Background: Natural killer T (NKT) cells have been reported to play a crucial role in the pathogenesis of asthma in a mouse model of acute asthma. The present study aimed to investigate the role of NKT cells in the immune pathogenesis of acute exacerbation of human asthma. Methods: Blood and sputum were obtained at baseline and 8 h after a challenge in 20 asthmatics who underwent allergen bronchial provocation testing and during exacerbation and convalescence in 9 asthmatics who were admitted to hospital with an acute exacerbation after an upper respiratory tract infection. 6B11+ or Vα24+ NKT cells were measured with flow cytometry. Inflammatory cells, cytokines and chemokines were determined in sputum. Results: The number of blood NKT cells did not change after a positive allergen challenge compared to the baseline. However, blood CD4+Vα24+ NKT cells decreased during infection-associated asthma exacerbations compared to the convalescence measurements of the same patients (p < 0.05) or the baseline measurements of asthmatics who underwent allergen challenges (p < 0.01). The number of sputum NKT cells did not change after a positive allergen challenge or during infection-associated asthma exacerbations. Eosinophils and various cytokines and chemokines increased in sputum during infection-associated asthma exacerbations. Blood CD4+Vα24+ NKT cells were inversely related to sputum eosinophils (Spearman’s correlation coefficient = –0.62; p < 0.01). Conclusion: Blood NKT cells decreased during infection-associated asthma exacerbation and were inversely associated with eosinophilic airway inflammation, suggesting that blood NKT cells might be mobilized to the airways and lungs during asthma exacerbation in humans.

Keywords:
Exacerbation, Infection, Natural killer T cells, Asthma
1.
National Asthma Education and Prevention Program: Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, National Institutes of Health/National Heart, Lung, and Blood Institute, 2007.
2.
Wark PA, Gibson PG: Asthma exacerbations. 3. Pathogenesis. Thorax 2006;61:909–915.
3.
Lane S, Molina J, Plusa T: An international observational prospective study to determine the cost of asthma exacerbations (COAX). Respir Med 2006;100:434–450.
4.
Skrepnek GH, Skrepnek SV: Epidemiology, clinical and economic burden, and natural history of chronic obstructive pulmonary disease and asthma. Am J Manag Care 2004;10:S129–S138.
5.
Andersson F, Borg S, Stahl E: The impact of exacerbations on the asthmatic patient’s preference scores. J Asthma 2003;40:615–623.
6.
Pauwels RA, Lofdahl CG, Postma DS, Tattersfield AE, O’Byrne P, Barnes PJ, Ullman A: Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997;337:1405–1411.
7.
Umetsu DT, DeKruyff RH: A role for natural killer T cells in asthma. Nat Rev Immunol 2006;6:953–958.
8.
Kronenberg M, Gapin L: The unconventional lifestyle of NKT cells. Nat Rev Immunol 2002;2:557–568.
9.
Akbari O, Stock P, Meyer E, Kronenberg M, Sidobre S, Nakayama T, Taniguchi M, Grusby MJ, DeKruyff RH, Umetsu DT: Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat Med 2003;9:582–588.
10.
Meyer EH, Goya S, Akbari O, Berry GJ, Savage PB, Kronenberg M, Nakayama T, DeKruyff RH, Umetsu DT: Glycolipid activation of invariant T cell receptor+ NKT cells is sufficient to induce airway hyperreactivity independent of conventional CD4+ T cells. Proc Natl Acad Sci USA 2006;103:2782–2787.
11.
Pichavant M, Goya S, Meyer EH, Johnston RA, Kim HY, Matangkasombut P, Zhu M, Iwakura Y, Savage PB, DeKruyff RH, Shore SA, Umetsu DT: Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of natural killer T cells and IL-17. J Exp Med 2008;205:385–393.
12.
Koh YI, Kim HY, Meyer EH, Pichavant M, Akbari O, Yasumi T, Savage PB, Dekruyff RH, Umetsu DT: Activation of nonclassical CD1d-restricted NKT cells induces airway hyperreactivity in beta 2-microglobulin-deficient mice. J Immunol 2008;181:4560–4569.
13.
Akbari O, Faul JL, Hoyte EG, Berry GJ, Wahlstrom J, Kronenberg M, DeKruyff RH, Umetsu DT: CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N Engl J Med 2006;354:1117–1129.
14.
Vijayanand P, Seumois G, Pickard C, Powell RM, Angco G, Sammut D, Gadola SD, Friedmann PS, Djukanovic R: Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N Engl J Med 2007;356:1410–1422.
15.
Koh YI, Shim JU, Wi JO, Han ER, Jin NC, Oh SH, Park CK, Park DJ: Inverse association of peripheral blood CD4(+) invariant natural killer T cells with atopy in human asthma. Hum Immunol 2010;71:186–191.
16.
Koh YI, Shim JU: Association between sputum natural killer T cells and eosinophilic airway inflammation in human asthma. Int Arch Allergy Immunol 2010;153:239–248.
17.
Global Initiative For Asthma: Global strategy for asthma management and prevention. Bethesda, National Institutes of Health/National Heart, Lung, and Blood Institute, 2002.
18.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the folin phenol reagent. J Biol Chem 1951;193:265–275.
19.
Melillo G, Aas K, Cartier A, Davies RJ, Debelic M, Dreborg S, Kerrebijn KF, Lassen A, Pinto Mendes J, Rizzo A, et al: Guidelines for the standardization of bronchial provocation tests with allergens. An update by an international committee. Allergy 1991;46:321–329.
20.
Boyson JE, Rybalov B, Koopman LA, Exley M, Balk SP, Racke FK, Schatz F, Masch R, Wilson SB, Strominger JL: CD1d and invariant NKT cells at the human maternal-fetal interface. Proc Natl Acad Sci USA 2002;99:13741–13746.
21.
Magnan A, Mely L, Prato S, Vervloet D, Romagne F, Camilla C, Necker A, Casano B, Montero-Jullian F, Fert V, Malissen B, Bongrand P: Relationships between natural T cells, atopy, IgE levels, and IL-4 production. Allergy 2000;55:286–290.
22.
Fraenkel DJ, Bardin PG, Sanderson G, Lampe F, Johnston SL, Holgate ST: Lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects. Am J Respir Crit Care Med 1995;151:879–886.
23.
Grunberg K, Smits HH, Timmers MC, de Klerk EP, Dolhain RJ, Dick EC, Hiemstra PS, Sterk PJ: Experimental rhinovirus 16 infection. Effects on cell differentials and soluble markers in sputum in asthmatic subjects. Am J Respir Crit Care Med 1997;156:609–616.
24.
Trigg CJ, Nicholson KG, Wang JH, Ireland DC, Jordan S, Duddle JM, Hamilton S, Davies RJ: Bronchial inflammation and the common cold: a comparison of atopic and non-atopic individuals. Clin Exp Allergy 1996;26:665–676.
25.
Schwarze J, Cieslewicz G, Hamelmann E, Joetham A, Shultz LD, Lamers MC, Gelfand EW: IL-5 and eosinophils are essential for the development of airway hyperresponsiveness following acute respiratory syncytial virus infection. J Immunol 1999;162:2997–3004.
26.
van Benten IJ, KleinJan A, Neijens HJ, Osterhaus AD, Fokkens WJ: Prolonged nasal eosinophilia in allergic patients after common cold. Allergy 2001;56:949–956.
27.
Thomas SY, Hou R, Boyson JE, Means TK, Hess C, Olson DP, Strominger JL, Brenner MB, Gumperz JE, Wilson SB, Luster AD: CD1d-restricted NKT cells express a chemokine receptor profile indicative of Th1-type inflammatory homing cells. J Immunol 2003;171:2571–2580.
28.
Kim EY, Battaile JT, Patel AC, You Y, Agapov E, Grayson MH, Benoit LA, Byers DE, Alevy Y, Tucker J, Swanson S, Tidwell R, Tyner JW, Morton JD, Castro M, Polineni D, Patterson GA, Schwendener RA, Allard JD, Peltz G, Holtzman MJ: Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat Med 2008;14:633–640.
29.
Lommatzsch M, Julius P, Kuepper M, Garn H, Bratke K, Irmscher S, Luttmann W, Renz H, Braun A, Virchow JC: The course of allergen-induced leukocyte infiltration in human and experimental asthma. J Allergy Clin Immunol 2006;118:91–97.
30.
Nocker RE, Out TA, Weller FR, Mul EP, Jansen HM, van der Zee JS: Influx of neutrophils into the airway lumen at 4 h after segmental allergen challenge in asthma. Int Arch Allergy Immunol 1999;119:45–53.
31.
Boulay ME, Prince P, Deschesnes F, Chakir J, Boulet LP: Metalloproteinase-9 in induced sputum correlates with the severity of the late allergen-induced asthmatic response. Respiration 2004;71:216–224.
32.
Teran LM, Carroll MP, Frew AJ, Redington AE, Davies DE, Lindley I, Howarth PH, Church MK, Holgate ST: Leukocyte recruitment after local endobronchial allergen challenge in asthma. Relationship to procedure and to airway interleukin-8 release. Am J Respir Crit Care Med 1996;154:469–476.
33.
Versluis M, van den Berge M, Timens W, Luijk B, Rutgers B, Lammers JW, Postma DS, Hylkema MN: Allergen inhalation decreases adenosine receptor expression in sputum and blood of asthma patients. Allergy 2008;63:1186–1194.
34.
De Monchy JG, Kauffman HF, Venge P, Koeter GH, Jansen HM, Sluiter HJ, De Vries K: Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions. Am Rev Respir Dis 1985;131:373–376.
35.
Silvestri M, Oddera S, Sacco O, Balbo A, Crimi E, Rossi GA: Bronchial and bronchoalveolar inflammation in single early and dual responders after allergen inhalation challenge. Lung 1997;175:277–285.
36.
Machado L, Stalenheim G: Factors influencing the occurrence of late bronchial reactions after allergen challenge. Allergy 1990;45:268–274.
37.
Rock M, Yoder S, Hoskins A, Ajayi WU, Sheller JR, Dworski R: Effect of allergen challenge on the percentage of natural killer T cells in patients with atopic asthma. Ann Allergy Asthma Immunol 2009;102:432–437.
38.
Thomas SY, Banerji A, Medoff BD, Lilly CM, Luster AD: Multiple chemokine receptors, including CCR6 and CXCR3, regulate antigen-induced T cell homing to the human asthmatic airway. J Immunol 2007;179:1901–1912.
39.
Reynolds C, Barkans J, Clark P, Kariyawasam H, Altmann D, Kay B, Boyton R: Natural killer T cells in bronchial biopsies from human allergen challenge model of allergic asthma. J Allergy Clin Immunol 2009;124:860–862.
40.
Brooks CR, Weinkove R, Hermans IF, van Dalen CJ, Douwes J: Invariant natural killer T cells and asthma: immunologic reality or methodologic artifact? J Allergy Clin Immunol 2010;126:882–885.
41.
Erin EM, Jenkins GR, Kon OM, Zacharasiewicz AS, Nicholson GC, Neighbour H, Tennant RC, Tan AJ, Leaker BR, Bush A, Jose PJ, Barnes PJ, Hansel TT: Optimized dialysis and protease inhibition of sputum dithiothreitol supernatants. Am J Respir Crit Care Med 2008;177:132–141.
42.
Wouters EF, Reynaert NL, Dentener MA, Vernooy JH: Systemic and local inflammation in asthma and chronic obstructive pulmonary disease: is there a connection? Proc Am Thorac Soc 2009;6:638–647.
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2012
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