bailey M, Zaunders J, Mrad N, Sacks R, et al. 2015. Cellular comparison of sinus mucosa versus polyp tissue from a single sinus cavity in chronic rhinosinusitis. Int. Forum Allergy Rhinol. 5(1):14-27
134. Jin J, Chang DY, Kim SH, Rha KS, Mo JH, et al. 2014. Role of hypoxia-inducible factor-1α expression in regulatory T cells on nasal polypogenesis. Laryngoscope 124(5):151-59
135. Van BruaeneN, Perez-Novo CA, Basinski TM, Van Zele T, Holtappels G, et al. 2008. T-cell regulation in chronic paranasal sinus disease. J. Allergy Clin. Immunol. 121(6):1435-41
136. Bachert C, Wagenmann M, Hauser U, Rudack C. 1997. IL-5 synthesis is upregulated in human nasal polyp tissue. J. Allergy Clin. Immunol. 99(6):837-42
137. Bolard F, Gosset P, Lamblin C, Bergoin C, Tonnel AB, et al. 2001. Cell and cytokine profiles in nasal secretions from patients with nasal polyposis: effects of topical steroids and surgical treatment. Allergy 56(4):333-38
138. Kim YM, Munoz A, Hwang PH, Nadeau KC. 2010. Migration of regulatory T cells toward airway epithelial cells is impaired in chronic rhinosinusitis with nasal polyposis. Clin. Immunol. 137(1):111-21
139. Riechelmann H, Deutschle T, Rozsasi A, Keck T, Polzehl D, et al. 2005. Nasal biomarker profiles in acute and chronic rhinosinusitis. Clin. Exp. Allergy 35(9):1186-91
140. Lan F, Zhang N, Zhang J, Krysko O, Zhang Q, et al. 2013. Forkhead box protein 3 in human nasal polyp regulatory T cells is regulated by the protein suppressor of cytokine signaling 3. J. Allergy Clin. Immunol. 132(6):1314-21
141. Liu T, Song CH, Liu AM, Xie C, Zhao F, et al. 2011. Forkhead box P3+ T cells express interleukin-17 in nasal mucosa of patients with both allergic rhinitis and polyposis. Clin. Exp. Immunol. 163(1):59-64
142. Oakley GM,CurtinK,Orb Q, Schaefer C, Orlandi RR, et al. 2015. Familial risk of chronic rhinosinusitis with and without nasal polyposis: genetics or environment. Int. Forum Allergy Rhinol. 5(4):276-82
143. Padia R, Curtin K, Peterson K, Orlandi RR, Alt J. 2016. Eosinophilic esophagitis strongly linked to chronic rhinosinusitis. Laryngoscope 126(6):1279-83
144. Hsu J, Avila PC, Kern RC, Hayes MG, Schleimer RP, et al. 2013. Genetics of chronic rhinosinusitis: state of the field and directions forward. J. Allergy Clin. Immunol. 131(4):977-93
145. Pinto JM, Hayes MG, Schneider D, Naclerio RM, Ober C. 2008. A genomewide screen for chronic rhinosinusitis genes identifies a locus on chromosome 7q. Laryngoscope 118(11):2067-72
146. Wang X, Moylan B, Leopold DA, Kim J, Rubenstein RC, et al. 2000. Mutation in the gene responsible for cystic fibrosis and predisposition to chronic rhinosinusitis in the general population. JAMA 284(14):1814-19
147. Bosse Y, Bacot F, Montpetit A, Rung J, Qu HQ, et al. 2009. Identification of susceptibility genes for complex diseases using pooling-based genome-wide association scans. Hum. Genet. 125(3):305-18
148. Mygind N, Dahl R, Bachert C. 2000. Nasal polyposis, eosinophil dominated inflammation, and allergy. Thorax 55(Suppl. 2):S79-83
149. Schleimer R, Kato A, Kern RC. 2012. Eosinophils and chronic rhinosinusitis. In Eosinophils in Health and Disease, ed. JJ Lee, H Rosenberg, pp 508-519. London: Elsevier
150. Tokunaga T, SakashitaM,HarunaT, Asaka D, Takeno S, et al. 2015. Novel scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC Study. Allergy 70(8):995-1003
151. George L, BrightlingCE. 2016. Eosinophilic airway inflammation: role in asthma and chronic obstructive pulmonary disease. Ther. Adv. Chronic Dis. 7(1):34-51
152. Lee JJ, Jacobsen EA, McGarry MP, Schleimer RP, Lee NA. 2010. Eosinophils in health and disease: the LIAR hypothesis. Clin. Exp. Allergy 40(4):563-75
153. Postma DS, Rabe KF. 2015. The asthma-COPD overlap syndrome. N. Engl. J. Med. 373(13):1241-49
154. Lavin J, Meen E, Lam K, Kato A, Huang H, et al. 2013. The impact and nature of inflammation in the olfactory cleft on olfaction in patients with chronic rhinosinusitis. J. Allergy Clin. Immunol. 131(2): AB59
155. Yoshimura K, Kawata R, Haruna S, Moriyama H, Hirakawa K, et al. 2011. Clinical epidemiological study of 553 patients with chronic rhinosinusitis in Japan. Allergol. Int. 60(4):491-96
156. Wang ET, Zheng Y, Liu PF, Guo LJ. 2014. Eosinophilic chronic rhinosinusitis in East Asians. World J. Clin. Cases 2(12):873-82
157. Kim SJ, Lee KH, Kim SW, Cho JS, Park YK, et al. 2013. Changes in histological features of nasal polyps in a Korean population over a 17-year period. Otolaryngol. Head Neck Surg. 149(3):431-37
158. Hu Y, Cao PP, Liang GT, Cui YH, Liu Z. 2012. Diagnostic significance of blood eosinophil count in eosinophilic chronic rhinosinusitis with nasal polyps in Chinese adults. Laryngoscope 122(3):498-503
159. Katotomichelakis M, Tantilipikorn P, Holtappels G, De Ruyck N, Feng L, et al. 2013. Inflammatory patterns in upper airway disease in the same geographical area may change over time. Am. J. Rhinol. Allergy 27(5):354-60
160. Matsusaka M, Kabata H, Fukunaga K, Suzuki Y, Masaki K, et al. 2015. Phenotype of asthma related with high serum periostin levels. Allergol. Int. 64(2):175-80
161. Mahdavinia M, Suh LA, Carter RG, Stevens WW, Norton JE, et al. 2015. Increased noneosinophilic nasal polyps in chronic rhinosinusitis in US second-generation Asians suggest genetic regulation of eosinophilia. J. Allergy Clin. Immunol.135(2):576-79
162. Alexander ES, Martin LJ, Collins MH, Kottyan LC, Sucharew H, et al. 2014. Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis. J. Allergy Clin. Immunol. 134(5):1084-92
163. Rothenberg ME. 2009. Biology and treatment of eosinophilic esophagitis. Gastroenterology 137(4):1238-49
164. Leong AB, Ramsey CD, Celedon JC. 2012. The challenge of asthma in minority populations. Clin. Rev. Allergy Immunol. 43(1-2):156-83
165. Pino-Yanes M, Thakur N, Gignoux CR, Galanter JM, Roth LA, et al. 2015. Genetic ancestry influences asthma susceptibility and lung function among Latinos. J. Allergy Clin. Immunol. 135(1):228-35
166. Soler ZM, Mace JC, Litvack JR, Smith TL. 2012. Chronic rhinosinusitis, race, and ethnicity. Am. J. Rhinol. Allergy 26(2):110-16
167. Mahdavinia M, Benhammuda M, Codispoti CD, Tobin MC, Losavio PS, et al. 2016. African American patients with chronic rhinosinusitis have a distinct phenotype of polyposis associated with increased asthma hospitalization. J. Allergy Clin. Immunol. Pract. 4(4):658-64
168. Pinto JM, Schneider J, Perez R, DeTineo M, Baroody FM, et al. 2008. Serum 25-hydroxyvitamin D levels are lower in urban African American subjects with chronic rhinosinusitis. J. Allergy Clin. Immunol. 122(2):415-17
169. Bush CM, Jang DW, Champagne JP, Kountakis SE. 2013. Epidemiologic factors and surgical outcomes in patients with nasal polyposis and asthma. ORL J. Otorhinolaryngol. Relat. Spec. 75(6):320-24
170. Ponikau JU, Sherris DA, Kephart GM, Adolphson C, Kita H. 2006. The role of ubiquitous airborne fungi in chronic rhinosinusitis. Clin. Rev. Allergy Immunol. 30(3):187-94
171. Fokkens WJ, van Drunen C, Georgalas C, Ebbens F. 2012. Role of fungi in pathogenesis of chronic rhinosinusitis: the hypothesis rejected. Curr. Opin. Otolaryngol. Head Neck Surg. 20(1):19-23
172. Bachert C, Gevaert P, van Cauwenberge P. 2002. Staphylococcus aureus enterotoxins: A key in airway disease? Allergy 57(6):480-87
173. Ramadan HH, Sanclement JA, Thomas JG. 2005. Chronic rhinosinusitis and biofilms. Otolaryngol. Head Neck Surg. 132(3):414-17
174. Sanderson AR, Leid JG, Hunsaker D. 2006. Bacterial biofilms on the sinus mucosa of human subjects with chronic rhinosinusitis. Laryngoscope 116(7):1121-26
175. Rank MA, Wollan P, Kita H, Yawn BP. 2010. Acute exacerbations of chronic rhinosinusitis occur in a distinct seasonal pattern. J. Allergy Clin. Immunol. 126(1):168-69
176. Chalermwatanachai T, Velasquez LC, Bachert C. 2015. The microbiome of the upper airways: focus on chronic rhinosinusitis. World Allergy Organ. J. 8(1):3
177. Mahdavinia M, Keshavarzian A, Tobin MC, Landay AL, Schleimer RP. 2016. A comprehensive review of the nasal microbiome in chronic rhinosinusitis (CRS). Clin. Exp. Allergy 46(1):21-41
178. Bachert C, Holtappels G. 2015. Pathophysiology of chronic rhinosinusitis, pharmaceutical therapy options. GMS Curr. Top. Otorhinolaryngol. Head Neck Surg. 14:Doc09
179. Gevaert P, Calus L, Van Zele T, Blomme K, De RuyckN, et al. 2013. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J. Allergy Clin. Immunol. 131(1):110-16
180. KiwamotoT, KawasakiN,Paulson JC,BochnerBS. 2012. Siglec-8 as a drugable target to treat eosinophil and mast cell-associated conditions. Pharmacol. Ther. 135(3):327-36
181. Krug N, Hohlfeld JM, Kirsten AM, Kornmann O, Beeh KM, et al. 2015. Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme. N. Engl. J. Med. 372(21):1987-95
182. Ly TW, Bacon KB. 2005. Small-molecule CRTH2 antagonists for the treatment of allergic inflammation: an overview. Expert Opin. Investig. Drugs 14(7):769-73
183. Markham A. 2016. Reslizumab: first global approval. Drugs 76(8):907-11. Erratum. 2016. Drugs 76(11):1159
184. CastroM,Wenzel SE, Bleecker ER, Pizzichini E, Kuna P, et al. 2014. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir. Med. 2(11):879-90
185. Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, et al. 2011. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365(12):1088-98
186. Schwartz DM, Bonelli M, Gadina M, O'Shea JJ. 2016. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat. Rev. Rheumatol. 12(1):25-36