ROLE OF ALLERGY AND MUCOSAL INFLAMMATION IN NASAL POLYPS AND CHRONIC SINUSITIS HAO JING NATIONAL UNIVERSITY OF SINGAPORE 2004 ROLE OF ALLERGY AND MUCOSAL INFLAMMATION IN NASAL POLYPS AND CHRONIC SINUSITIS HAO JING （Bachelor of Medicine, Tianjin Medical University） A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF OTOLARYNGOLOGY NATIONAL UNIVERSITY OF SINGAPORE 2004 Acknowledgments I would like to thank my supervisor, Dr. Wang De-Yun, for his guidance throughout my years of study in the National University of Singapore. I am also very grateful to Dr. Pang Yoke-Teen, without his help in collecting samples from clinics, my study would have been impossible. I wish to thank A/Prof Luke Tan (Head) and Prof Yeoh Kian Hian (former head) of the department for giving me the opportunity to work in our department. I would also like to thank all colleagues and administrative staff in our department for their kind help and assistance in my study. I want to thank Dr. Chew Fook-Tim and the following individuals in his group: Dr Shang Huishen, Dr. Bi Xuezhi, Wang Xiaoshan, Ong Tan Ching, Gao Yunfeng and so many others. Thank you so much for helping me out in my experiments. It has been a pleasure to work and share happiness together with you all. I wish to thank Professor Ling Eng Ang from department of Anatomy for giving me the opportunity to practice immunohistochemistry in his lab. My gratitude also goes to Mr. Ow Cheok Kee from the department of Pathology for his help in the establishment of our immunohistochemistry procedures. i I would like to thank all of my friends and colleagues, especially Li Xiujin, Chen Zhiqiang, Zhang Pengchi, Ouyang Hongwei, Foong Kok Heng, Liang Xiaohui, Li Chunwei and all the others. Thank you for your friendship. I would like to thank Professor Alan Kerr for kindly reviewing my paper. I owe a big thanks to Madam Christina for her kind help in the revision of my thesis. Lastly, I want to thank the National Medical Research Council (NMRC) of Singapore for the research grant (NMRC 0396/1999) which funded the work described in this thesis. I dedicate this thesis to my family. Thanks for standing by me all the way. Hao Jing 2004, Singapore ii Table of Contents Summary vii List of Tables x List of Figures xvi List of Abbreviations xxi Illustration of Contents xxv Publications and Presentations at Conferences xxvi Chapter 1. Nasal polyps and chronic sinusitis: state of the art 1.1 Anatomy and physiology of the nose 1.2 Prevalence of nasal polyps and chronic sinusitis 1.2.1 Nasal polyps, a disease with a long history 1.2.2 Prevalence of nasal polyps 1.2.3 Prevalence of chronic sinusitis 1.3 Nasal polyps and chronic sinusitis: multi-factorial diseases 1.3.1 Diseases related with nasal polyps 1.3.2 Diseases related with chronic sinusitis 1.4 Diagnosis of nasal polyps and chronic sinusitis 1.4.1 Diagnosis of nasal polyps 1.4.2 Diagnosis of chronic sinusitis 1.5 Histopathology of nasal polyps and chronic sinusitis 1.5.1 Histology of nasal polyps 1.5.2 Histology of chronic sinusitis 1.6 Pathogenesis of nasal polyps and chronic sinusitis 1.6.1 Pathogenesis of nasal polyps and chronic sinusitis 1.6.2 Inflammatory cell and chemical mediators in nasal polyps and chronic sinusitis 1.7 Treatment of nasal polyps and chronic sinusitis 1.7.1 Treatment of nasal polyps 1.7.2 Treatment of chronic sinusitis Reference list 1 3 8 25 30 30 34 39 39 41 42 43 56 Chapter 2. Inflammatory cell patterns in nasal polyps and chronic sinusitis 2.1 Introduction 2.2 Aim of study 2.2.1 Hypothesis 2.2.2 Specific aims 135 94 95 98 100 135 136 136 137 iii 2.3 Methodology 2.3.1 Working definitions 2.3.2 Study patients 2.3.3 Immunohistochemical study 2.3.4 Allergy test 2.3.5 Statistical analysis 2.4 Histology, etiology and serum IgE 2.4.1 Quality control staining for CD4+ and CD8+ T cells 2.4.2 Histopathology changes 2.4.3 Etiology of nasal polyps 2.4.4 Etiology of chronic sinusitis 2.5 Inflammatory cell scores in nasal polyps and chronic sinusitis 2.5.1 Inflammatory cell scores in nasal polyps and its paired middle turbinate, and middle turbinate of allergic rhinitis patients and controls 2.5.2 Inflammatory cell scores in inflamed sinus mucosa and its paired middle turbinate, middle turbinate from allergic rhinitis patients and controls 2.5.3 Inflammatory cell scores in the six patients with nasal polyp tissue, inflamed sinus mucosa and middle turbinate from the same side 2.6 Exact cell count of CD4+ and CD8+ T cells 2.6.1 CD4+ and CD8+ T cell numbers in nasal polyps 2.6.2 CD4+ and CD8+ T cell numbers in chronic sinusitis 2.7 Key results 2.7.1 Atopy and tIgE 2.7.2 Inflammatory cell scores in paired samples 2.7.3 Cell scores of nasal polyps and chronic sinusitis compared with allergic rhinitis and controls 2.7.4 Inflammatory cell scores comparison between nasal polyp and chronic sinusitis patients 2.7.5 CD4+ and CD8+ T cell numbers in nasal polyps and chronic sinusitis 2.8 Discussion 2.8.1 The role of inflammatory cells in the pathogenesis of nasal polyps 2.8.2 The role of inflammatory cells in the pathogenesis of chronic sinusitis 2.8.3 Relationship between nasal polyps and chronic sinusitis 2.8.4 Does persistent allergic rhinitis predispose for nasal polyps and chronic sinusitis? 2.9 Conclusion Reference list 138 138 139 141 144 145 147 147 148 149 151 152 152 173 190 194 194 204 211 211 211 212 216 220 223 225 233 238 240 246 247 iv Chapter 3. Role of natural killer cell in the pathogenesis of nasal polyps and chronic sinusitis 3.1 Biology of natural killer cells 3.1.1 Lymphocytes in innate and adaptive immunity 3.1.2 The role of NK cells in innate and adaptive immunity 3.1.3 NK cells in nasal polyps and chronic sinusitis 3.2 Aim of study 3.3 Methodology 3.3.1 Study patients 3.3.2 Method 3.4 Results 3.4.1 Allergy test 3.4.2 Specificity control 3.4.3 Correlation of NK cell with tIgE and sIgE 3.4.4 NK cell and other inflammatory cells in the same sample 3.4.5 NK cells in patients with and without atopy 3.4.6 NK cells in different study groups 3.4.7 Percentage of NK cells in total lymphocytes in different study groups 3.5 Discussion Reference list Chapter 4. Evaluating the association of IgE-mediated allergy in the pathogenesis of nasal polyps and chronic sinusitis by an immunodot blot array system 4.1 Testing for IgE-mediated allergy, a review 4.1.1 Allergy and IgE 4.1.2 Diagnosis of allergy 4.2 Aim of study 4.3 Methodology 4.3.1 Study patients 4.3.2 Immunoarray system 4.3.3 Determination of sIgE to Trichophyton rubrum by the ImmunoCAP system 4.3.4 Determination of sIgE to Trichophyton rubrum by ELISA 4.3.5 Statistical analysis 4.4 Result 4.4.1 Optimization of supporting media 4.4.2 Evaluation of transfer efficiency 4.4.3 Optimization of washing buffer 4.4.4 Validation of the immunoarray system 4.4.5 Common allergens identified in the study groups 256 256 256 256 258 259 260 260 262 264 264 265 266 266 269 269 272 273 279 283 283 283 286 287 288 288 289 299 299 299 300 300 300 301 302 306 v 4.4.6 Quantified sIgE to Trichophyton rubrum in nasal polyp and chronic sinusitis patients via ImmunoCAP 4.4.7 Quantified sIgE to Trichophyton rubrum in nasal polyp and chronic sinusitis patients via ELISA 4.5 Discussion Reference list Chapter 5. The involvement of Trichophyton rubrum in the pathogenesis of nasal polyps and chronic sinusitis 5.1 Role of fungi in the pathogenesis of nasal polyps and chronic sinusitis 5.1.1 Incidence of allergic fungal sinusitis (AFS) in nasal polyps and chronic sinusitis 5.1.2 Mechanism of AFS, IgE-Mediated allergy? 5.1.3 Superantigen, a rising theory in the pathogenesis of nasal polyps and chronic sinusitis 5.2 Epidemiology and biology of Trichophyton rubrum 5.2.1 Epidemiology of Trichophyton rubrum 5.2.2 Trichophyton rubrum related diseases 5.2.3 Role of Trichophyton rubrum in related diseases 5.3 Aim of study 5.4 Methodology 5.4.1 IgE Western blot 5.4.2 Protein identification by Micromass Q-ToF Tandem Mass spectrometer (Q-TOF™-MS/MS) 5.4.3 N-terminal sequencing of purified proteins by high-performance liquid chromatography (HPLC) 5.5 Results 5.5.1 One-dimensional SDS gel electrophoresis 5.5.2 IgE western blot of the study groups 5.5.3 IgE western blot to Trichophyton rubrum from different companies 5.5.4 Q-TOF™-MS/MS, HPLC and N-terminal sequencing 5.5.5 Homology identified by BLAST 5.6 Discussion 5.6.1 Evaluation of ImmunoCAP and commercial ELISA kit by western blot 5.6.2 Role of T. rubrum in the pathogenesis of nasal polyps and chronic sinusitis Conclusion and further studies proposed Conclusion Further studies proposed Reference list 306 306 308 311 312 312 312 314 315 319 319 320 323 330 330 330 336 341 342 342 343 350 350 354 356 357 357 370 370 373 376 vi Summary Background: Nasal polyps and chronic sinusitis are closely related diseases commonly identified worldwide. Their etiology and pathogenesis are still incompletely understood. Objective: To investigate the association between allergy and type of cellular inflammation in Asian patients with chronic sinusitis and/or nasal polyps. Methods: Immunohistochemical staining with a panel of antibodies against CD4+ and CD8+ T cells, B cells, Langerhans cells, mast cells, eosinophils, neutrophils, and natural killer (NK) cells was performed to investigate the pattern of cell present in nasal polyp tissue/inflamed sinus mucosa and the paired middle turbinate from the same side, as well as in middle turbinate from allergic rhinitis and control patients. Serum specific IgE (sIgE) levels to common local allergens were tested using the ImmunoCAP system. A self-developed immunoarray dot blot system was used to evaluate the presence of sIgE against a total of 185 allergens in nasal polyp, chronic sinusitis, allergic rhinitis and nonallergic rhinitis patients. Western blot experiments on the most important antigen source identified using sera nasal polyps and chronic sinusitis patients, Trichophyton rubrum, was carried out. Proteins with the strongest antigenicity were characterized by Q-TOF™-MS/MS. The proteins were further purified by HPLC and sent for N-terminal sequencing. Sequence alignment to the NCBI Genebank was performed by using the BLAST algorithm. Results: Cell scores were strongly correlated between the paired samples from nasal polyp patients. Nasal polyp and inflamed sinus mucosa showed a mixed cell pattern with significantly higher CD8+ T cells, eosinophils and neutrophils, a relatively vii higher percentage of NK cell, and an inverse median ratio of CD4+ and CD8+ T cells, as compared to the middle turbinate from control patients. The dot blot system revealed that Trichophyton rubrum was the most important allergen in nasal polyp and chronic sinusitis patients. A 15 kD and 60 kD of Trichophyton rubrum IgE reaction was shown to have the strongest allergenicity by western blot. These proteins showed homology to a 35 kD heat shock protein (sti35) and 1, 3-β-glucanosyltransferase of Fusarium spp. Conclusion: The similarity between the immunohistochemical cell pattern observed in nasal polyps and the paired middle turbinate suggested a diffuse mucosal inflammation. This is the first study that showed a combined inflammatory cell pattern in nasal polyps/inflamed sinus mucosa and adjacent middle turbinate, especially in Asian patients. This could explain the high recurrence rate of nasal polyps/chronic sinusitis, suggesting anti-inflammatory treatment of the adjacent mucosal is necessary in combination with a surgical removal of polyps/inflamed sinus mucosa. 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Curr Opin Otolaryngol Head Neck Surg 2003; 11(1):6-12. 134 [...]... the term sinusitis Lanza et al.27 in 1997 suggested a broader definition of sinusitis, including inflammation of the nasal cavity and paranasal sinuses and of the fluid within these cavities and/ or the underlying bone Sinusitis can be classified into acute, recurrent, subacute and chronic sinusitis which will be briefly introduced in chapter 1.4 Chronic sinusitis is one of the most common chronic diseases... mucosa 1.2 Prevalence of Nasal Polyps and Chronic Sinusitis Chronic sinusitis is one of the most common chronic diseases reported worldwide It is closely related to nasal polyps, as 20% of the patients with chronic sinusitis have nasal polyps while the incidence rate of chronic sinusitis in nasal polyps varies from 65% to 90%.7-9 The multitude of factors underlying these conditions and their high recurrence... diseases such as sinusitis, asthma, aspirin intolerance and cystic fibrosis The epidemiology of nasal polyps will be discussed further in chapter 1.3 1.2.3 Prevalence of Chronic Sinusitis Generally speaking, sinusitis is inflammation of paranasal sinuses Because of the 6 high frequency of coexistence of inflammation of the nasal cavity, it has also been suggested that the term “rhinosinusitis” should... Wang Role of allergy and inflammation in nasal polyposis and sinusitis (Poster) American Academy of otolaryngology, Head & Neck Surgery Annual Meeting, Orlando, USA, 21-14 September 2003 5 Hao J, Pang YT, Wang DY Role of allergy and inflammation in nasal polyps and sinusitis J Allergy Clin Immunol 2003 (Part 2); 111 (N 2) P589 Papers Submitted and in Preparation 1 Hao J, Pang YT, Wang DY A diffuse mucosal. ..allergenic to nasal polyp and chronic sinusitis patients Further studies on the interaction between these antigens and hosts with nasal polyps and chronic sinusitis will provide important information towards a better understand of the underlying pathogenesis Vaccine development based on the recombinant proteins may be promising potential in the treatment of nasal polyps and chronic sinusitis ix List of Tables... the presence of nasal polyps 9 Table 2 Similarities between nasal polyps and aspirin intolerance 12 Table 3 Etiologic factors of chronic sinusitis 27 Table 4 Classification of sinusitis 35 Table 5 Pathogenesis of nasal polyps 43 Table 6 Principle cell sources and main functions of major Th1 and Th2 cytokines 61 Table 7 Medical treatment of sinusitis 99 Table 8 Patient groups in the study of inflammatory... scores in nasal polyp, inflamed sinus mucosa and paired middle turbinate from the same side of the six patients with both nasal polyps and chronic sinusitis 190 xi List of Tables, Continued Table 26 Kendall’s W test exact significance (2-tailed) and coefficient of concordance of nasal polyp tissue, inflamed sinus mucosa and middle turbinate mucosa from the same side in patients with nasal polyps and chronic. .. the treatment of chronic sinusitis and nasal polyps complicated Understanding the pathogenesis of nasal polyps and chronic sinusitis is critical for treatment 1.2.1 Nasal Polyps, a Disease with a Long History Nasal polyps represent one of the most common mass lesions of the nose It is an outgrowth of nasal mucosa whose appearance is smooth, semitranslucent, gelatinous and pale (Figure 2) Polyps with... middle turbinate mucosa of allergic rhinitis patients (n=15) and controls (n=14) 208 Table 39 Median and interquartile range of CD4+/CD8+ T cell ratios in inflamed sinus mucosa and paired middle turbinate (n=20), middle turbinate from allergic rhinitis patients (n=15) and controls (n=14) 210 Table 40 Incidence rate of atopy in nasal polyps and chronic sinusitis patients and its correlation with inflammatory... healthy nasal cavity and nasal polyps 32 Figure 4 Coronal CT scans of a normal ostiomeatal and that of a patient with nasal polyps 33 Figure 5 Endoscopic view of left nasal cavity in a patient with chronic sinusitis 36 Figure 6 Coronal CT image of chronic sinusitis caused by obstruction of the anterior middle meatus 38 Figure 7 Quality controls of anti-CD4 and anti-CD8 antibodies staining in tonsils . ROLE OF ALLERGY AND MUCOSAL INFLAMMATION IN NASAL POLYPS AND CHRONIC SINUSITIS HAO JING NATIONAL UNIVERSITY OF SINGAPORE 2004 ROLE OF ALLERGY AND MUCOSAL INFLAMMATION. Pathogenesis of nasal polyps and chronic sinusitis 43 1.6.2 Inflammatory cell and chemical mediators in nasal 56 polyps and chronic sinusitis 1.7 Treatment of nasal polyps and chronic sinusitis. Histopathology of nasal polyps and chronic sinusitis 39 1.5.1 Histology of nasal polyps 39 1.5.2 Histology of chronic sinusitis 41 1.6 Pathogenesis of nasal polyps and chronic sinusitis 42 1.6.1