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? Laryngoscope 2003; 113(2):264-269 11 Lebowitz RA, Waltzman MN, Jacobs JB, Pearlman A, Tierno PM Isolation of fungi by standard laboratory methods in patients with chronic rhinosinusitis Laryngoscope 2002; 112(12):2189-2191 12 Catten MD, Murr AH, Goldstein JA, Mhatre AN, Lalwani AK Detection of fungi in the nasal mucosa using polymerase chain reaction Laryngoscope 2001; 111(3):399-403 13 Manning SC, Mabry RL, Schaefer SD, Close LG Evidence of IgE-mediated hypersensitivity in allergic fungal sinusitis Laryngoscope 1993; 103(7):717-721 14 Manning SC, Holman M Further evidence for allergic pathophysiology in allergic fungal sinusitis Laryngoscope 1998; 108(10):1485-1496 15 Stewart AE, Hunsaker DH Fungus-specific IgG and IgE in allergic fungal 376 rhinosinusitis Otolaryngol Head Neck Surg 2002; 127(4):324-332 16 Mabry RL, Marple BF, Mabry CS Mold testing by RAST and skin test methods in patients with allergic fungal sinusitis Otolaryngol Head Neck Surg 1999; 121(3):252-254 17 Corey JP, Delsupehe KG, Ferguson BJ Allergic fungal sinusitis: allergic, infectious, or both? Otolaryngol Head Neck Surg 1995; 113(1):110119 18 Dennis DP Chronic sinusitis: defective T-cells responding to superantigens, treated by reduction of fungi in the nose and air Arch Environ Health 2003; 58(7):433-441 19 Schubert MS A superantigen hypothesis for the pathogenesis of chronic hypertrophic rhinosinusitis, allergic fungal sinusitis, and related disorders Ann Allergy Asthma Immunol 2001; 87(3):181-188 20 Schubert MS, Goetz DW Evaluation and treatment of allergic fungal sinusitis II Treatment and follow-up J Allergy Clin Immunol 1998; 102(3):395-402 21 Krakauer T Immune response to staphylococcal superantigens Immunol Res 1999; 20(2):163-173 22 Bachert C, Gevaert P, van Cauwenberge P Staphylococcus aureus superantigens and airway disease Curr Allergy Asthma Rep 2002; 2(3):252-258 23 Bernstein JM, Ballow M, Schlievert PM, Rich G, Allen C, Dryja D A superantigen hypothesis for the pathogenesis of chronic hyperplastic sinusitis with massive nasal polyposis Am J Rhinol 2003; 17(6):321326 24 Scheuber PH, Denzlinger C, Wilker D, Beck G, Keppler D, Hammer DK Cysteinyl leukotrienes as mediators of staphylococcal enterotoxin B in the monkey Eur J Clin Invest 1987; 17(5):455-459 25 Hofer MF, Harbeck RJ, Schlievert PM, Leung DY Staphylococcal toxins augment specific IgE responses by atopic patients exposed to allergen J Invest Dermatol 1999; 112(2):171-176 26 de Bievre C, Dauguet C, Nguyen VH, Ibrahim-Granet O Polymorphism in mitochondrial DNA of several Trichophyton rubrum isolates from clinical specimens Ann Inst Pasteur Microbiol 1987; 138(6):719-727 27 Foster KW, Ghannoum MA, Elewski BE Epidemiologic surveillance of cutaneous fungal infection in the United States from 1999 to 2002 J Am Acad Dermatol 2004; 50(5):748-752 28 Vella ZL, Gatt P, Boffa MJ, Borg E, Mifsud E, Scerri L et al Characteristics of superficial mycoses in Malta Int J Dermatol 2003; 42(4):265-271 29 Falahati M, Akhlaghi L, Lari AR, Alaghehbandan R Epidemiology of dermatophytoses in an area south of Tehran, Iran Mycopathologia 2003; 156(4):279-287 30 Woodfolk JA, Wheatley LM, Piyasena RV, Benjamin DC, Platts-Mills TA Trichophyton antigens associated with IgE antibodies and delayed 377 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 type hypersensitivity Sequence homology to two families of serine proteinases J Biol Chem 1998; 273(45):29489-29496 Velez A, Linares MJ, Fenandez-Roldan JC, Casal M Study of onychomycosis in Cordoba, Spain: prevailing fungi and pattern of infection Mycopathologia 1997; 137(1):1-8 Sinski JT, Flouras K A survey of dermatophytes isolated from human patients in the United States from 1979 to 1981 with chronological listings of worldwide incidence of five dermatophytes often isolated in the United States Mycopathologia 1984; 85(1-2):97-120 Sinski JT, Kelley LM A survey of dermatophytes isolated from human patients in the United States from 1982 to 1984 Mycopathologia 1987; 98(1):35-40 Sinski JT, Kelley LM A survey of dermatophytes from human patients in the United States from 1985 to 1987 Mycopathologia 1991; 114(2):117-126 Singh D, Patel DC, Rogers K, Wood N, Riley D, Morris AJ Epidemiology of dermatophyte infection in Auckland, New Zealand Australas J Dermatol 2003; 44(4):263-266 Mackenzie DW Imported fungal infections Postgrad Med J 1979; 55(647):595-597 Vismer HF, Findlay GH Superficial fungal infections in the Transvaal A contemporary analysis of dermatophytoses in this region S Afr Med J 1988; 73(10):587-592 Muir DB, Pritchard RC, Gregory JD Dermatophytes identified at the Australian National Reference Laboratory in Medical Mycology 1966-1982 Pathology 1984; 16(2):179-183 Hay RJ Chronic dermatophyte infections I Clinical and mycological features Br J Dermatol 1982; 106(1):1-7 Wu S, Liao W, Guo N Epidemiological study of pathogenic fungi in China: 1986 and 1996 Chin Med J (Engl ) 2001; 114(3):294-296 Banerjee U, Sethi M, Pasricha JS Study of onychomycosis in India Mycoses 1990; 33(7-8):411-415 Sentamilselvi G, Kamalam A, Ajithadas K, Janaki C, Thambiah AS Scenario of chronic dermatophytosis: an Indian study Mycopathologia 1997; 140(3):129-135 Cheng S, Chong L A prospective epidemiological study on tinea pedis and onychomycosis in Hong Kong Chin Med J (Engl ) 2002; 115(6):860-865 Imwidthaya S, Thianprasit M A study of dermatophytoses in Bangkok (Thailand) Mycopathologia 1988; 102(1):13-16 Taplin D Dermatophytosis in Vietnam Cutis 2001; 67(5 Suppl):19-20 Han MH, Choi JH, Sung KJ, Moon KC, Koh JK Onychomycosis and Trichosporon beigelii in Korea Int J Dermatol 2000; 39(4):266-269 Kam KM, Au WF, Wong PY, Cheung MM Onychomycosis in Hong Kong 378 Int J Dermatol 1997; 36(10):757-761 48 Ng KP, Saw TL, Madasamy M, Soo HT Onychomycosis in Malaysia Mycopathologia 1999; 147(1):29-32 49 Nowicki R Dermatophytoses in the Gdansk area, Poland: a 12-year survey Mycoses 1996; 39(9-10):399-402 50 Ellabib MS, Khalifa Z, Kavanagh K Dermatophytes and other fungi associated with skin mycoses in Tripoli, Libya Mycoses 2002; 45(34):101-104 51 Korstanje MJ, Staats CC Fungal infections in the Netherlands Prevailing fungi and pattern of infection Dermatology 1995; 190(1):39-42 52 Ponnighaus JM, Clayton Y, Warndorff D The spectrum of dermatophytes in northern Malawi (Africa) Mycoses 1996; 39(7-8):293-297 53 Filipello M, V, Preve L, Tullio V Fungi responsible for skin mycoses in Turin (Italy) Mycoses 1996; 39(3-4):141-150 54 Chinelli PA, Sofiatti AA, Nunes RS, Martins JE Dermatophyte agents in the city of Sao Paulo, from 1992 to 2002 Rev Inst Med Trop Sao Paulo 2003; 45(5):259-263 55 Bonifaz A, Ramirez-Tamayo T, Saul A Tinea barbae (tinea sycosis): experience with nine cases J Dermatol 2003; 30(12):898-903 56 Lateur N, Mortaki A, Andre J Two hundred ninety-six cases of onychomycosis in children and teenagers: a 10-year laboratory survey Pediatr Dermatol 2003; 20(5):385-388 57 Gupta AK, Skinner AR, Baran R Onychomycosis in children: an overview J Drugs Dermatol 2003; 2(1):31-34 58 Jennings MB, Weinberg JM, Koestenblatt EK, Lesczczynski C Study of clinically suspected onychomycosis in a podiatric population J Am Podiatr Med Assoc 2002; 92(6):327-330 59 Geary RJ, Lucky AW Tinea pedis in children presenting as unilateral inflammatory lesions of the sole Pediatr Dermatol 1999; 16(4):255258 60 Tanuma H, Doi M, Abe M, Kume H, Nishiyama S, Katsuoka K Case report Kerion Celsi effectively treated with terbinafine Characteristics of kerion Celsi in the elderly in Japan Mycoses 1999; 42(9-10):581585 61 Verneuil L, Datry A, Le Flour N, Dompmartin A, Derenne JP, Chosidow O Acute fungal pustulosis on a bedridden patient's back Dermatology 2003; 206(3):263-264 62 Espiritu BR, Szpindor-Watson A, Zeitz HJ, Thomas LL IgE-mediated sensitivity to Trichophyton rubrum in a patient with chronic dermatophytosis and Cushing's syndrome J Allergy Clin Immunol 1988; 81(5 Pt 1):847-851 63 Watanabe S Dermatophytosis of the external auditory meatus J Med Vet Mycol 1986; 24(6):485-486 64 Smith KJ, Welsh M, Skelton H Trichophyton rubrum showing deep dermal 379 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 invasion directly from the epidermis in immunosuppressed patients Br J Dermatol 2001; 145(2):344-348 Korting HC, Blecher P, Stallmann D, Hamm G Dermatophytes on the feet of HIV-infected patients: frequency, species distribution, localization and antimicrobial susceptibility Mycoses 1993; 36(7-8):271-274 Tlacuilo-Parra A, Guevara-Gutierrez E, Mayorga J, Garcia-De La Torre I, Salazar-Paramo M Onychomycosis in systemic lupus erythematosus: a case control study J Rheumatol 2003; 30(7):1491-1494 Boonchai W, Kulthanan K, Maungprasat C, Suthipinittham P Clinical characteristics and mycology of onychomycosis in autoimmune patients J Med Assoc Thai 2003; 86(11):995-1000 Sentamil SG, Kamalam A, Ajithados K, Janaki C, Thambiah AS Clinical and mycological features of dermatophytosis in renal transplant recipients Mycoses 1999; 42(1-2):75-78 Lugo-Somolinos A, Sanchez JL Prevalence of dermatophytosis in patients with diabetes J Am Acad Dermatol 1992; 26(3 Pt 2):408-410 Ungpakorn R, Lohaprathan S, Reangchainam S Prevalence of foot diseases in outpatients attending the Institute of Dermatology, Bangkok, Thailand Clin Exp Dermatol 2004; 29(1):87-90 Clemons KV, Schar G, Stover EP, Feldman D, Stevens DA Dermatophytehormone relationships: characterization of progesterone-binding specificity and growth inhibition in the genera Trichophyton and Microsporum J Clin Microbiol 1988; 26(10):2110-2115 Celik E, Ilkit M, Tanir F Prevalence and causative agents of superficial mycoses in a textile factory in Adana, Turkey Mycoses 2003; 46(8):311-315 Hay RJ Failure of treatment in chronic dermatophyte infections Postgrad Med J 1979; 55(647):608-610 Smijs TG, Schuitmaker HJ Photodynamic inactivation of the dermatophyte Trichophyton rubrum Photochem Photobiol 2003; 77(5):556-560 Faergemann J, Baran R Epidemiology, clinical presentation and diagnosis of onychomycosis Br J Dermatol 2003; 149 Suppl 65:1-4 Bale S Families infected with Trichophyton rubrum Cutis 2001; 67(5 Suppl):36-37 Jang KA, Chi DH, Choi JH, Sung KJ, Moon KC, Koh JK Tinea pedis in Korean children Int J Dermatol 2000; 39(1):25-27 Nissen D, Petersen LJ, Esch R, Svejgaard E, Skov PS, Poulsen LK et al IgE-sensitization to cellular and culture filtrates of fungal extracts in patients with atopic dermatitis Ann Allergy Asthma Immunol 1998; 81(3):247-255 Svejgaard E, Faergeman J, Jemec G, Kieffer M, Ottevanger V Recent investigations on the relationship between fungal skin diseases and atopic dermatitis Acta Derm Venereol Suppl (Stockh) 1989; 144:140-142 380 80 Guneser S, Atici A, Koksal F, Yaman A Mold allergy in Adana, Turkey Allergol Immunopathol (Madr ) 1994; 22(2):52-54 81 Scalabrin DM, Bavbek S, Perzanowski MS, Wilson BB, Platts-Mills TA, Wheatley LM Use of specific IgE in assessing the relevance of fungal and dust mite allergens to atopic dermatitis: a comparison with asthmatic and nonasthmatic control subjects J Allergy Clin Immunol 1999; 104(6):1273-1279 82 Elewski BE, Schwartz HJ Asthma induced by allergy to Trichophyton rubrum J Eur Acad Dermatol Venereol 1999; 12(3):250-253 83 Abramson C, Wilton J Nail dust aerosols from onychomycotic toenails Part II Clinical and serologic aspects 1984 J Am Podiatr Med Assoc 1992; 82(2):116-123 84 Hurlimann A, Fah J Asthma, rhinitis and dermatitis triggered by fungal infection: therapeutic effects of terbinafine Dermatology 2001; 202(4):330-332 85 Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA New insights into atopic dermatitis J Clin Invest 2004; 113(5):651-657 86 Ward GW, Jr., Karlsson G, Rose G, Platts-Mills TA Trichophyton asthma: sensitisation of bronchi and upper airways to dermatophyte antigen Lancet 1989; 1(8643):859-862 87 Schwartz HJ, Ward GW Onychomycosis, Trichophyton allergy and asthma-a causal relationship? Ann Allergy Asthma Immunol 1995; 74(6):523-524 88 Gumowski P, Lech B, Chaves I, Girard JP Chronic asthma and rhinitis due to Candida albicans, epidermophyton, and trichophyton Ann Allergy 1987; 59(1):48-51 89 Kaaman T Skin reactivity in atopic patients with dermatophytosis Mykosen 1985; 28(4):183, 186-183, 190 90 Escalante MT, Sanchez-Borges M, Capriles-Hulett A, Belfort E, Di Biagio E, Gonzalez-Aveledo L Trichophyton-specific IgE in patients with dermatophytosis is not associated with aeroallergen sensitivity J Allergy Clin Immunol 2000; 105(3):547-551 91 Svejgaard E, Christiansen AH, Stahl D, Thomsen K Clinical and immunological studies in chronic dermatophytosis caused by Trichophyton rubrum Acta Derm Venereol 1984; 64(6):493-500 92 Lambkin I, Hamilton AJ, Hay RJ Partial purification and characterization of a 235,000M(r) extracellular proteinase from Trichophyton rubrum Mycoses 1994; 37(3-4):85-92 93 Apodaca G, McKerrow JH Purification and characterization of a 27,000-Mr extracellular proteinase from Trichophyton rubrum Infect Immun 1989; 57(10):3072-3080 94 Asahi M, Lindquist R, Fukuyama K, Apodaca G, Epstein WL, McKerrow JH Purification and characterization of major extracellular proteinases from Trichophyton rubrum Biochem J 1985; 232(1):139-144 381 95 Zurita J, Hay RJ Adherence of dermatophyte microconidia and arthroconidia to human keratinocytes in vitro J Invest Dermatol 1987; 89(5):529-534 96 Abdel-Gawad KM Mycological and some physiological studies of keratinophilic and other moulds associated with sheep wool Microbiol Res 1997; 152(2):181-188 97 Oycka CA, Gugnani HC Keratin degradation by Scytalidium species and Fusarium solani Mycoses 1998; 41(1-2):73-76 98 Apodaca G, McKerrow JH Expression of proteolytic activity by cultures of Trichophyton rubrum J Med Vet Mycol 1990; 28(2):159-171 99 Woodfolk JA, Platts-Mills TA The immune response to dermatophytes Res Immunol 1998; 149(4-5):436-445 100 Esquenazi D, Alviano CS, de Souza W, Rozental S The influence of surface carbohydrates during in vitro infection of mammalian cells by the dermatophyte Trichophyton rubrum Res Microbiol 2004; 155(3):144-153 101 Calderon RA, Hay RJ, Shennan GI Circulating antigens and antibodies in human and mouse dermatophytosis: use of monoclonal antibody reactive to phosphorylcholine-like epitopes J Gen Microbiol 1987; 133 ( Pt 9):2699-2705 102 Sorensen GW, Jones HE Immediate and delayed hypersensitivity in chronic dermatophytosis Arch Dermatol 1976; 112(1):40-42 103 Woodfolk JA, Slunt JB, Deuell B, Hayden ML, Platts-Mills TA Definition of a Trichophyton protein associated with delayed hypersensitivity in humans Evidence for immediate (IgE and IgG4) and delayed hypersensitivity to a single protein J Immunol 1996; 156(4):16951701 104 Svejgaard E, Lowenstein H Trichophyton rubrum specific IgE in serum in patients with chronic T rubrum infection as demonstrated by crossed radio-immuno-electrophoresis Acta Derm Venereol Suppl (Stockh) 1985; 120:72-75 105 Slunt JB, Taketomi EA, Woodfolk JA, Hayden ML, Platts-Mills TA The immune response to Trichophyton tonsurans: distinct T cell cytokine profiles to a single protein among subjects with immediate and delayed hypersensitivity J Immunol 1996; 157(11):5192-5197 106 Sato N, Tagami H Severe measles in a young female patient with chronic, generalized Trichophyton rubrum infection showing type helper T cell-dominant immunologic reactivity J Am Acad Dermatol 2003; 48(5 Suppl):S43-S46 107 Kanda N, Tani K, Enomoto U, Nakai K, Watanabe S The skin fungusinduced Th1- and Th2-related cytokine, chemokine and prostaglandin E2 production in peripheral blood mononuclear cells from patients with atopic dermatitis and psoriasis vulgaris Clin Exp Allergy 2002; 32(8):1243-1250 382 108 Ludwig RJ, Woodfolk JA, Grundmann-Kollmann M, Enzensberger R, Runne U, Platts-Mills TA et al Chronic dermatophytosis in lamellar ichthyosis: relevance of a T-helper 2-type immune response to Trichophyton rubrum Br J Dermatol 2001; 145(3):518-521 109 Leyden JL Tinea pedis pathophysiology and treatment J Am Acad Dermatol 1994; 31(3 Pt 2):S31-S33 110 Kaaman T, Petrini B, Wasserman J In vivo and in vitro immune responses to trichophytin in dermatophytosis Acta Derm Venereol 1979; 59(3):229-233 111 Jones HE, Reinhardt JH, Rinaldi MG Acquired immunity to dermatophytes Arch Dermatol 1974; 109(6):840-848 112 McGregor JM, Hamilton AJ, Hay RJ Possible mechanisms of immune modulation in chronic dermatophytoses: an in vitro study Br J Dermatol 1992; 127(3):233-238 113 Svejgaard E, Thomsen M, Morling N, Hein Christiansen AH Lymphocyte transformation in vitro in dermatophytosis Acta Pathol Microbiol Scand [C ] 1976; 84C(6):511-523 114 Grando SA, Hostager BS, Herron MJ, Dahl MV, Nelson RD Binding of Trichophyton rubrum mannan to human monocytes in vitro J Invest Dermatol 1992; 98(6):876-880 115 Dahl MV, Grando SA Chronic dermatophytosis: what is special about Trichophyton rubrum? Adv Dermatol 1994; 9:97-109 116 Grando SA, Herron MJ, Dahl MV, Nelson RD Binding and uptake of Trichophyton rubrum mannan by human epidermal keratinocytes: a time-course study Acta Derm Venereol 1992; 72(4):273-276 117 Hay RJ, Shennan G Chronic dermatophyte infections II Antibody and cellmediated immune responses Br J Dermatol 1982; 106(2):191-198 118 Wang SR, Zweiman B Histamine suppression of human lymphocyte responses to mitogens Cell Immunol 1978; 36(1):28-36 119 Abraham S, Pandhi RK, Kumar R, Mohapatra LN, Bhutani LK A study of the immunological status of patients with dermatophytoses Dermatologica 1975; 151(5):281-287 120 Maleszka R, Adamski Z, Dworacki G Evaluation of lymphocytes subpopulations and natural killer cells in peripheral blood of patients treated for dermatophyte onychomycosis Mycoses 2001; 44(1112):487-492 121 Petrini B, Kaaman T T-lymphocyte subpopulations in patients with chronic dermatophytosis Int Arch Allergy Appl Immunol 1981; 66(1):105109 122 Hamouda T, Jeffries CD, Ekladios EM, el Mishad AM, el Koomy M, Saleh N Class-specific antibody in human dermatophytosis reactive with Trichophyton rubrum derived antigen Mycopathologia 1994; 127(2):83-88 123 Murphy JW Immunity to fungi Curr Opin Immunol 1989; 2(3):360-367 383 124 Swan JW, Dahl MV, Coppo PA, Hammerschmidt DE Complement activation by trichophyton rubrum J Invest Dermatol 1983; 80(3):156-158 125 Davies RR, Zaini F Enzymic activities of Trichophyton rubrum and the chemotaxis of polymorphonuclear leucocytes Sabouraudia 1984; 22(3):235-241 126 Ray TL, Wuepper KD Experimental cutaneous candidiasis in rodents; II Role of the stratum corneum barrier and serum complement as a mediator of a protective infalmmatory response Arch Dermatol 1978; 114(4):539-543 127 Dahl MV, Carpenter R Polymorphonuclear leukocytes, complement, and Trichophyton rubrum J Invest Dermatol 1986; 86(2):138-141 128 Calderon RA, Hay RJ Fungicidal activity of human neutrophils and monocytes on dermatophyte fungi, Trichophyton quinckeanum and Trichophyton rubrum Immunology 1987; 61(3):289-295 129 Djeu JY, Blanchard DK, Halkias D, Friedman H Growth inhibition of Candida albicans by human polymorphonuclear neutrophils: activation by interferon-gamma and tumor necrosis factor J Immunol 1986; 137(9):2980-2984 130 Hidore MR, Murphy JW Murine natural killer cell interactions with a fungal target, Cryptococcus neoformans Infect Immun 1989; 57(7):19901997 131 Kawakami K, Koguchi Y, Qureshi MH, Yara S, Kinjo Y, Uezu K et al NK cells eliminate Cryptococcus neoformans by potentiating the fungicidal activity of macrophages rather than by directly killing them upon stimulation with IL-12 and IL-18 Microbiol Immunol 2000; 44(12):1043-1050 132 Akiba H, Motoki Y, Satoh M, Iwatsuki K, Kaneko F Recalcitrant trichophytic granuloma associated with NK-cell deficiency in a SLE patient treated with corticosteroid Eur J Dermatol 2001; 11(1):58-62 133 Lambkin I, Hamilton AJ, Hay RJ Purification and characterisation of a novel 34,000-Mr cell-associated proteinase from the dermatophyte Trichophyton rubrum FEMS Immunol Med Microbiol 1996; 13(2):131-140 134 Rezaie S, Ban J, Mildner M, Poitschek C, Brna C, Tschachler E Characterization of a cDNA clone, encoding a 70 kDa heat shock protein from the dermatophyte pathogen Trichophyton rubrum Gene 2000; 241(1):27-33 135 Davies RR Human nail dust in chiropodial practice: irritant, allergen and source of antibodies to Trichophyton rubrum J R Soc Health 1984; 104(1):1-5 136 Karlsson G, Holmberg K Does allergic rhinitis predispose to sinusitis? Acta Otolaryngol Suppl 1994; 515:26-28 137 Chee L, Graham SM, Carothers DG, Ballas ZK Immune dysfunction in 384 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 refractory sinusitis in a tertiary care setting Laryngoscope 2001; 111(2):233-235 Kaaman T Cell-mediated reactivity in dermatophytosis: differences in skin responses to purified trichophytin in tinea pedis and tinea cruris Acta Derm Venereol 1981; 61(2):119-123 Kaaman T, Wasserman J Cell mediated cross-reactivity in vivo and in vitro to purified dermatophyte antigen preparations in sensitized guinea pigs Acta Derm Venereol 1981; 61(3):213-217 Gupta AK, Ahmad I, Borst I, Summerbell RC Detection of xanthomegnin in epidermal materials infected with Trichophyton rubrum J Invest Dermatol 2000; 115(5):901-905 Kocabas CN, Sekerel BE Does systemic exposure to aflatoxin B(1) cause allergic sensitization? Allergy 2003; 58(4):363-365 Scheeren RA, Keehnen RM, Meijer CJ, van der BS Defects in cellular immunity in chronic upper airway infections are associated with immunosuppressive retroviral p15E-like proteins Arch Otolaryngol Head Neck Surg 1993; 119(4):439-443 Scapini P, Lapinet-Vera JA, Gasperini S, Calzetti F, Bazzoni F, Cassatella MA The neutrophil as a cellular source of chemokines Immunol Rev 2000; 177:195-203 Maghazachi AA, al Aoukaty A, Schall TJ C-C chemokines induce the chemotaxis of NK and IL-2-activated NK cells Role for G proteins J Immunol 1994; 153(11):4969-4977 Loetscher P, Seitz M, Clark-Lewis I, Baggiolini M, Moser B Activation of NK cells by CC chemokines Chemotaxis, Ca2+ mobilization, and enzyme release J Immunol 1996; 156(1):322-327 Chambers BJ, Salcedo M, Ljunggren HG Triggering of natural killer cells by the costimulatory molecule CD80 (B7-1) Immunity 1996; 5(4):311-317 Assarsson E, Kambayashi T, Schatzle JD, Cramer SO, von Bonin A, Jensen PE et al NK cells stimulate proliferation of T and NK cells through 2B4/CD48 interactions J Immunol 2004; 173(1):174-180 Perussia B Lymphokine-activated killer cells, natural killer cells and cytokines Curr Opin Immunol 1991; 3(1):49-55 Lauwerys BR, Garot N, Renauld JC, Houssiau FA Cytokine production and killer activity of NK/T-NK cells derived with IL-2, IL-15, or the combination of IL-12 and IL-18 J Immunol 2000; 165(4):1847-1853 Bachert C, Gevaert P, Holtappels G, Johansson SG, van Cauwenberge P Total and specific IgE in nasal polyps is related to local eosinophilic inflammation J Allergy Clin Immunol 2001; 107(4):607-614 Youssef N, Wyborn CH, Holt G Antibiotic production by dermatophyte fungi J Gen Microbiol 1978; 105(1):105-111 Tos M, Larsen PL Nasal polyps:origin, etiology, pathogenesis, and structure In: Kennedy DW, Bolger W.E., Zinreich S.J., editors Diseases of the 385 153 154 155 156 157 158 159 160 161 162 163 164 165 166 sinuses : diagnosis and management Hamilton, Ont ; Lewiston, N.Y : B.C Decker, Inc., 2001: 57-68 Hamilos DL Chronic sinusitis J Allergy Clin Immunol 2000; 106(2):213227 Hoff M, Ballmer-Weber BK, Niggemann B, Cistero-Bahima A, MiguelMoncin M, Conti A et al Molecular cloning and immunological characterisation of potential allergens from the mould Fusarium culmorum Mol Immunol 2003; 39(15):965-975 Dillen L, Miserez B, Claeys M, Aunis D, De Potter W Posttranslational processing of proenkephalins and chromogranins/secretogranins Neurochem Int 1993; 22(4):315-352 Kurien M, Anandi V, Raman R, Brahmadathan KN Maxillary sinus fusariosis in immunocompetent hosts J Laryngol Otol 1992; 106(8):733-736 Wickern GM Fusarium allergic fungal sinusitis J Allergy Clin Immunol 1993; 92(4):624-625 Rea WJ, Didriksen N, Simon TR, Pan Y, Fenyves EJ, Griffiths B Effects of toxic exposure to molds and mycotoxins in building-related illnesses Arch Environ Health 2003; 58(7):399-405 Prohaszka Z, Fust G Immunological aspects of heat-shock proteins-the optimum stress of life Mol Immunol 2004; 41(1):29-44 Choi GH, Marek ET, Schardl CL, Richey MG, Chang SY, Smith DA sti35, a stress-responsive gene in Fusarium spp J Bacteriol 1990; 172(8):4522-4528 Kubodera T, Yamashita N, Nishimura A Pyrithiamine resistance gene (ptrA) of Aspergillus oryzae: cloning, characterization and application as a dominant selectable marker for transformation Biosci Biotechnol Biochem 2000; 64(7):1416-1421 Ueda G, Tamura Y, Hirai I, Kamiguchi K, Ichimiya S, Torigoe T et al Tumor-derived heat shock protein 70-pulsed dendritic cells elicit tumor-specific cytotoxic T lymphocytes (CTLs) and tumor immunity Cancer Sci 2004; 95(3):248-253 Chen K, Lu J, Wang L, Gan YH Mycobacterial heat shock protein 65 enhances antigen cross-presentation in dendritic cells independent of Toll-like receptor signaling J Leukoc Biol 2004; 75(2):260-266 Gastpar R, Gross C, Rossbacher L, Ellwart J, Riegger J, Multhoff G The cell surface-localized heat shock protein 70 epitope TKD induces migration and cytolytic activity selectively in human NK cells J Immunol 2004; 172(2):972-980 Lichtenwalner AB, Patton DL, Van Voorhis WC, Sweeney YT, Kuo CC Heat shock protein 60 is the major antigen which stimulates delayedtype hypersensitivity reaction in the macaque model of Chlamydia trachomatis salpingitis Infect Immun 2004; 72(2):1159-1161 Granucci F, Feau S, Angeli V, Trottein F, Ricciardi-Castagnoli P Early IL-2 386 167 168 169 170 171 172 173 174 175 176 177 178 production by mouse dendritic cells is the result of microbial-induced priming J Immunol 2003; 170(10):5075-5081 Lesage G, Sdicu AM, Menard P, Shapiro J, Hussein S, Bussey H Analysis of beta-1,3-glucan assembly in Saccharomyces cerevisiae using a synthetic interaction network and altered sensitivity to caspofungin Genetics 2004; 167(1):35-49 Tomishige N, Noda Y, Adachi H, Shimoi H, Takatsuki A, Yoda K Mutations that are synthetically lethal with a gas1Delta allele cause defects in the cell wall of Saccharomyces cerevisiae Mol Genet Genomics 2003; 269(4):562-573 Kalebina TS, Laurinavichiute DK, Packeiser AN, Morenkov OS, Ter Avanesyan MD, Kulaev IS Correct GPI-anchor synthesis is required for the incorporation of endoglucanase/glucanosyltransferase Bgl2p into the Saccharomyces cerevisiae cell wall FEMS Microbiol Lett 2002; 210(1):81-85 Mouyna I, Fontaine T, Vai M, Monod M, Fonzi WA, Diaquin M et al Glycosylphosphatidylinositol-anchored glucanosyltransferases play an active role in the biosynthesis of the fungal cell wall J Biol Chem 2000; 275(20):14882-14889 Mouyna I, Hartland RP, Fontaine T, Diaquin M, Simenel C, Delepierre M et al A 1,3-beta-glucanosyltransferase isolated from the cell wall of Aspergillus fumigatus is a homologue of the yeast Bgl2p Microbiology 1998; 144 ( Pt 11):3171-3180 Delgado N, Xue J, Yu JJ, Hung CY, Cole GT A recombinant beta-1,3glucanosyltransferase homolog of Coccidioides posadasii protects mice against coccidioidomycosis Infect Immun 2003; 71(6):30103019 Masuoka J Surface glycans of Candida albicans and other pathogenic fungi: physiological roles, clinical uses, and experimental challenges Clin Microbiol Rev 2004; 17(2):281-310 Vetvicka V, Yvin JC Effects of marine beta-1,3 glucan on immune reactions Int Immunopharmacol 2004; 4(6):721-730 Kanbe T, Morishita M, Ito K, Tomita K, Utsunomiya K, Ishiguro A Evidence for the presence of immunoglobulin E antibodies specific to the cell wall phosphomannoproteins of Candida albicans in patients with allergies Clin Diagn Lab Immunol 1996; 3(6):645-650 Wan GH, Li CS, Guo SP, Rylander R, Lin RH An airbone mold-derived product, beta-1,3-D-glucan, potentiates airway allergic responses Eur J Immunol 1999; 29(8):2491-2497 Douwes J, Zuidhof A, Doekes G, van der Zee SC, Wouters I, Boezen MH et al (1 >3)-beta-D-glucan and endotoxin in house dust and peak flow variability in children Am J Respir Crit Care Med 2000; 162(4 Pt 1):1348-1354 Schoffelmeer EA, Klis FM, Sietsma JH, Cornelissen BJ The cell wall of 387 Fusarium oxysporum Fungal Genet Biol 1999; 27(2-3):275-282 179 Mouyna I, Monod M, Fontaine T, Henrissat B, Lechenne B, Latge JP Identification of the catalytic residues of the first family of beta(13)glucanosyltransferases identified in fungi Biochem J 2000; 347 Pt 3:741-747 180 Azuma I, Kimura H, Yamamura Y Purification and characterization of an immunologically active glycoprotein from Asperigillus fumigatus J Bacteriol 1968; 96(1):272-273 181 Bruneau JM, Magnin T, Tagat E, Legrand R, Bernard M, Diaquin M et al Proteome analysis of Aspergillus fumigatus identifies glycosylphosphatidylinositol-anchored proteins associated to the cell wall biosynthesis Electrophoresis 2001; 22(13):2812-2823 182 Kondori N, Edebo L, Mattsby-Baltzer I Circulating beta (1-3) glucan and immunoglobulin G subclass antibodies to Candida albicans cell wall antigens in patients with systemic candidiasis Clin Diagn Lab Immunol 2004; 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