過敏性氣喘是一個慢性呼吸道發炎反應，它的特徵包含了呼吸道中，家塵蹣過敏原引發的Th2細胞和嗜酸性白血球滲透、呼吸道呈現高度敏感性、以及分泌過多黏液。Dermatophagoides pteronyssinus（Der p）歐洲塵蹣是和過敏性氣喘相關最常見和最重要的一種家塵蹣。然而，Der p在先天性免疫中的機制至今還不清楚。肺泡表面活性蛋白質D，surfactant protein D（SP-D），是collectin家族中的一位成員，它可以利用carbohydrate recognition domain(CRD) 和微生物、灰塵及過敏原上許多不同醣蛋白motif結合，對於我們肺部的第一道防線，SP-D扮演一個非常重要的角色。近年來的研究中，更強調SP-D不僅加強先天性免疫系統對入侵微生物的反應，而且也可以作用在後天性免疫系統的功能，例如，樹突狀結胞的成熟與T細胞的增生。過去有報告指出SP-D可以經由調節吞噬細胞的功能去控制呼吸道過敏的發炎反應，也可以抑制組織胺的釋放和過敏原所引發淋巴球的增生；而這兩者正是氣喘致病機轉的主要原因。SP-D雖然具有保護細胞降低發炎反應功能，但其分子機轉仍舊有待釐清。過去實驗結果證明小鼠經由Der p刺激後六小時，再給予重組SP-D蛋白（rSP-D）可以降低肺泡沖洗液中嗜酸性球的滲透，且同時降低細胞激素IL-4、IL-5、eotaxin和TNF- 的產生量（治療性的），但是在Der p刺激老鼠二十四小時前給予rSP-D並沒有發現顯著的改變（預防性的）（A部分）。另外，我們也發現Der p有可能會經由TLR和CD14這兩個接受器去活化下游反應（B部分）。可是到目前為止，關於Der p在細胞表面的接受器以及所傳遞的下游訊息尚不清楚。因此，我們利用不同的TLR（TLR2、3、4、5、7、8和9）基因改造的人類HEK細胞，接上NF-B的啟動子，來證明Der p是否經由TLR4/MD-2-CD14來活化下游NF-B活性，並進一步瞭此機制是否和脂多醣Lipopolysaccharide（LPS）所引發的TLR4訊息傳遞機制不同。結果顯示Der p可以活化TLR4/CD14/MD-2和TLR2為主的NF-B訊息傳遞；同時在螢光顯微鏡的觀察下，我們發現Der p可以直接活化NF-B；此外，利用西方墨點法，我們也發現Der p可以磷酸化IRAK和MKK蛋白質；而上述兩種訊息傳遞都會受到SP-D的抑制。更進一步，我們利用MKK/ERK和p38訊息傳導的抑制劑UO126和SB203580可成功的抑制Der p所引起的發炎反應。以此結果似乎顯示Der p會活化myeloid differentiation protein 88 (MyD88)為主的訊息傳遞路徑。另一方面，過去的研究對於LPS會引起Th1反應，並且產生Th1細胞激素（IL-12）已清楚瞭解。令人覺得有趣的是，在MH-S細胞株中，先給予Der p刺激之後再給予LPS，會降低原本LPS活化T-bet的表現及IL-12的產生，且Der p可以引起Th2反應的chemokine MDC（macrophage-derived chemokine, CCL22）。在先前的實驗中指出，先給予Der p可以抑制LPS引發Th1的反應，然而，Der p調控LPS引發的T-bet和IL-12的表現至今還不清楚。另一方面，我們的研究亦證實先給予巨噬細胞SP-D處理後，可以抑制LPS或Der p引起肺泡巨噬細胞所產生的一氧化氮（NO）和TNF-產生，同時也可以抑制Der p引起MKK3/6及P38訊息傳遞的活化和NF-kB的活化（C部分）。換言之，關於SP-D如何抑制Der p所引起的發炎反應及發炎媒介物同時，我們提出三種假說，(一) SP-D可以和Der p接觸並防止SP-D結合到TLR4/CD14/MD-2上，經由競爭反應Der p結合到CD14上；(二) SP-D可以直接結合到CD14或TLR4上，進而抑制Der p結合到TLR4/CD14/MD2上；(三) SP-D本身存在一種抑制的功能，它可以經由另一條負調控機制進而抑制Der p引發的發炎反應，例如：DC-SIGN接受器，藉此去調控Der p引發的Th2免疫反應及吞噬細胞的活化。經由我們的實驗証實，SP-D可以經由直接和CD14結合來抑制Der p和CD14的結合，同時，也能調控DC-SIGN使其表現降低，並經由一個負調控訊號抑制Der p所引起的發炎反應。最後，綜合研究結果，我們結論，在老鼠肺泡細胞的細胞株中，塵蹣過敏原Der p可以經由TLR4和TLR2共同活化，進而活化NF-B為主的NO和TNF-發炎性媒介物，同時也可以抑制LPS引起的IL-12和T-bet的產生；另外，SP-D可以抑制Der p所引起的發炎反應訊息傳遞及發炎媒介物。而對於先天性免疫來講，Der p所引發的發炎反應，SP-D扮演一個非常重要的角色。藉由這些發現探討過敏疾病的機制，針對那些接受器及相關的訊息傳遞加上釐清SP-D在抑制Der p引發肺部的發炎反應及可能的訊息傳遞所扮演的角色可進而幫助發展新的製藥方式，另外也可以提供治療過敏氣喘疾病在臨床上的應用。

Allergic asthma is a chronic airway inflammation, characterized by the infiltration of T helper 2 (Th2) cells and eosinophils, airway hyperresponsiveness, and excessive mucus secretion. Dermatophagoides pteronyssinus (Der p) is among the most prominent and important allergens that cause allergic asthma around the world. However, the mechanism of Der p-induced inflammation in the innate immunity of lung is not fully understood. Surfactant protein D (SP-D) is a member of the collectin family that binds to sugar motifs of microorganisms as well as airborne allergens. It plays an important role in the first-line defense of the lung. In this study, we used different TLR-transfected (TLR2, 3, 4, 5, 6, 7, 8 and 9) human embryonic kidney cells (HEK) to verify whether Der p signal activate NF-B through TLR4/MD-2/CD14. The results suggested that Der p triggered not only TLR4/CD14/MD-2 but also TLR2-dependent NF-B activation. In addition, Der p-induced NF-B activation and IRAK and MKK3/6 proteins phosphorylations observed respectively by fluorescence microscopy and western blot are both inhibited by SP-D pretreatment. It is well known that LPS activates Th1 cytokine response including IL-12, secretion by macrophages. Interestingly, we found that pretreatment with Der p inhibited LPS-induced IL-12 production and T-bet expression in MH-S cell, while Der p alone triggered Th2 cell recruiting chemokine, MDC (macrophage-derived chemokine, CCL22), in MH-S cells. On the other hand, pretreatment with SP-D in MH-S cells could inhibit Der p-induced NO and TNF- production, as well as Der-p-induced MKK3/6 and P38 pathways activation and NF-B translocation. Furthermore, our results revealed that SP-D can directly bind to CD14 molecule and prevent the binding of Der p to CD14 and inhibit Der p-induced TLR4/CD14/MD2 signal activation. Moreover, SP-D can also regulate Der p-induced down-regulation of DC-SIGN expression, which may also act as an inhibitory signal to inhibit Der p-induced inflammatory response. Our finding suggested that molecular mechanisms of the regulatory role of SP-D are through the direct interaction with cellular surface CD14 preventing Der p-induced macrophage activation and indirectly regulating DC-SIGN expression that resulting in the inhibition of Der p-induced inflammatory response. These results may have major implications in the way of exploring new anti-asthmatic pharmaceuticals agents that target allergen receptors and allergen-induced inflammatory signals, as well as enhancing endogenous SP-D production.

1. Adam, E., K. K. Hansen, O. Astudillo Fernandez, L. Coulon, F. Bex, X. Duhant, E. Jaumotte, M. D. Hollenberg, and A. Jacquet. 2006. The house dust mite allergen Der p 1, unlike Der p 3, stimulates the expression of interleukin-8 in human airway epithelial cells via a proteinase-activated receptor-2-independent mechanism. J Biol Chem 281:6910-6923.
2. Aderem, A., and D. M. Underhill. 1999. Mechanisms of phagocytosis in macrophages. Annu Rev Immunol 17:593-623.
3. Akdis, C. A., F. Kussebi, B. Pulendran, M. Akdis, R. P. Lauener, C. B. Schmidt-Weber, S. Klunker, G. Isitmangil, N. Hansjee, T. A. Wynn, S. Dillon, P. Erb, G. Baschang, K. Blaser, and S. S. Alkan. 2003. Inhibition of T helper 2-type responses, IgE production and eosinophilia by synthetic lipopeptides. Eur J Immunol 33:2717-2726.
4. Akira, S. 2003. Mammalian Toll-like receptors. Curr Opin Immunol 15:5-11.
5. Alexopoulou, L., A. C. Holt, R. Medzhitov, and R. A. Flavell. 2001. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732-738.
6. Alexopoulou, L., V. Thomas, M. Schnare, Y. Lobet, J. Anguita, R. T. Schoen, R. Medzhitov, E. Fikrig, and R. A. Flavell. 2002. Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat Med 8:878-884.
7. Anderson, K. V., L. Bokla, and C. Nusslein-Volhard. 1985. Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell 42:791-798.
8. Anderson, K. V., and C. Nusslein-Volhard. 1984. Information for the dorsal--ventral pattern of the Drosophila embryo is stored as maternal mRNA. Nature 311:223-227.
9. Anzueto, A., A. Jubran, J. A. Ohar, C. A. Piquette, S. I. Rennard, G. Colice, E. N. Pattishall, J. Barrett, M. Engle, K. A. Perret, and B. K. Rubin. 1997. Effects of aerosolized surfactant in patients with stable chronic bronchitis: a prospective randomized controlled trial. JAMA 278:1426-1431.
10. Arbour, N. C., E. Lorenz, B. C. Schutte, J. Zabner, J. N. Kline, M. Jones, K. Frees, J. L. Watt, and D. A. Schwartz. 2000. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25:187-191.
11. Arlian, L. G. 1991. House-dust-mite allergens: a review. Exp Appl Acarol 10:167-186.
12. Asturias, J. A., M. C. Arilla, N. Gomez-Bayon, A. Martinez, J. Martinez, and R. Palacios. 1998. Sequencing and high level expression in Escherichia coli of the tropomyosin allergen (Der p 10) from Dermatophagoides pteronyssinus. Biochim Biophys Acta 1397:27-30.
13. Atochina, E. N., M. F. Beers, Y. Tomer, S. T. Scanlon, S. J. Russo, R. A. Panettieri, Jr., and A. Haczku. 2003. Attenuated allergic airway hyperresponsiveness in C57BL/6 mice is associated with enhanced surfactant protein (SP)-D production following allergic sensitization. Respir Res 4:15.
14. Babu, K. S., D. A. Woodcock, S. E. Smith, J. N. Staniforth, S. T. Holgate, and J. H. Conway. 2003. Inhaled synthetic surfactant abolishes the early allergen-induced response in asthma. Eur Respir J 21:1046-1049.
15. Baribaud, F., S. Pohlmann, T. Sparwasser, M. T. Kimata, Y. K. Choi, B. S. Haggarty, N. Ahmad, T. Macfarlan, T. G. Edwards, G. J. Leslie, J. Arnason, T. A. Reinhart, J. T. Kimata, D. R. Littman, J. A. Hoxie, and R. W. Doms. 2001. Functional and antigenic characterization of human, rhesus macaque, pigtailed macaque, and murine DC-SIGN. J Virol 75:10281-10289.
16. Barnes, K. C., and D. G. Marsh. 1998. The genetics and complexity of allergy and asthma. Immunol Today 19:325-332.
17. Barnes, P. J. 2008. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol 8:183-192.
18. Beg, A. A. 2002. Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol 23:509-512.
19. Beharka, A. A., C. D. Gaynor, B. K. Kang, D. R. Voelker, F. X. McCormack, and L. S. Schlesinger. 2002. Pulmonary surfactant protein A up-regulates activity of the mannose receptor, a pattern recognition receptor expressed on human macrophages. J Immunol 169:3565-3573.
20. Beisswenger, C., and R. Bals. 2008. Interaction of allergic airway inflammation and innate immunity: hygiene and beyond. J Occup Med Toxicol 3 Suppl 1:S3.
21. Beisswenger, C., K. Kandler, C. Hess, H. Garn, K. Felgentreff, M. Wegmann, H. Renz, C. Vogelmeier, and R. Bals. 2006. Allergic airway inflammation inhibits pulmonary antibacterial host defense. J Immunol 177:1833-1837.
22. Borron, P., F. X. McCormack, B. M. Elhalwagi, Z. C. Chroneos, J. F. Lewis, S. Zhu, J. R. Wright, V. L. Shepherd, F. Possmayer, K. Inchley, and L. J. Fraher. 1998. Surfactant protein A inhibits T cell proliferation via its collagen-like tail and a 210-kDa receptor. Am J Physiol 275:L679-686.
23. Borron, P., J. C. McIntosh, T. R. Korfhagen, J. A. Whitsett, J. Taylor, and J. R. Wright. 2000. Surfactant-associated protein A inhibits LPS-induced cytokine and nitric oxide production in vivo. Am J Physiol Lung Cell Mol Physiol 278:L840-847.
24. Borron, P., R. A. Veldhuizen, J. F. Lewis, F. Possmayer, A. Caveney, K. Inchley, R. G. McFadden, and L. J. Fraher. 1996. Surfactant associated protein-A inhibits human lymphocyte proliferation and IL-2 production. Am J Respir Cell Mol Biol 15:115-121.
25. Borron, P. J., E. C. Crouch, J. F. Lewis, J. R. Wright, F. Possmayer, and L. J. Fraher. 1998. Recombinant rat surfactant-associated protein D inhibits human T lymphocyte proliferation and IL-2 production. J Immunol 161:4599-4603.
26. Bottcher, I., I. Bellinghausen, B. Konig, J. Knop, and J. Saloga. 2008. Different regulation of T helper 1- and T helper 2-promoting cytokine signalling factors in human dendritic cells after exposure to protein versus contact allergens. Immunology 123:139-144.
27. Bousquet, J., P. K. Jeffery, W. W. Busse, M. Johnson, and A. M. Vignola. 2000. Asthma. From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 161:1720-1745.
28. Braun-Fahrlander, C., J. Riedler, U. Herz, W. Eder, M. Waser, L. Grize, S. Maisch, D. Carr, F. Gerlach, A. Bufe, R. P. Lauener, R. Schierl, H. Renz, D. Nowak, and E. von Mutius. 2002. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 347:869-877.
29. Brinker, K. G., H. Garner, and J. R. Wright. 2003. Surfactant protein A modulates the differentiation of murine bone marrow-derived dendritic cells. Am J Physiol Lung Cell Mol Physiol 284:L232-241.
30. Brinker, K. G., E. Martin, P. Borron, E. Mostaghel, C. Doyle, C. V. Harding, and J. R. Wright. 2001. Surfactant protein D enhances bacterial antigen presentation by bone marrow-derived dendritic cells. Am J Physiol Lung Cell Mol Physiol 281:L1453-1463.
31. Bufe, A. 1998. The biological function of allergens: relevant for the induction of allergic diseases? Int Arch Allergy Immunol 117:215-219.
32. Busse, W. W. 2000. Mechanisms and advances in allergic diseases. J Allergy Clin Immunol 105:S593-598.
33. Calhoun, W. J., N. N. Jarjour, G. J. Gleich, C. A. Stevens, and W. W. Busse. 1993. Increased airway inflammation with segmental versus aerosol antigen challenge. Am Rev Respir Dis 147:1465-1471.
34. Careau, E., and E. Y. Bissonnette. 2004. Adoptive transfer of alveolar macrophages abrogates bronchial hyperresponsiveness. Am J Respir Cell Mol Biol 31:22-27.
35. Chanez, P., A. M. Vignola, T. O'Shaugnessy, I. Enander, D. Li, P. K. Jeffery, and J. Bousquet. 1997. Corticosteroid reversibility in COPD is related to features of asthma. Am J Respir Crit Care Med 155:1529-1534.
36. Chapman, M. D., and T. A. Platts-Mills. 1980. Purification and characterization of the major allergen from Dermatophagoides pteronyssinus-antigen P1. J Immunol 125:587-592.
37. Chaudhuri, N., S. K. Dower, M. K. Whyte, and I. Sabroe. 2005. Toll-like receptors and chronic lung disease. Clin Sci (Lond) 109:125-133.
38. Chen, C. L., C. T. Lee, Y. C. Liu, J. Y. Wang, H. Y. Lei, and C. K. Yu. 2003. House dust mite Dermatophagoides farinae augments proinflammatory mediator productions and accessory function of alveolar macrophages: implications for allergic sensitization and inflammation. J Immunol 170:528-536.
39. Cheng, G., T. Ueda, T. Numao, Y. Kuroki, H. Nakajima, Y. Fukushima, S. Motojima, and T. Fukuda. 2000. Increased levels of surfactant protein A and D in bronchoalveolar lavage fluids in patients with bronchial asthma. Eur Respir J 16:831-835.
40. Choudhry, S., P. C. Avila, S. Nazario, N. Ung, J. Kho, J. R. Rodriguez-Santana, J. Casal, H. J. Tsai, A. Torres, E. Ziv, M. Toscano, J. S. Sylvia, M. Alioto, M. Salazar, I. Gomez, J. K. Fagan, J. Salas, C. Lilly, H. Matallana, R. A. Castro, M. Selman, S. T. Weiss, J. G. Ford, J. M. Drazen, W. Rodriguez-Cintron, R. Chapela, E. K. Silverman, and E. G. Burchard. 2005. CD14 tobacco gene-environment interaction modifies asthma severity and immunoglobulin E levels in Latinos with asthma. Am J Respir Crit Care Med 172:173-182.
41. Chroneos, Z. C., R. Abdolrasulnia, J. A. Whitsett, W. R. Rice, and V. L. Shepherd. 1996. Purification of a cell-surface receptor for surfactant protein A. J Biol Chem 271:16375-16383.
42. Chua, K. Y., P. K. Kehal, W. R. Thomas, P. R. Vaughan, and I. G. Macreadie. 1992. High-frequency binding of IgE to the Der p allergen expressed in yeast. J Allergy Clin Immunol 89:95-102.
43. Chung, K. F. 2000. Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation? Eur Respir J 15:961-968.
44. Clark, H., N. Palaniyar, P. Strong, J. Edmondson, S. Hawgood, and K. B. Reid. 2002. Surfactant protein D reduces alveolar macrophage apoptosis in vivo. J Immunol 169:2892-2899.
45. Clark, H. W., K. B. Reid, and R. B. Sim. 2000. Collectins and innate immunity in the lung. Microbes Infect 2:273-278.
46. Clements, J. A. 1957. Surface tension of lung extracts. Proc Soc Exp Biol Med 95:170-172.
47. Cohn, L., J. A. Elias, and G. L. Chupp. 2004. Asthma: mechanisms of disease persistence and progression. Annu Rev Immunol 22:789-815.
48. Cook, D. N., D. S. Pisetsky, and D. A. Schwartz. 2004. Toll-like receptors in the pathogenesis of human disease. Nat Immunol 5:975-979.
49. Croner, S., and N. I. Kjellman. 1992. Natural history of bronchial asthma in childhood. A prospective study from birth up to 12-14 years of age. Allergy 47:150-157.
50. Currie, A. J., G. A. Stewart, and A. S. McWilliam. 2000. Alveolar macrophages bind and phagocytose allergen-containing pollen starch granules via C-type lectin and integrin receptors: implications for airway inflammatory disease. J Immunol 164:3878-3886.
51. De Monchy, J. G., H. F. Kauffman, P. Venge, G. H. Koeter, H. M. Jansen, H. J. Sluiter, and K. De Vries. 1985. Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions. Am Rev Respir Dis 131:373-376.
52. Djukanovic, R. 2002. Airway inflammation in asthma and its consequences: implications for treatment in children and adults. J Allergy Clin Immunol 109:S539-548.
53. Djukanovic, R., W. R. Roche, J. W. Wilson, C. R. Beasley, O. P. Twentyman, R. H. Howarth, and S. T. Holgate. 1990. Mucosal inflammation in asthma. Am Rev Respir Dis 142:434-457.
54. Duez, C., P. Gosset, and A. B. Tonnel. 2006. Dendritic cells and toll-like receptors in allergy and asthma. Eur J Dermatol 16:12-16.
55. Durieux, J. J., N. Vita, O. Popescu, F. Guette, J. Calzada-Wack, R. Munker, R. E. Schmidt, J. Lupker, P. Ferrara, H. W. Ziegler-Heitbrock, and et al. 1994. The two soluble forms of the lipopolysaccharide receptor, CD14: characterization and release by normal human monocytes. Eur J Immunol 24:2006-2012.
56. Eggleton, P., and K. B. Reid. 1999. Lung surfactant proteins involved in innate immunity. Curr Opin Immunol 11:28-33.
57. Eisenbarth, S. C., D. A. Piggott, J. W. Huleatt, I. Visintin, C. A. Herrick, and K. Bottomly. 2002. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med 196:1645-1651.
58. Epton, M. J., R. J. Dilworth, W. Smith, and W. R. Thomas. 2001. Sensitisation to the lipid-binding apolipophorin allergen Der p 14 and the peptide Mag-1. Int Arch Allergy Immunol 124:57-60.
59. Feleszko, W., J. Jaworska, and E. Hamelmann. 2006. Toll-like receptors--novel targets in allergic airway disease (probiotics, friends and relatives). Eur J Pharmacol 533:308-318.
60. Ferguson, J. S., D. R. Voelker, F. X. McCormack, and L. S. Schlesinger. 1999. Surfactant protein D binds to Mycobacterium tuberculosis bacilli and lipoarabinomannan via carbohydrate-lectin interactions resulting in reduced phagocytosis of the bacteria by macrophages. J Immunol 163:312-321.
61. Finotto, S., M. F. Neurath, J. N. Glickman, S. Qin, H. A. Lehr, F. H. Green, K. Ackerman, K. Haley, P. R. Galle, S. J. Szabo, J. M. Drazen, G. T. De Sanctis, and L. H. Glimcher. 2002. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science 295:336-338.
62. Fisher, J. H., J. Larson, C. Cool, and S. W. Dow. 2002. Lymphocyte activation in the lungs of SP-D null mice. Am J Respir Cell Mol Biol 27:24-33.
63. Ford, S. A., E. R. Tovey, and B. A. Baldo. 1990. The spectrum of low molecular weight house dust mite (Dermatophagoides pteronyssinus) allergens with emphasis on Der p II. Clin Exp Allergy 20:27-31.
64. Furmonaviciene, R., A. M. Ghaemmaghami, S. E. Boyd, N. S. Jones, K. Bailey, A. C. Willis, H. F. Sewell, D. A. Mitchell, and F. Shakib. 2007. The protease allergen Der p 1 cleaves cell surface DC-SIGN and DC-SIGNR: experimental analysis of in silico substrate identification and implications in allergic responses. Clin Exp Allergy 37:231-242.
65. Gant, V., M. Cluzel, Z. Shakoor, P. J. Rees, T. H. Lee, and A. S. Hamblin. 1992. Alveolar macrophage accessory cell function in bronchial asthma. Am Rev Respir Dis 146:900-904.
66. Gardai, S. J., Y. Q. Xiao, M. Dickinson, J. A. Nick, D. R. Voelker, K. E. Greene, and P. M. Henson. 2003. By binding SIRPalpha or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation. Cell 115:13-23.
67. Gavett, S. H., D. J. O'Hearn, X. Li, S. K. Huang, F. D. Finkelman, and M. Wills-Karp. 1995. Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice. J Exp Med 182:1527-1536.
68. Gereda, J. E., D. Y. Leung, A. Thatayatikom, J. E. Streib, M. R. Price, M. D. Klinnert, and A. H. Liu. 2000. Relation between house-dust endotoxin exposure, type 1 T-cell development, and allergen sensitisation in infants at high risk of asthma. Lancet 355:1680-1683.
69. Glimcher, L. H. 2007. Trawling for treasure: tales of T-bet. Nat Immunol 8:448-450.
70. Gough, L., E. Campbell, D. Bayley, G. Van Heeke, and F. Shakib. 2003. Proteolytic activity of the house dust mite allergen Der p 1 enhances allergenicity in a mouse inhalation model. Clin Exp Allergy 33:1159-1163.
71. Gratziou, C., M. Carroll, S. Montefort, L. Teran, P. H. Howarth, and S. T. Holgate. 1996. Inflammatory and T-cell profile of asthmatic airways 6 hours after local allergen provocation. Am J Respir Crit Care Med 153:515-520.
72. Greiff, L., I. Erjefalt, C. Svensson, P. Wollmer, U. Alkner, M. Andersson, and C. G. Persson. 1993. Plasma exudation and solute absorption across the airway mucosa. Clin Physiol 13:219-233.
73. Haas, H., F. H. Falcone, M. J. Holland, G. Schramm, K. Haisch, B. F. Gibbs, A. Bufe, and M. Schlaak. 1999. Early interleukin-4: its role in the switch towards a Th2 response and IgE-mediated allergy. Int Arch Allergy Immunol 119:86-94.
74. Hackett, T. L., and D. A. Knight. 2007. The role of epithelial injury and repair in the origins of asthma. Curr Opin Allergy Clin Immunol 7:63-68.
75. Haczku, A., K. Takeda, E. Hamelmann, J. Loader, A. Joetham, I. Redai, C. G. Irvin, J. J. Lee, H. Kikutani, D. Conrad, and E. W. Gelfand. 2000. CD23 exhibits negative regulatory effects on allergic sensitization and airway hyperresponsiveness. Am J Respir Crit Care Med 161:952-960.
76. Haczku, A., K. Takeda, E. Hamelmann, J. Loader, A. Joetham, I. Redai, C. G. Irvin, J. J. Lee, H. Kikutani, D. Conrad, and E. W. Gelfand. 2000. CD23 exhibits negative regulatory effects on allergic sensitization and airway hyperresponsiveness. Am J Respir Crit Care Med 161:952-960.
77. Haczku, A., G. Vass, and S. Kierstein. 2004. Surfactant protein D and asthma. Clin Exp Allergy 34:1815-1818.
78. Hajjar, A. M., R. K. Ernst, J. H. Tsai, C. B. Wilson, and S. I. Miller. 2002. Human Toll-like receptor 4 recognizes host-specific LPS modifications. Nat Immunol 3:354-359.
79. Hales, B. J., A. C. Martin, L. J. Pearce, I. A. Laing, C. M. Hayden, J. Goldblatt, P. N. Le Souef, and W. R. Thomas. 2006. IgE and IgG anti-house dust mite specificities in allergic disease. J Allergy Clin Immunol 118:361-367.
80. Hamann, C. P., P. A. Rodgers, and K. M. Sullivan. 2004. Occupational allergens in dentistry. Curr Opin Allergy Clin Immunol 4:403-409.
81. Hamelmann, E., U. Wahn, and E. W. Gelfand. 1999. Role of the Th2 cytokines in the development of allergen-induced airway inflammation and hyperresponsiveness. Int Arch Allergy Immunol 118:90-94.
82. Hammad, H., and B. N. Lambrecht. 2008. Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma. Nat Rev Immunol 8:193-204.
83. Hammad, H., H. H. Smits, C. Ratajczak, A. Nithiananthan, E. A. Wierenga, G. A. Stewart, A. Jacquet, A. B. Tonnel, and J. Pestel. 2003. Monocyte-derived dendritic cells exposed to Der p 1 allergen enhance the recruitment of Th2 cells: major involvement of the chemokines TARC/CCL17 and MDC/CCL22. Eur Cytokine Netw 14:219-228.
84. Hashimoto, C., K. L. Hudson, and K. V. Anderson. 1988. The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein. Cell 52:269-279.
85. Hayashi, F., K. D. Smith, A. Ozinsky, T. R. Hawn, E. C. Yi, D. R. Goodlett, J. K. Eng, S. Akira, D. M. Underhill, and A. Aderem. 2001. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410:1099-1103.
86. Haziot, A., B. Z. Tsuberi, and S. M. Goyert. 1993. Neutrophil CD14: biochemical properties and role in the secretion of tumor necrosis factor-alpha in response to lipopolysaccharide. J Immunol 150:5556-5565.
87. Heine, H., and E. Lien. 2003. Toll-like receptors and their function in innate and adaptive immunity. Int Arch Allergy Immunol 130:180-192.
88. Hemmi, H., T. Kaisho, O. Takeuchi, S. Sato, H. Sanjo, K. Hoshino, T. Horiuchi, H. Tomizawa, K. Takeda, and S. Akira. 2002. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3:196-200.
89. Hemmi, H., O. Takeuchi, T. Kawai, T. Kaisho, S. Sato, H. Sanjo, M. Matsumoto, K. Hoshino, H. Wagner, K. Takeda, and S. Akira. 2000. A Toll-like receptor recognizes bacterial DNA. Nature 408:740-745.
90. Henneke, P., O. Takeuchi, J. A. van Strijp, H. K. Guttormsen, J. A. Smith, A. B. Schromm, T. A. Espevik, S. Akira, V. Nizet, D. L. Kasper, and D. T. Golenbock. 2001. Novel engagement of CD14 and multiple toll-like receptors by group B streptococci. J Immunol 167:7069-7076.
91. Herbert, C. A., C. M. King, P. C. Ring, S. T. Holgate, G. A. Stewart, P. J. Thompson, and C. Robinson. 1995. Augmentation of permeability in the bronchial epithelium by the house dust mite allergen Der p1. Am J Respir Cell Mol Biol 12:369-378.
92. Hewitt, C. R., A. P. Brown, B. J. Hart, and D. I. Pritchard. 1995. A major house dust mite allergen disrupts the immunoglobulin E network by selectively cleaving CD23: innate protection by antiproteases. J Exp Med 182:1537-1544.
93. Heymann, P. W., M. D. Chapman, R. C. Aalberse, J. W. Fox, and T. A. Platts-Mills. 1989. Antigenic and structural analysis of group II allergens (Der f II and Der p II) from house dust mites (Dermatophagoides spp). J Allergy Clin Immunol 83:1055-1067.
94. Hickman-Davis, J. M., F. C. Fang, C. Nathan, V. L. Shepherd, D. R. Voelker, and J. R. Wright. 2001. Lung surfactant and reactive oxygen-nitrogen species: antimicrobial activity and host-pathogen interactions. Am J Physiol Lung Cell Mol Physiol 281:L517-523.
95. Holmskov, U., S. Thiel, and J. C. Jensenius. 2003. Collections and ficolins: humoral lectins of the innate immune defense. Annu Rev Immunol 21:547-578.
96. Holt, P. G., J. Oliver, N. Bilyk, C. McMenamin, P. G. McMenamin, G. Kraal, and T. Thepen. 1993. Downregulation of the antigen presenting cell function(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages. J Exp Med 177:397-407.
97. Holtzman, M. J., D. Sampath, M. Castro, D. C. Look, and S. Jayaraman. 1996. The one-two of T helper cells: does interferon-gamma knock out the Th2 hypothesis for asthma? Am J Respir Cell Mol Biol 14:316-318.
98. Huang, H. W., K. H. Lue, R. H. Wong, H. L. Sun, J. N. Sheu, and K. H. Lu. 2006. Distribution of allergens in children with different atopic disorders in central Taiwan. Acta Paediatr Taiwan 47:127-134.
99. Huss, K., N. F. Adkinson, Jr., P. A. Eggleston, C. Dawson, M. L. Van Natta, and R. G. Hamilton. 2001. House dust mite and cockroach exposure are strong risk factors for positive allergy skin test responses in the Childhood Asthma Management Program. J Allergy Clin Immunol 107:48-54.
100. Illi, S., and E. von Mutius. 2003. House-dust mite allergen exposure and the development of asthma in children. Ann Allergy Asthma Immunol 90:6-7.
101. Jeffery, P. K. 1996. Bronchial biopsies and airway inflammation. Eur Respir J 9:1583-1587.
102. Jurk, M., F. Heil, J. Vollmer, C. Schetter, A. M. Krieg, H. Wagner, G. Lipford, and S. Bauer. 2002. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 3:499.
103. Kawamoto, S., T. Suzuki, T. Aki, T. Katsutani, S. Tsuboi, S. Shigeta, and K. Ono. 2002. Der f 16: a novel gelsolin-related molecule identified as an allergen from the house dust mite, Dermatophagoides farinae. FEBS Lett 516:234-238.
104. Kay, A. B. 1992. "Helper" (CD4+) T cells and eosinophils in allergy and asthma. Am Rev Respir Dis 145:S22-26.
105. Kedda, M. A., F. Lose, D. Duffy, E. Bell, P. J. Thompson, and J. Upham. 2005. The CD14 C-159T polymorphism is not associated with asthma or asthma severity in an Australian adult population. Thorax 60:211-214.
106. King, C., S. Brennan, P. J. Thompson, and G. A. Stewart. 1998. Dust mite proteolytic allergens induce cytokine release from cultured airway epithelium. J Immunol 161:3645-3651.
107. King, C., R. J. Simpson, R. L. Moritz, G. E. Reed, P. J. Thompson, and G. A. Stewart. 1996. The isolation and characterization of a novel collagenolytic serine protease allergen (Der p 9) from the dust mite Dermatophagoides pteronyssinus. J Allergy Clin Immunol 98:739-747.
108. Kishore, U., A. L. Bernal, M. F. Kamran, S. Saxena, M. Singh, P. U. Sarma, T. Madan, and T. Chakraborty. 2005. Surfactant proteins SP-A and SP-D in human health and disease. Arch Immunol Ther Exp (Warsz) 53:399-417.
109. Kishore, U., T. J. Greenhough, P. Waters, A. K. Shrive, R. Ghai, M. F. Kamran, A. L. Bernal, K. B. Reid, T. Madan, and T. Chakraborty. 2006. Surfactant proteins SP-A and SP-D: structure, function and receptors. Mol Immunol 43:1293-1315.
110. Koch, A., M. Raidl, M. Lux, K. Muller, H. Buning, S. Humme, and E. Erdmann. 2007. IL-12-induced T-bet expression and IFNgamma release in lymphocytes from asthmatics--role of MAPkinases ERK-1/-2, p38(MAPK) and effect of dexamethasone. Respir Med 101:1321-1330.
111. Komai, M., H. Tanaka, T. Masuda, K. Nagao, M. Ishizaki, M. Sawada, and H. Nagai. 2003. Role of Th2 responses in the development of allergen-induced airway remodelling in a murine model of allergic asthma. Br J Pharmacol 138:912-920.
112. Koopmans, J. G., J. S. van der Zee, E. J. Krop, C. E. Lopuhaa, H. M. Jansen, and J. J. Batenburg. 2004. Serum surfactant protein D is elevated in allergic patients. Clin Exp Allergy 34:1827-1833.
113. Koppelman, G. H., N. E. Reijmerink, O. Colin Stine, T. D. Howard, P. A. Whittaker, D. A. Meyers, D. S. Postma, and E. R. Bleecker. 2001. Association of a promoter polymorphism of the CD14 gene and atopy. Am J Respir Crit Care Med 163:965-969.
114. Kurashima, K., H. Ogawa, T. Ohka, M. Fujimura, T. Matsuda, and T. Kobayashi. 1991. A pilot study of surfactant inhalation in the treatment of asthmatic attack. Arerugi 40:160-163.
115. Kurashima, K., H. Ogawa, T. Ohka, M. Fujimura, T. Matsuda, and T. Kobayashi. 1991. A pilot study of surfactant inhalation in the treatment of asthmatic attack. Arerugi 40:160-163.
116. Lake, F. R., L. D. Ward, R. J. Simpson, P. J. Thompson, and G. A. Stewart. 1991. House dust mite-derived amylase: allergenicity and physicochemical characterization. J Allergy Clin Immunol 87:1035-1042.
117. Lauener, R. P., T. Birchler, J. Adamski, C. Braun-Fahrlander, A. Bufe, U. Herz, E. von Mutius, D. Nowak, J. Riedler, M. Waser, and F. H. Sennhauser. 2002. Expression of CD14 and Toll-like receptor 2 in farmers' and non-farmers' children. Lancet 360:465-466.
118. Lee, C. S., L. C. Tsai, P. L. Chao, C. Y. Lin, M. W. Hung, A. I. Chien, Y. T. Chiang, and S. H. Han. 2004. Protein sequence analysis of a novel 103-kDa Dermatophagoides pteronyssinus mite allergen and prevalence of serum immunoglobulin E reactivity to rDer p 11 in allergic adult patients. Clin Exp Allergy 34:354-362.
119. Lee, N. A., and J. J. Lee. 1999. The macroimportance of the pulmonary immune microenvironment. Am J Respir Cell Mol Biol 21:298-302.
120. Lemaitre, B. 2004. The road to Toll. Nat Rev Immunol 4:521-527.
121. LeVine, A. M., J. Elliott, J. A. Whitsett, A. Srikiatkhachorn, E. Crouch, N. DeSilva, and T. Korfhagen. 2004. Surfactant protein-d enhances phagocytosis and pulmonary clearance of respiratory syncytial virus. Am J Respir Cell Mol Biol 31:193-199.
122. Lim, B. L., J. Y. Wang, U. Holmskov, H. J. Hoppe, and K. B. Reid. 1994. Expression of the carbohydrate recognition domain of lung surfactant protein D and demonstration of its binding to lipopolysaccharides of gram-negative bacteria. Biochem Biophys Res Commun 202:1674-1680.
123. Lin, K. L., K. H. Hsieh, W. R. Thomas, B. L. Chiang, and K. Y. Chua. 1994. Characterization of Der p V allergen, cDNA analysis, and IgE-mediated reactivity to the recombinant protein. J Allergy Clin Immunol 94:989-996.
124. Liu, C. F., Y. L. Chen, W. T. Chang, C. C. Shieh, C. K. Yu, K. B. Reid, and J. Y. Wang. 2005. Mite allergen induces nitric oxide production in alveolar macrophage cell lines via CD14/toll-like receptor 4, and is inhibited by surfactant protein D. Clin Exp Allergy 35:1615-1624.
125. Liu, C. F., Y. L. Chen, C. C. Shieh, C. K. Yu, K. B. Reid, and J. Y. Wang. 2005. Therapeutic effect of surfactant protein D in allergic inflammation of mite-sensitized mice. Clin Exp Allergy 35:515-521.
126. Liu, M., L. Wang, E. Li, and G. Enhorning. 1996. Pulmonary surfactant given prophylactically alleviates an asthma attack in guinea-pigs. Clin Exp Allergy 26:270-275.
127. Louis, R., L. C. Lau, A. O. Bron, A. C. Roldaan, M. Radermecker, and R. Djukanovic. 2000. The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med 161:9-16.
128. Lynch, N. R., W. R. Thomas, Y. Chua, N. Garcia, M. C. Di Prisco, and R. Lopez. 1994. In vivo biological activity of recombinant Der p II allergen of house-dust mite. Int Arch Allergy Immunol 105:70-74.
129. Madan, T., U. Kishore, A. Shah, P. Eggleton, P. Strong, J. Y. Wang, S. S. Aggrawal, P. U. Sarma, and K. B. Reid. 1997. Lung surfactant proteins A and D can inhibit specific IgE binding to the allergens of Aspergillus fumigatus and block allergen-induced histamine release from human basophils. Clin Exp Immunol 110:241-249.
130. Madan, T., U. Kishore, M. Singh, P. Strong, H. Clark, E. M. Hussain, K. B. Reid, and P. U. Sarma. 2001. Surfactant proteins A and D protect mice against pulmonary hypersensitivity induced by Aspergillus fumigatus antigens and allergens. J Clin Invest 107:467-475.
131. Madan, T., K. B. Reid, M. Singh, P. U. Sarma, and U. Kishore. 2005. Susceptibility of mice genetically deficient in the surfactant protein (SP)-A or SP-D gene to pulmonary hypersensitivity induced by antigens and allergens of Aspergillus fumigatus. J Immunol 174:6943-6954.
132. Maeda, N., J. Nigou, J. L. Herrmann, M. Jackson, A. Amara, P. H. Lagrange, G. Puzo, B. Gicquel, and O. Neyrolles. 2003. The cell surface receptor DC-SIGN discriminates between Mycobacterium species through selective recognition of the mannose caps on lipoarabinomannan. J Biol Chem 278:5513-5516.
133. Maestrelli, P., M. Saetta, A. Di Stefano, P. G. Calcagni, G. Turato, M. P. Ruggieri, A. Roggeri, C. E. Mapp, and L. M. Fabbri. 1995. Comparison of leukocyte counts in sputum, bronchial biopsies, and bronchoalveolar lavage. Am J Respir Crit Care Med 152:1926-1931.
134. Marsh, D. G., J. D. Neely, D. R. Breazeale, B. Ghosh, L. R. Freidhoff, E. Ehrlich-Kautzky, C. Schou, G. Krishnaswamy, and T. H. Beaty. 1994. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science 264:1152-1156.
135. Marshall, J. S., J. D. McCurdy, and T. Olynych. 2003. Toll-like receptor-mediated activation of mast cells: implications for allergic disease? Int Arch Allergy Immunol 132:87-97.
136. Martin, T. R., and C. W. Frevert. 2005. Innate immunity in the lungs. Proc Am Thorac Soc 2:403-411.
137. Maruo, K., T. Akaike, T. Ono, T. Okamoto, and H. Maeda. 1997. Generation of anaphylatoxins through proteolytic processing of C3 and C5 by house dust mite protease. J Allergy Clin Immunol 100:253-260.
138. McCormack, F. X., and J. A. Whitsett. 2002. The pulmonary collectins, SP-A and SP-D, orchestrate innate immunity in the lung. J Clin Invest 109:707-712.
139. Medzhitov, R., P. Preston-Hurlburt, and C. A. Janeway, Jr. 1997. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394-397.
140. Meurs, H., H. Maarsingh, and J. Zaagsma. 2003. Arginase and asthma: novel insights into nitric oxide homeostasis and airway hyperresponsiveness. Trends Pharmacol Sci 24:450-455.
141. Meyer, E. H., R. H. DeKruyff, and D. T. Umetsu. 2008. T cells and NKT cells in the pathogenesis of asthma. Annu Rev Med 59:281-292.
142. Meyers, D. A., D. S. Postma, C. I. Panhuysen, J. Xu, P. J. Amelung, R. C. Levitt, and E. R. Bleecker. 1994. Evidence for a locus regulating total serum IgE levels mapping to chromosome 5. Genomics 23:464-470.
143. Miyamura, K., L. E. Leigh, J. Lu, J. Hopkin, A. Lopez Bernal, and K. B. Reid. 1994. Surfactant protein D binding to alveolar macrophages. Biochem J 300 ( Pt 1):237-242.
144. Montefort, S., C. Gratziou, D. Goulding, R. Polosa, D. O. Haskard, P. H. Howarth, S. T. Holgate, and M. P. Carroll. 1994. Bronchial biopsy evidence for leukocyte infiltration and upregulation of leukocyte-endothelial cell adhesion molecules 6 hours after local allergen challenge of sensitized asthmatic airways. J Clin Invest 93:1411-1421.
145. Moseman, E. A., X. Liang, A. J. Dawson, A. Panoskaltsis-Mortari, A. M. Krieg, Y. J. Liu, B. R. Blazar, and W. Chen. 2004. Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+CD25+ regulatory T cells. J Immunol 173:4433-4442.
146. Murakami, S., D. Iwaki, H. Mitsuzawa, H. Sano, H. Takahashi, D. R. Voelker, T. Akino, and Y. Kuroki. 2002. Surfactant protein A inhibits peptidoglycan-induced tumor necrosis factor-alpha secretion in U937 cells and alveolar macrophages by direct interaction with toll-like receptor 2. J Biol Chem 277:6830-6837.
147. Nelson, H. S. 2000. The importance of allergens in the development of asthma and the persistence of symptoms. J Allergy Clin Immunol 105:S628-632.
148. Nigou, J., C. Zelle-Rieser, M. Gilleron, M. Thurnher, and G. Puzo. 2001. Mannosylated lipoarabinomannans inhibit IL-12 production by human dendritic cells: evidence for a negative signal delivered through the mannose receptor. J Immunol 166:7477-7485.
149. Nogee, L. M. 2004. Genetic mechanisms of surfactant deficiency. Biol Neonate 85:314-318.
150. Nogee, L. M. 2004. Alterations in SP-B and SP-C expression in neonatal lung disease. Annu Rev Physiol 66:601-623.
151. O'Brien, R. M., K. A. Byron, G. A. Varigos, and W. R. Thomas. 1997. House dust mite immunotherapy results in a decrease in Der p 2-specific IFN-gamma and IL-4 expression by circulating T lymphocytes. Clin Exp Allergy 27:46-51.
152. O'Donnell, A. R., B. G. Toelle, G. B. Marks, C. M. Hayden, I. A. Laing, J. K. Peat, J. Goldblatt, and P. N. Le Souef. 2004. Age-specific relationship between CD14 and atopy in a cohort assessed from age 8 to 25 years. Am J Respir Crit Care Med 169:615-622.
153. Oetomo, S. B., C. Dorrepaal, H. Bos, J. Gerritsen, T. W. van der Mark, G. H. Koeter, and W. M. van Aalderen. 1996. Surfactant nebulization does not alter airflow obstruction and bronchial responsiveness to histamine in asthmatic children. Am J Respir Crit Care Med 153:1148-1152.
154. Oetomo, S. B., C. Dorrepaal, H. Bos, J. Gerritsen, T. W. van der Mark, G. H. Koeter, and W. M. van Aalderen. 1996. Surfactant nebulization does not alter airflow obstruction and bronchial responsiveness to histamine in asthmatic children. Am J Respir Crit Care Med 153:1148-1152.
155. Ohya, M., C. Nishitani, H. Sano, C. Yamada, H. Mitsuzawa, T. Shimizu, T. Saito, K. Smith, E. Crouch, and Y. Kuroki. 2006. Human pulmonary surfactant protein D binds the extracellular domains of Toll-like receptors 2 and 4 through the carbohydrate recognition domain by a mechanism different from its binding to phosphatidylinositol and lipopolysaccharide. Biochemistry 45:8657-8664.
156. O'Neill, G. M., G. R. Donovan, and B. A. Baldo. 1994. Cloning and characterization of a major allergen of the house dust mite, Dermatophagoides pteronyssinus, homologous with glutathione S-transferase. Biochim Biophys Acta 1219:521-528.
157. Palaniyar, N., J. Nadesalingam, H. Clark, M. J. Shih, A. W. Dodds, and K. B. Reid. 2004. Nucleic acid is a novel ligand for innate, immune pattern recognition collectins surfactant proteins A and D and mannose-binding lectin. J Biol Chem 279:32728-32736.
158. Panettieri, R. A., Jr. 2003. Airway smooth muscle: immunomodulatory cells that modulate airway remodeling? Respir Physiol Neurobiol 137:277-293.
159. Parham, C., M. Chirica, J. Timans, E. Vaisberg, M. Travis, J. Cheung, S. Pflanz, R. Zhang, K. P. Singh, F. Vega, W. To, J. Wagner, A. M. O'Farrell, T. McClanahan, S. Zurawski, C. Hannum, D. Gorman, D. M. Rennick, R. A. Kastelein, R. de Waal Malefyt, and K. W. Moore. 2002. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol 168:5699-5708.
160. Park, C. G., K. Takahara, E. Umemoto, Y. Yashima, K. Matsubara, Y. Matsuda, B. E. Clausen, K. Inaba, and R. M. Steinman. 2001. Five mouse homologues of the human dendritic cell C-type lectin, DC-SIGN. Int Immunol 13:1283-1290.
161. Parker, L. C., L. R. Prince, and I. Sabroe. 2007. Translational mini-review series on Toll-like receptors: networks regulated by Toll-like receptors mediate innate and adaptive immunity. Clin Exp Immunol 147:199-207.
162. Parkinson, T. 2008. The future of toll-like receptor therapeutics. Curr Opin Mol Ther 10:21-31.
163. Pastva, A. M., J. R. Wright, and K. L. Williams. 2007. Immunomodulatory roles of surfactant proteins A and D: implications in lung disease. Proc Am Thorac Soc 4:252-257.
164. Patel, M., D. Xu, P. Kewin, B. Choo-Kang, C. McSharry, N. C. Thomson, and F. Y. Liew. 2005. TLR2 agonist ameliorates established allergic airway inflammation by promoting Th1 response and not via regulatory T cells. J Immunol 174:7558-7563.
165. Paul-Clark, M. J., S. K. McMaster, E. Belcher, R. Sorrentino, J. Anandarajah, M. Fleet, S. Sriskandan, and J. A. Mitchell. 2006. Differential effects of Gram-positive versus Gram-negative bacteria on NOSII and TNFalpha in macrophages: role of TLRs in synergy between the two. Br J Pharmacol 148:1067-1075.
166. Paul-Clark, M. J., S. K. McMaster, E. Belcher, R. Sorrentino, J. Anandarajah, M. Fleet, S. Sriskandan, and J. A. Mitchell. 2006. Differential effects of Gram-positive versus Gram-negative bacteria on NOSII and TNFalpha in macrophages: role of TLRs in synergy between the two. Br J Pharmacol 148:1067-1075.
167. Peake, H. L., A. J. Currie, G. A. Stewart, and A. S. McWilliam. 2003. Nitric oxide production by alveolar macrophages in response to house dust mite fecal pellets and the mite allergens, Der p 1 and Der p 2. J Allergy Clin Immunol 112:531-537.
168. Persson, A., K. Rust, D. Chang, M. Moxley, W. Longmore, and E. Crouch. 1988. CP4: a pneumocyte-derived collagenous surfactant-associated protein. Evidence for heterogeneity of collagenous surfactant proteins. Biochemistry 27:8576-8584.
169. Platts-Mills, T. A., W. R. Thomas, R. C. Aalberse, D. Vervloet, and M. D. Champman. 1992. Dust mite allergens and asthma: report of a second international workshop. J Allergy Clin Immunol 89:1046-1060.
170. Platts-Mills, T. A., J. A. Woodfolk, E. A. Erwin, and R. Aalberse. 2004. Mechanisms of tolerance to inhalant allergens: the relevance of a modified Th2 response to allergens from domestic animals. Springer Semin Immunopathol 25:271-279.
171. Poltorak, A., X. He, I. Smirnova, M. Y. Liu, C. Van Huffel, X. Du, D. Birdwell, E. Alejos, M. Silva, C. Galanos, M. Freudenberg, P. Ricciardi-Castagnoli, B. Layton, and B. Beutler. 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085-2088.
172. Ragas, A., L. Roussel, G. Puzo, and M. Riviere. 2007. The Mycobacterium tuberculosis cell-surface glycoprotein apa as a potential adhesin to colonize target cells via the innate immune system pulmonary C-type lectin surfactant protein A. J Biol Chem 282:5133-5142.
173. Raschke, W. C., S. Baird, P. Ralph, and I. Nakoinz. 1978. Functional macrophage cell lines transformed by Abelson leukemia virus. Cell 15:261-267.
174. Re, F., and J. L. Strominger. 2004. IL-10 released by concomitant TLR2 stimulation blocks the induction of a subset of Th1 cytokines that are specifically induced by TLR4 or TLR3 in human dendritic cells. J Immunol 173:7548-7555.
175. Redecke, V., H. Hacker, S. K. Datta, A. Fermin, P. M. Pitha, D. H. Broide, and E. Raz. 2004. Cutting edge: activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. J Immunol 172:2739-2743.
176. Reis e Sousa, C., A. Sher, and P. Kaye. 1999. The role of dendritic cells in the induction and regulation of immunity to microbial infection. Curr Opin Immunol 11:392-399.
177. Renz, H., and U. Herz. 2002. The bidirectional capacity of bacterial antigens to modulate allergy and asthma. Eur Respir J 19:158-171.
178. Rescigno, M., and P. Borrow. 2001. The host-pathogen interaction: new themes from dendritic cell biology. Cell 106:267-270.
179. Revets, H., G. Pynaert, J. Grooten, and P. De Baetselier. 2005. Lipoprotein I, a TLR2/4 ligand modulates Th2-driven allergic immune responses. J Immunol 174:1097-1103.
180. Robinson, D., Q. Hamid, A. Bentley, S. Ying, A. B. Kay, and S. R. Durham. 1993. Activation of CD4+ T cells, increased TH2-type cytokine mRNA expression, and eosinophil recruitment in bronchoalveolar lavage after allergen inhalation challenge in patients with atopic asthma. J Allergy Clin Immunol 92:313-324.
181. Rodriguez, D., A. C. Keller, E. L. Faquim-Mauro, M. S. de Macedo, F. Q. Cunha, J. Lefort, B. B. Vargaftig, and M. Russo. 2003. Bacterial lipopolysaccharide signaling through Toll-like receptor 4 suppresses asthma-like responses via nitric oxide synthase 2 activity. J Immunol 171:1001-1008.
182. Romagnani, S. 2004. The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both? Immunology 112:352-363.
183. Sackesen, C., C. Karaaslan, O. Keskin, N. Tokol, F. Tahan, E. Civelek, O. U. Soyer, G. Adalioglu, A. Tuncer, E. Birben, C. Oner, and O. Kalayci. 2005. The effect of polymorphisms at the CD14 promoter and the TLR4 gene on asthma phenotypes in Turkish children with asthma. Allergy 60:1485-1492.
184. Salo, P. M., S. J. Arbes, Jr., P. W. Crockett, P. S. Thorne, R. D. Cohn, and D. C. Zeldin. 2008. Exposure to multiple indoor allergens in US homes and its relationship to asthma. J Allergy Clin Immunol 121:678-684 e672.
185. Sano, H., H. Chiba, D. Iwaki, H. Sohma, D. R. Voelker, and Y. Kuroki. 2000. Surfactant proteins A and D bind CD14 by different mechanisms. J Biol Chem 275:22442-22451.
186. Sano, H., H. Sohma, T. Muta, S. Nomura, D. R. Voelker, and Y. Kuroki. 1999. Pulmonary surfactant protein A modulates the cellular response to smooth and rough lipopolysaccharides by interaction with CD14. J Immunol 163:387-395.
187. Sato, M., H. Sano, D. Iwaki, K. Kudo, M. Konishi, H. Takahashi, T. Takahashi, H. Imaizumi, Y. Asai, and Y. Kuroki. 2003. Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-kappa B activation and TNF-alpha secretion are down-regulated by lung collectin surfactant protein A. J Immunol 171:417-425.
188. Schagat, T. L., J. A. Wofford, and J. R. Wright. 2001. Surfactant protein A enhances alveolar macrophage phagocytosis of apoptotic neutrophils. J Immunol 166:2727-2733.
189. Schaub, B., R. M. Westlake, H. He, R. Arestides, K. J. Haley, M. Campo, G. Velasco, A. Bellou, S. Hawgood, F. R. Poulain, D. L. Perkins, and P. W. Finn. 2004. Surfactant protein D deficiency influences allergic immune responses. Clin Exp Allergy 34:1819-1826.
190. Schroder, N. W., and M. Arditi. 2007. The role of innate immunity in the pathogenesis of asthma: evidence for the involvement of Toll-like receptor signaling. J Endotoxin Res 13:305-312.
191. Schroder, N. W., and R. R. Schumann. 2005. Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis 5:156-164.
192. Schulz, O., H. F. Sewell, and F. Shakib. 1998. Proteolytic cleavage of CD25, the alpha subunit of the human T cell interleukin 2 receptor, by Der p 1, a major mite allergen with cysteine protease activity. J Exp Med 187:271-275.
193. Scobie, G., V. Ravindran, S. M. Deam, M. Thomas, S. K. Sreedharan, K. Brocklehurst, and N. Kalsheker. 1994. Expression cloning of a dust mite cysteine proteinase, Der p1, a major allergen associated with asthma and hypersensitivity reactions. Biochem Soc Trans 22:448S.
194. Shakib, F., O. Schulz, and H. Sewell. 1998. A mite subversive: cleavage of CD23 and CD25 by Der p 1 enhances allergenicity. Immunol Today 19:313-316.
195. Sharma, M., J. Batra, U. Mabalirajan, S. Goswami, D. Ganguly, B. Lahkar, N. K. Bhatia, A. Kumar, and B. Ghosh. 2004. Suggestive evidence of association of C-159T functional polymorphism of the CD14 gene with atopic asthma in northern and northwestern Indian populations. Immunogenetics 56:544-547.
196. Shirakawa, T., T. Enomoto, S. Shimazu, and J. M. Hopkin. 1997. The inverse association between tuberculin responses and atopic disorder. Science 275:77-79.
197. Sigsgaard, T., H. J. Hoffmann, and P. S. Thorne. 2008. The role of innate immunity in occupational allergy: recent findings. Curr Opin Allergy Clin Immunol 8:120-125.
198. Singh, M., T. Madan, P. Waters, S. K. Parida, P. U. Sarma, and U. Kishore. 2003. Protective effects of a recombinant fragment of human surfactant protein D in a murine model of pulmonary hypersensitivity induced by dust mite allergens. Immunol Lett 86:299-307.
199. Slack, J. L., K. Schooley, T. P. Bonnert, J. L. Mitcham, E. E. Qwarnstrom, J. E. Sims, and S. K. Dower. 2000. Identification of two major sites in the type I interleukin-1 receptor cytoplasmic region responsible for coupling to pro-inflammatory signaling pathways. J Biol Chem 275:4670-4678.
200. Smith, J. M., and V. H. Springett. 1979. Atopic disease and month of birth. Clin Allergy 9:153-157.
201. Spahn, J., R. Covar, and D. A. Stempel. 2002. Asthma: addressing consistency in results from basic science, clinical trials, and observational experience. J Allergy Clin Immunol 109:S490-502.
202. Stamme, C., E. Walsh, and J. R. Wright. 2000. Surfactant protein A differentially regulates IFN-gamma- and LPS-induced nitrite production by rat alveolar macrophages. Am J Respir Cell Mol Biol 23:772-779.
203. Staros, E. B. 2005. Innate immunity: New approaches to understanding its clinical significance. Am J Clin Pathol 123:305-312.
204. Stewart, G. A., S. M. Boyd, C. H. Bird, K. D. Krska, M. R. Kollinger, and P. J. Thompson. 1994. Immunobiology of the serine protease allergens from house dust mites. Am J Ind Med 25:105-107.
205. Stewart, G. A., and P. J. Thompson. 1996. The biochemistry of common aeroallergens. Clin Exp Allergy 26:1020-1044.
206. Stewart, G. A., L. D. Ward, R. J. Simpson, and P. J. Thompson. 1992. The group III allergen from the house dust mite Dermatophagoides pteronyssinus is a trypsin-like enzyme. Immunology 75:29-35.
207. Strachan, D. P. 1989. Hay fever, hygiene, and household size. BMJ 299:1259-1260.
208. Strickland, D. H., U. R. Kees, and P. G. Holt. 1994. Suppression of T-cell activation by pulmonary alveolar macrophages: dissociation of effects on TcR, IL-2R expression, and proliferation. Eur Respir J 7:2124-2130.
209. Strong, P., U. Kishore, C. Morgan, A. Lopez Bernal, M. Singh, and K. B. Reid. 1998. A novel method of purifying lung surfactant proteins A and D from the lung lavage of alveolar proteinosis patients and from pooled amniotic fluid. J Immunol Methods 220:139-149.
210. Strong, P., P. Townsend, R. Mackay, K. B. Reid, and H. W. Clark. 2003. A recombinant fragment of human SP-D reduces allergic responses in mice sensitized to house dust mite allergens. Clin Exp Immunol 134:181-187.
211. Sultzer, B. M. 1968. Endotoxin-induced resistance to a staphylococcal infection: cellular and humoral responses compared in two mouse strains. J Infect Dis 118:340-348.
212. Takahashi, K., T. Aoki, S. Kohmoto, H. Nishimura, Y. Kodera, A. Matsushima, and Y. Inada. 1990. Activation of kallikrein-kinin system in human plasma with purified serine protease from Dermatophagoides farinae. Int Arch Allergy Appl Immunol 91:80-85.
213. Takeda, K., N. Miyahara, Y. H. Rha, C. Taube, E. S. Yang, A. Joetham, T. Kodama, A. M. Balhorn, A. Dakhama, C. Duez, A. J. Evans, D. R. Voelker, and E. W. Gelfand. 2003. Surfactant protein D regulates airway function and allergic inflammation through modulation of macrophage function. Am J Respir Crit Care Med 168:783-789.
214. Takeuchi, O., T. Kawai, P. F. Muhlradt, M. Morr, J. D. Radolf, A. Zychlinsky, K. Takeda, and S. Akira. 2001. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol 13:933-940.
215. Takeuchi, O., S. Sato, T. Horiuchi, K. Hoshino, K. Takeda, Z. Dong, R. L. Modlin, and S. Akira. 2002. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol 169:10-14.
216. Tan, C. Y., Y. L. Chen, L. S. Wu, C. F. Liu, W. T. Chang, and J. Y. Wang. 2006. Association of CD14 promoter polymorphisms and soluble CD14 levels in mite allergen sensitization of children in Taiwan. J Hum Genet 51:59-67.
217. Tang, R. B., L. C. Tsai, H. M. Hwang, B. Hwang, K. G. Wu, and M. W. Hung. 1990. The prevalence of allergic disease and IgE antibodies to house dust mite in schoolchildren in Taiwan. Clin Exp Allergy 20:33-38.
218. Taube, C., A. Dakhama, K. Takeda, J. A. Nick, and E. W. Gelfand. 2003. Allergen-specific early neutrophil infiltration after allergen challenge in a murine model. Chest 123:410S-411S.
219. Taylor, R. C., P. Richmond, and J. W. Upham. 2006. Toll-like receptor 2 ligands inhibit TH2 responses to mite allergen. J Allergy Clin Immunol 117:1148-1154.
220. Taylor-Robinson, A. W., F. Y. Liew, A. Severn, D. Xu, S. J. McSorley, P. Garside, J. Padron, and R. S. Phillips. 1994. Regulation of the immune response by nitric oxide differentially produced by T helper type 1 and T helper type 2 cells. Eur J Immunol 24:980-984.
221. Tenner, A. J., S. L. Robinson, J. Borchelt, and J. R. Wright. 1989. Human pulmonary surfactant protein (SP-A), a protein structurally homologous to C1q, can enhance FcR- and CR1-mediated phagocytosis. J Biol Chem 264:13923-13928.
222. Thepen, T., K. Hoeben, J. Breve, and G. Kraal. 1992. Alveolar macrophages down-regulate local pulmonary immune responses against intratracheally administered T-cell-dependent, but not T-cell-independent antigens. Immunology 76:60-64.
223. Toshchakov, V., B. W. Jones, P. Y. Perera, K. Thomas, M. J. Cody, S. Zhang, B. R. Williams, J. Major, T. A. Hamilton, M. J. Fenton, and S. N. Vogel. 2002. TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nat Immunol 3:392-398.
224. Trinchieri, G. 2003. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3:133-146.
225. Umetsu, D. T., and R. H. DeKruyff. 2006. The regulation of allergy and asthma. Immunol Rev 212:238-255.
226. van der Pouw Kraan, T. C., L. C. Boeije, E. R. de Groot, S. O. Stapel, A. Snijders, M. L. Kapsenberg, J. S. van der Zee, and L. A. Aarden. 1997. Reduced production of IL-12 and IL-12-dependent IFN-gamma release in patients with allergic asthma. J Immunol 158:5560-5565.
227. Van Vyve, T., P. Chanez, A. Bernard, J. Bousquet, P. Godard, R. Lauwerijs, and Y. Sibille. 1995. Protein content in bronchoalveolar lavage fluid of patients with asthma and control subjects. J Allergy Clin Immunol 95:60-68.
228. Velasco, G., M. Campo, O. J. Manrique, A. Bellou, H. He, R. S. Arestides, B. Schaub, D. L. Perkins, and P. W. Finn. 2005. Toll-like receptor 4 or 2 agonists decrease allergic inflammation. Am J Respir Cell Mol Biol 32:218-224.
229. Vercelli, D. 2002. The functional genomics of CD14 and its role in IgE responses: an integrated view. J Allergy Clin Immunol 109:14-21.
230. Vercelli, D. 2004. Genetics, epigenetics, and the environment: switching, buffering, releasing. J Allergy Clin Immunol 113:381-386; quiz 387.
231. Viksman, M. Y., M. C. Liu, C. A. Bickel, R. P. Schleimer, and B. S. Bochner. 1997. Phenotypic analysis of alveolar macrophages and monocytes in allergic airway inflammation. I. Evidence for activation of alveolar macrophages, but not peripheral blood monocytes, in subjects with allergic rhinitis and asthma. Am J Respir Crit Care Med 155:858-863.
232. von Mutius, E. 2007. Allergies, infections and the hygiene hypothesis--the epidemiological evidence. Immunobiology 212:433-439.
233. Wan, H., H. L. Winton, C. Soeller, E. R. Tovey, D. C. Gruenert, P. J. Thompson, G. A. Stewart, G. W. Taylor, D. R. Garrod, M. B. Cannell, and C. Robinson. 1999. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J Clin Invest 104:123-133.
234. Wang, J. L., N. S. Shaw, and M. D. Kao. 2007. Magnesium deficiency and its lack of association with asthma in Taiwanese elementary school children. Asia Pac J Clin Nutr 16 Suppl 2:579-584.
235. Wang, J. Y., U. Kishore, B. L. Lim, P. Strong, and K. B. Reid. 1996. Interaction of human lung surfactant proteins A and D with mite (Dermatophagoides pteronyssinus) allergens. Clin Exp Immunol 106:367-373.
236. Wang, J. Y., and K. B. Reid. 2007. The immunoregulatory roles of lung surfactant collectins SP-A, and SP-D, in allergen-induced airway inflammation. Immunobiology 212:417-425.
237. Wang, J. Y., C. C. Shieh, P. F. You, H. Y. Lei, and K. B. Reid. 1998. Inhibitory effect of pulmonary surfactant proteins A and D on allergen-induced lymphocyte proliferation and histamine release in children with asthma. Am J Respir Crit Care Med 158:510-518.
238. Wang, J. Y., C. C. Shieh, C. K. Yu, and H. Y. Lei. 2001. Allergen-induced bronchial inflammation is associated with decreased levels of surfactant proteins A and D in a murine model of asthma. Clin Exp Allergy 31:652-662.
239. Wang, J. Y., L. M. Wang, C. G. Lin, A. C. Chang, and L. S. Wu. 2005. Association study using combination analysis of SNP and STRP markers: CD14 promoter polymorphism and IgE level in Taiwanese asthma children. J Hum Genet 50:36-41.
240. Ward, M. D., S. L. Madison, D. M. Sailstad, S. H. Gavett, and M. K. Selgrade. 2000. Allergen-triggered airway hyperresponsiveness and lung pathology in mice sensitized with the biopesticide Metarhizium anisopliae. Toxicology 143:141-154.
241. Weaver, T. E. 1991. Surfactant proteins and SP-D. Am J Respir Cell Mol Biol 5:4-5.
242. Weigt, H., P. F. Muhlradt, M. Larbig, N. Krug, and A. Braun. 2004. The Toll-like receptor-2/6 agonist macrophage-activating lipopeptide-2 cooperates with IFN-gamma to reverse the Th2 skew in an in vitro allergy model. J Immunol 172:6080-6086.
243. Wenzel, S. E., L. B. Schwartz, E. L. Langmack, J. L. Halliday, J. B. Trudeau, R. L. Gibbs, and H. W. Chu. 1999. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 160:1001-1008.
244. Williams, C. M., and S. J. Galli. 2000. Mast cells can amplify airway reactivity and features of chronic inflammation in an asthma model in mice. J Exp Med 192:455-462.
245. Williams, L. K., D. R. Ownby, M. J. Maliarik, and C. C. Johnson. 2005. The role of endotoxin and its receptors in allergic disease. Ann Allergy Asthma Immunol 94:323-332.
246. Wills-Karp, M. 2007. Complement activation pathways: a bridge between innate and adaptive immune responses in asthma. Proc Am Thorac Soc 4:247-251.
247. Wright, J. R. 1997. Immunomodulatory functions of surfactant. Physiol Rev 77:931-962.
248. Wright, J. R. 2003. Pulmonary surfactant: a front line of lung host defense. J Clin Invest 111:1453-1455.
249. Wright, J. R. 2005. Immunoregulatory functions of surfactant proteins. Nat Rev Immunol 5:58-68.
250. Wright, J. R., P. Borron, K. G. Brinker, and R. J. Folz. 2001. Surfactant Protein A: regulation of innate and adaptive immune responses in lung inflammation. Am J Respir Cell Mol Biol 24:513-517.
251. Wu, F., and T. K. Takaro. 2007. Childhood asthma and environmental interventions. Environ Health Perspect 115:971-975.
252. Wu, H., A. Kuzmenko, S. Wan, L. Schaffer, A. Weiss, J. H. Fisher, K. S. Kim, and F. X. McCormack. 2003. Surfactant proteins A and D inhibit the growth of Gram-negative bacteria by increasing membrane permeability. J Clin Invest 111:1589-1602.
253. Yasueda, H., H. Mita, K. Akiyama, T. Shida, T. Ando, S. Sugiyama, and H. Yamakawa. 1993. Allergens from Dermatophagoides mites with chymotryptic activity. Clin Exp Allergy 23:384-390.
254. Ying, S., S. R. Durham, C. J. Corrigan, Q. Hamid, and A. B. Kay. 1995. Phenotype of cells expressing mRNA for TH2-type (interleukin 4 and interleukin 5) and TH1-type (interleukin 2 and interferon gamma) cytokines in bronchoalveolar lavage and bronchial biopsies from atopic asthmatic and normal control subjects. Am J Respir Cell Mol Biol 12:477-487.
255. Zambelli-Weiner, A., E. Ehrlich, M. L. Stockton, A. V. Grant, S. Zhang, P. N. Levett, T. H. Beaty, and K. C. Barnes. 2005. Evaluation of the CD14/-260 polymorphism and house dust endotoxin exposure in the Barbados Asthma Genetics Study. J Allergy Clin Immunol 115:1203-1209.
256. Zhang, D., G. Zhang, M. S. Hayden, M. B. Greenblatt, C. Bussey, R. A. Flavell, and S. Ghosh. 2004. A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303:1522-1526.
257. Zhou, L. F., and K. S. Yin. 2004. Toll-like receptors: function and roles in asthma. Chin Med J (Engl) 117:1709-1715.