Role of allergy and mucosal inflammation in nasal polyps and chronic sinusitis 3

Chapter 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 Both specific and nonspecific immunity play important roles in protecting the host against microorganism infection The central role of lymphocytes in adaptive immunity was discussed in chapter The NK cell (natural killer cell) is an important cell in innate immunity CD4+ and CD8+ T cells, B cells and NK cells are all differentiated from pluripotent stem cells in bone marrow under the influence of varieties of soluble factors The proportion of T cells, B cells and NK cells in peripheral blood lymphocytes is about 75%, 10% and 15%, respectively.1 CD4+ (CD3+, CD4+, CD8-) T cells recognize class II MHC (major histocompatibility complex) molecules whereas CD8+ (CD3+, CD4-, CD8+) T cells recognize MHC class I molecules The CD3 T cell receptor (alpha, beta, gamma, delta) is absent from NK cells CD56 is the marker which differentiates NK cell from other non-T lymphocytes in humans There is also a lymphocyte subset called NKT cells This type expresses both TCR (α and β chains) and NK1.1+ marker It is thought to account for 20%-30% of the lymphocyte population in bone marrow and liver and is able to secrete IL-4 as well as INF-γ when activated 3.1.2 The Role of NK Cells in Innate and Adaptive Immunity The NK cell is a large granulated lymphocyte customarily defined as ‘a lymphocyte 256 found in the blood of normal individuals which is capable of lysing tumor cell lines in the apparent absence of disease, prior sensitization, or deliberate immunization’.2 The mechanisms by which NK cells function in innate immunity has been well defined It has the ability to recognize and induce lysis of target cells, such as infected cells, tumor cells and allogeneic cells without prior sensitization In addition, NK cell may eliminate target cells through antibody-dependent cellular cytotoxicity (ADCC) which is also involved in adaptive immunity NK cells are also the source of varieties of cytokines and chemokines In addition to its well known role in INF-γ and TNF-α production in viral infections, it can also secrete IL-5 which may contribute to eosinophil inflammation.3 The proliferation and maturation of NK cell is under the influence of multiple chemical mediators, including IL-2, IL-15, IL-12 and IL-18.3 Chemokines have been proven to play a critical role in NK cell recruitment and activation.4,5 These chemokines include CC chemokines, such as monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3, RANTES, macrophage inflammatory protein-1 (MIP-1α), and MIP-1β; as well as CXC chemokines, such as IL-8 and IP-10 For example, it has been proven that in invasive Aspergilosis, chemokine-mediated NK cell recruitment may provide the first line of host defense When designated CC chemokine ligand-2 (MCP-1/CCL2) neutralizes monocyte chemotactic protein-1, a decreased infiltration of NK cells is induced, but not in other leukocytes.6 257 There is a complicated interplay between NK cells and professional phagocytes, i.e., neutrophils, macrophages and dendritic cells, either directly or through the role of chemical mediators Neutrophil derived chemokines have a potential role in NK cell recruitment and activation.4,5 NK cells may induce activation of macrophages through the role of INF-γ,7 whereas IL-12 secreted from macrophages will upregulate NK cell proliferation and maturation.8 The dendritic cell (DC) is the link between innate and adaptive immunity, acting both as a professional phagocyte and an antigen presenting cell Through the process of uptake and presentation of an antigen, an immature DC becomes a mature DC, leading to activation of naïve and memory CD4+ and CD8+ T cells Upon microbial encounter, DC will release IL-2 at an early phase, thus mediating NK cell and B cell activation as well as T cell responses.9,10 On the other hand, DC-activated NK cells efficiently kill immature DCs through the NKp30 natural cytotoxicity receptor.11 In addition, when the NK cell is activated by virus-infected cells with low expression of MHC class I, it will prime the secretion of IL-12 from DC through INF-γ dependent signals.12 This will result in cytotoxic T lymphocytes (CTL) response Thus, the innate immune response of NK cell will also lead to an adaptive response 3.1.3 NK Cells in Nasal Polyp and Chronic Sinusitis Nasal polyp and chronic sinusitis exhibit chronic inflammation Patients often show recurrent and persistent infection Although the role of CD4+ and CD8+ T cells has been suggested to contribute to the pathogenesis of nasal polyps and chronic sinusitis, 258 studies of the role of NK cell and its function in the two diseases are lacking In normal nasal mucosa, lymphocytes are mainly CD4+ and CD8+ T cells, whereas NK cells were reported to account for less than 2% of the total amount of lymphocytes.13 It was reported that in nasal polyps and chronic sinusitis, there was no change in the proportion of NK cells.14,15 There are also case reports of patients with dysfunction of NK cells and pansinusitis, or nasal polyps together with recurrent infection.16,17 Taken together, although a dysfunction of NK cells may lead to persistent or recurrent infection, there is no study identifying NK cells as an important inflammatory cell in nasal polyps or chronic sinusitis 3.2 Aim of Study In chapter 2, we discussed the important role of T cells in the pathogenesis of nasal polyps and chronic sinusitis An inverse CD4+/CD8+ T cell ratio in nasal polyp or inflamed sinus mucosa compared to controls suggests a T cell disorder CD8+ T cell may act as a suppressive and a specific cytotoxic T cell against infection In addition, a previous study reported upregulation of IL-2, which is a growth factor for NK cells in nasal polyp tissue.18 The infiltration of the macrophage, an important cell in innate immunity, has been demonstrated in nasal polyps and inflamed sinus mucosa in many studies.19-21 These studies as well as our results from the inflammatory cell pattern study (chapter 2) initiated our interest in the role of NK cells in the development of nasal polyps and chronic sinusitis The aim of our study is to investigate the involvement of NK cells in the chronic inflammation of nasal polyps and chronic 259 sinusitis; to explore its correlation with other inflammatory cell infiltration, i.e., CD8+ T cells, CD4+ T cells, eosinophils, neutrophils and mast cells; and to explore its correlation with other medical conditions 3.3 Methodology 3.3.1 Study Patients Patients with nasal polyps and chronic sinusitis, allergic rhinitis and non-atopic, nonrhinitis controls were randomly selected for this study from the department of Otolaryngology, Head & Neck Surgery in the National University Hospital of Singapore Working definitions used are shown in chapter 2.3.1 Information of the study groups was summarized in Table 46 I Thirteen patients, nine males and four females, aged from 21 to 58 years (mean age 47) with unilateral/bilateral nasal polyps, who were scheduled for functional endoscopic sinus surgery The diagnosis of nasal polyps was based on medical history and clinical examinations, including nasal endoscopic examination and CT scan II Nine patients, eight males and one female, aged from 20 to 64 years (mean age 38) with unilateral/bilateral chronic sinusitis, who were scheduled for functional endoscopic sinus surgery in our department The diagnosis of chronic sinusitis was based on medical history and clinical examinations, including nasal endoscopic examination and CT scan 260 III Eleven patients, all males, aged from 13 to 55 years (mean age 28) with allergic rhinitis, who were scheduled for septal surgery in our department These patients had no history of chronic sinusitis or nasal polyps IV A control group of five non-rhinitis, non-atopic patients, three males and two females, aged from 19 to 68 years (mean age 40), with septal deviation who were scheduled for septal plastic surgery Patients with nasal polyps, sinusitis, allergic rhinitis and atopy were excluded All patients had a trial of intranasal glucocorticosteroids spray but did not show a symptomatic relief of their symptoms Their medication was discontinued for more than one month prior to the surgery.22,23 A signed informed consent was obtained from the study patients before surgery Approval to conduct this study was granted by the National Medical Research Council of Singapore and the institutional review board of the Medical Faculty of National University of Singapore Table 46 Patient groups in the study of natrul killer cells Patient group Mean age Number of patients Male/Female Nasal polyps 47 13 9/4 Chronic sinusitis 38 8/1 Allergic rhinitis 28 11 11/0 Control patients 40 3/2 261 3.3.2 Method 3.3.2.1 Immunohistochemistry A nasal polyp tissue/inflamed sinus mucosa biopsy was obtained from all patients with nasal polyps/chronic sinusitis during surgery One biopsy sample was taken from the middle turbinate of allergic rhinitis and control patients during septal plastic surgery The specimens were embedded in tissue a freezing medium (Leica Instruments GmbH) in liquid nitrogen immediately after resection The frozen samples were kept at -80°C for further study Immunohistochemical staining was applied according to the protocol described in chapter 2.3.3.2 CD56/NCAM-1 Ab-1 (Lab Vision NeoMarker, clone ERIC-1) was used for NK cell staining Meanwhile, a series of antibodies was used to investigate the involvement of CD4+ and CD8+ T cells, eosinophils, neutrophils sand mast cells The monoclonal antibodies used for these cells were described in Table 9, chapter2 To test the specificity of CD56/NCAM-1 Ab-1, immunohistochemical staining of fresh human tonsils by CD56/NCAM-1 Ab-1 together with anti-CD3 (Lab Vision NeoMarker, Rabbit anti-human monoclonal CD3, clone SP7) was applied The CD56/NCAM-1 Ab-1 was shown to be specific for CD3- NK cell but not for CD3+ NKT cell Positive cells stained with peroxidase-labeled monoclonal antibody on cell membrane were counted under a light microscope at 400 times magnification Three areas with high intensity of positive cell distribution were selected in each section The cell numbers of the three areas were averaged 262 3.3.2.2 Allergy Test Three milliliters of peripheral blood was taken during the surgery Serum total IgE (tIgE) and specific IgE (sIgE) to a common panel of inhalant allergens, including dust mite (Dermatophagoides pteronyssinus, Dermatophagoides farinae), cockroach, common pollen and ragweed mixtures (Bermuda grass, Ambrosia artemisiifolia, Ambrosia elatior), common mould and yeast mixtures (Aspergillus fumigatus, Penicillum notatum, Cladosporium herbarum, Candida albicans, Alternaria tenius), and food (egg white, milk, codfish, peanut, soybean) were determined using the ImmunoCAP system Patients with sIgE ≥0.35 IU/ml to at least one of the testing allergens were considered as atopic 3.3.2.3 Statistics A standard personal computer with SPSS (Statistical Package for the Social Sciences) 11.5 software (SPSS, Inc., Chicago, Illinois, US) was used for the statistical evaluation of the results In all the tests, a P value of less than 0.05 was regarded as significant I One-sample t test was used to test the normality of cell counting II Pearson’s correlation was used for the analysis of the correlations between CD56+ NK cells and other inflammatory cells, i.e., CD4+ and CD8+ T cells, eosinophils, neutrophils and mast cells; and of the correlations between NK cells and tIgE or sIgE to common allergens tested A correlation coefficient above was taken to be a positive correlation; 0-0.3 263 a weak correlation, 0.3-0.5 a medium correlation, and above 0.5 a strong correlation III Mann-Whitney test was used to compare the infiltration of NK cells with the infiltration of other inflammatory cells in the same sample; the NK cell numbers in patients with and without atopy; and the NK cell numbers in patients in different study groups, i.e., nasal polyps, chronic sinusitis, allergic rhinitis patients and controls 3.4 Results 3.4.1 Allergy test All of our study patients were Asians In the nasal polyp group, there were seven Chinese, two Malays, three Indians and one Philippino In the chronic sinusitis group, there were one Indian and eight Chinese In the allergic rhinitis group, there were seven Chinese, three Indians and one Malay In the control group, there were three Chinese, one Malay and one Indian All the patients in the nasal polyp, chronic sinusitis and allergic rhinitis groups made serum available for allergy test In the control group, serum was only made available by three patients The percentage of patients with high levels of total serum IgE (tIgE ≥100 IU/ml) and atopy (diagnosis criteria: at least has one serum specific IgE ≥0.35 IU/ml to the common allergens tested) is shown in Table 47 264 Table 47 Percentage of a high level of tIgE (tIgE≥100 IU/ml) and atopy of nasal polyp patients (n=13), chronic sinusitis patients (n=9), allergic rhinitis patients (n=11) and controls (n=3) Group Total IgE (≥100 IU/ml) Atopy Nasal polyp (38.5%) (38.5%) Chronic sinusitis (55.6%) (44.4%) Allergic rhinitis (72.7%) 11 (100%) Controls 0 3.4.2 Specificity Control A B Figure 30 Immunohistochemistry staining of a human tonsil with anti-CD56 and anti-CD3 antibodies (light microscope 100 times magnification) A Staining with anti-CD56 B Staining with anti-CD3 265 studies have suggested that the incidence of immuno disturbance in chronic sinusitis may be underestimated Therefore, further studies of systemic examinations of the patients, especially blood tests, may be of great help to understand the predisposing factors of the development of nasal polyps and chronic sinusitis T rubrum, an inhalant allergen? The discrepancy between serum specific IgE to T rubrum and lack of langerhans cells or increased mast cell levels may be due to prior sensitization though nail or skin rather than the airway Therefore, it was strongly suggested that all our nasal polyp and chronic sinusitis patients should be carefully examined by dermatologists with a fungal culture to test the involved species Further study to raise polyclonal antibodies against the antigens of interest will help us to evaluate the presence of T rubrum in the actual tissues, including nail and skin tissues, and especially nasal polyp or inflamed sinus mucosa Immunohistochemistry study of diseased skin or nail tissue caused by trichophytosis may help us to understand the development of the T rubrum infection, including the question whether the theory of superantigen is applicable or not Sti35 and 1, 3-β-glucanosyltransferase, promising antigens for understanding biological functions of T rubrum and vaccine development Due to the short amino acids sequence determined by N-terminal sequencing, 374 homologus information was quite limited in our study A good match would be one that would have more than one peak matching the sequence of the interest As discussed in chapter 5.6.2.6, most eukaryotic cells are blocked as a result of posttranslational modification Deblocking the protein or internal sequencing may provide important homologous information The antigenecity of proteins from T rubrum is quite consistent in our study The function of the heat shock protein and 1, 3-β-glucanosyltransferase, although highly conserved in eukaryotes, are not well characterized Because of the lack of a database, cDNA clone of the allergens is necessary In vivo and in vitro tests, such as lymphocyte challenge with crude extract, and recombinant proteins will give important information on immuno reactions caused by sti35 and 1, 3-βglucanosyltransferase, including and their unique features in T rubrum or common features conserved by other eukaryotes Also, studies in normal controls may provide important information on different host reactions to the same allergen In addition, vaccine developed based on the recombinant proteins may be very promising in the treatment of nasal polyps and chronic sinusitis 375 Reference List Stewart GA, Robinson C Allergen structure and function In: Adkinson NF, Yunginger JW, Busse WW, Bochner BS, Holgate ST, Simons FR, editors Middleton's allergy principles & practice St Louis : Mosby: 2003: 585-609 Morpeth JF, Rupp NT, Dolen WK, Bent JP, Kuhn FA Fungal sinusitis: an update Ann Allergy Asthma Immunol 1996; 76(2):128-139 Stroud RH, Calhoun KH, Wright ST, Kennedy KL Prevalence of hypersensitivity to specific fungal allergens as determined by intradermal dilutional testing Otolaryngol Head Neck Surg 2001; 125(5):491-494 Marple BF Allergic fungal rhinosinusitis: current theories and management strategies Laryngoscope 2001; 111(6):1006-1019 Ponikau JU, Sherris DA, Kern EB, Homburger HA, Frigas E, Gaffey TA et al The diagnosis and incidence of allergic fungal sinusitis Mayo Clin Proc 1999; 74(9):877-884 Gutman M, Torres A, Keen KJ, Houser SM Prevalence of allergy in patients with chronic rhinosinusitis Otolaryngol Head Neck Surg 2004; 130(5):545-552 Rupa V, Jacob M, Mathews MS, Job A, Kurien M, Chandi SM Clinicopathological and mycological spectrum of allergic fungal sinusitis in South India Mycoses 2002; 45(9-10):364-367 Asero R, Bottazzi G Nasal polyposis: a study of its association with airborne allergen hypersensitivity Ann Allergy Asthma Immunol 2001; 86(3):283-285 Noble JA, Crow SA, Ahearn DG, Kuhn FA Allergic fungal sinusitis in the southeastern USA: involvement of a new agent Epicoccum nigrum Ehrenb ex Schlecht 1824 J Med Vet Mycol 1997; 35(6):405-409 10 Braun H, Buzina W, Freudenschuss K, Beham A, Stammberger H 'Eosinophilic fungal rhinosinusitis': a common disorder in Europe? 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11(2):344-350 388 ... association of allergy in the pathogenesis of nasal 287 polyps and chronic sinusitis Whether allergy plays a cause -and- effect role in the pathogenesis of nasal polyps and chronic sinusitis remains controversial... 2) initiated our interest in the role of NK cells in the development of nasal polyps and chronic sinusitis The aim of our study is to investigate the involvement of NK cells in the chronic inflammation. .. of allergy and understanding its role in the pathogenesis of nasal polyps and chronic sinusitis 4 .3 Methodology 4 .3. 1 Study Patients Four groups of patients are included in this study Their information