Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 144 No. 5152 (2014)

Childhood asthma: causes, risks, and protective factors; a role of innate immunity

  • Georgios T Noutsios
  • Joanna Floros
DOI
https://doi.org/10.4414/smw.2014.14036
Cite this as:
Swiss Med Wkly. 2014;144:w14036
Published
15.12.2014

Summary

Childhood asthma is an umbrella of multifactorial diseases with similar clinical features such as mast cell and eosinophil infiltration causing airway hyper responsiveness, inflammation, and airway obstruction. There are various factors that are implicated in childhood asthma pathogenesis. A combined contribution of genetic predisposition, environmental insults, and epigenetic changes account for polarisation of the immune system towards T helper (Th) type 2 cell responses that include production of pro-inflammatory cytokines, IgE, and eosinophil infiltrates, shown to associate with asthma. Environmental cues in prenatal, perinatal, and early childhood seem to determine development of asthma incidence or protection against it. Mode of birth delivery, use of antibiotics, oxidative stress, exposure to tobacco smoke and an industrialised lifestyle are significant contributors to childhood asthma exacerbation. Environmental stimuli such as exposure to maternal antibodies through breast milk, and certain early infections favour Th1 cell responses, leading to the production of anti-inflammatory cytokines that protect from asthma. Aside from the Th cell responses the role of innate immunity in the context of alveolar macrophages, dendritic cells, and surfactant protein A (SP-A) and SP-D is discussed. SP-A and SP-D enhance pathogen phagocytosis and cytokine production by alveolar macrophages, bind and clear pathogens, and interact with dendritic cells to mediate adaptive immunity responses. Further study of the interactions between genetic variants of genes of interest (SP-A and SP-D) and the environment may provide valuable knowledge about the underlying mechanisms of various interactions that differentially affect asthma susceptibility, disease severity, and reveal potential points for therapeutic interventions.

References

  1. Barnett SB, Nurmagambetov TA. Costs of asthma in the United States: 2002–2007. J Allergy Clin Immunol. 2011;127(1):145–52.
  2. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18(5):716–25.
  3. Ricciardolo FL. Revisiting the role of exhaled nitric oxide in asthma. Curr Opin Pulm Med. 2014;20(1):53–9.
  4. Lötvall J, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011;127(2):355–60.
  5. Tantisira KG, Colvin R, Tonascia J, Strunk RC, Weiss ST, Fuhlbrigge AL, Group CAMPR. Airway responsiveness in mild to moderate childhood asthma: sex influences on the natural history. Am J Respir Crit Care Med. 2008;178(4):325–31.
  6. Drevenstedt GL, Crimmins EM, Vasunilashorn S, Finch CE. The rise and fall of excess male infant mortality. Proc Natl Acad Sci U S A. 2008;105(13):5016–21.
  7. Doctor TH, Trivedi SS, Chudasama RK. Pulmonary function test in healthy school children of 8 to 14 years age in south Gujarat region, India. Lung India. 2010;27(3):145–8.
  8. Kirchengast S, Hartmannm B. The Male Disadvantage Hypothesis Reconsidered: Is There Really a Weaker Sex? An Analysis of Gender Differences in Newborn Somatometrics and Vital Parameters. In., vol. 1. J Life Sci; 2009:63–71.
  9. Hussein MH, Daoud GA, Kakita H, Hattori A, Murai H, Yasuda M, et al. The sex differences of cerebrospinal fluid levels of interleukin 8 and antioxidants in asphyxiated newborns. Shock. 2007;28(2):154–9.
  10. Etzel RA. How environmental exposures influence the development and exacerbation of asthma. Pediatrics. 2003;112(1 Pt 2):233–9.
  11. Ley D, Wide-Swensson D, Lindroth M, Svenningsen N, Marsal K. Respiratory distress syndrome in infants with impaired intrauterine growth. Acta Paediatr. 1997;86(10):1090–6.
  12. Collier CH, Risnes K, Norwitz ER, Bracken MB, Illuzzi JL. Maternal Infection in Pregnancy and Risk of Asthma in Offspring. Matern Child Health J. 2013.
  13. Alshehri MA, Almegamesi TM, Alfrayh AS. Predictors of short-term hospital readmissions of asthmatic children. J Family Community Med. 2005;12(1):11–7.
  14. Pido-Lopez J, Imami N, Aspinall R. Both age and gender affect thymic output: more recent thymic migrants in females than males as they age. Clin Exp Immunol. 2001;125(3):409–13.
  15. Arshad SH, Karmaus W, Raza A, Kurukulaaratchy RJ, Matthews SM, Holloway JW, et al. The effect of parental allergy on childhood allergic diseases depends on the sex of the child. J Allergy Clin Immunol. 2012;130(2):427–34.e426.
  16. Litonjua AA, Carey VJ, Burge HA, Weiss ST, Gold DR. Parental history and the risk for childhood asthma. Does mother confer more risk than father? Am J Respir Crit Care Med. 1998;158(1):176–81.
  17. de Marco R, Pattaro C, Locatelli F, Svanes C, Group ES. Influence of early life exposures on incidence and remission of asthma throughout life. J Allergy Clin Immunol. 2004;113(5):845–52.
  18. Warner JO, Boner A. Paediatric allergy and asthma, vol. Chapter 18: Elsevier Ltd; 2012.
  19. Klinnert MD, Nelson HS, Price MR, Adinoff AD, Leung DY, Mrazek DA. Onset and persistence of childhood asthma: predictors from infancy. Pediatrics. 2001;108(4):E69.
  20. Metsälä J, Kilkkinen A, Kaila M, Tapanainen H, Klaukka T, Gissler M, Virtanen SM. Perinatal factors and the risk of asthma in childhood – a population-based register study in Finland. Am J Epidemiol. 2008;168(2):170–8.
  21. Goodwin RD. Environmental tobacco smoke and the epidemic of asthma in children: the role of cigarette use. Ann Allergy Asthma Immunol. 2007;98(5):447–54.
  22. Morgan WJ, Stern DA, Sherrill DL, Guerra S, Holberg CJ, Guilbert TW, Taussig LM, Wright AL, Martinez FD. Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence. Am J Respir Crit Care Med. 2005;172(10):1253–8.
  23. Traherne JA, Hill MR, Hysi P, D’Amato M, Broxholme J, et al. LD mapping of maternally and non-maternally derived alleles and atopy in FcepsilonRI-beta: Hum Mol Genet. 2003;12(20):2577–85.
  24. Gilliland FD, Li YF, Dubeau L, Berhane K, Avol E, McConnell R, et al. Effects of glutathione S-transferase M1, maternal smoking during pregnancy, and environmental tobacco smoke on asthma and wheezing in children. Am J Respir Crit Care Med. 2002;166(4):457–63.
  25. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 201;363(13):1211–21.
  26. Torgerson DG, Ampleford EJ, Chiu GY, Gauderman WJ, Gignoux CR, Graves PE, et al. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat Genet. 2011;43(9):887–92.
  27. Ober C, Yao TC. The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev. 2011;242(1):10–30.
  28. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461(7265):747–53.
  29. Parker CC, Palmer AA. Dark matter: are mice the solution to missing heritability? Front Genet. 2011;2:32.
  30. Hansen G, Berry G, DeKruyff RH, Umetsu DT. Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J Clin Invest. 1999;103(2):175–83.
  31. Berger A. Th1 and Th2 responses: what are they? BMJ. 2000;321(7258):424.
  32. Finn PW, Bigby TD: Innate immunity and asthma. Proc Am Thorac Soc. 2009;6(3):260–5.
  33. Vock C, Hauber HP, Wegmann M. The other T helper cells in asthma pathogenesis. J Allergy (Cairo). 2010;2010:519298.
  34. Kreymborg K, Etzensperger R, Dumoutier L, Haak S, Rebollo A, Buch T, Heppner FL, Renauld JC, Becher B. IL-22 is expressed by Th17 cells in an IL-23–dependent fashion, but not required for the development of autoimmune encephalomyelitis. J Immunol. 2007;179(12):8098–104.
  35. Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007;13(2):139–45.
  36. Bullens DM, Truyen E, Coteur L, Dilissen E, Hellings PW, Dupont LJ, Ceuppens JL. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Respir Res. 2006;7:135.
  37. Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol. 2009;10(8):857–63.
  38. Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, Martin B, Wilhelm C, Stockinger B. Transforming growth factor-beta “reprograms” the differentiation of T helper 2 cells and promotes an interleukin 9–producing subset. Nat Immunol. 2008;9(12):1341–6.
  39. Presser K, Schwinge D, Wegmann M, Huber S, Schmitt S, Quaas A, Maxeiner JH, Finotto S, Lohse AW, Blessing M et al. Coexpression of TGF-beta1 and IL-10 enables regulatory T cells to completely suppress airway hyperreactivity. J Immunol. 2008;181(11):7751–8.
  40. Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med. 2004;199(11):1567–75.
  41. Tan Z, Randall G, Fan J, Camoretti-Mercado B, Brockman-Schneider R, Pan L, et al. Allele-specific targeting of microRNAs to HLA-G and risk of asthma. Am J Hum Genet. 2007;81(4):829–34.
  42. Li YF, Langholz B, Salam MT, Gilliland FD. Maternal and grandmaternal smoking patterns are associated with early childhood asthma. Chest. 2005;127(4):1232–41.
  43. Lima MR, Andrade MoA, Araújo AP, Figueroa JN, Andrade LB. Influence of maternal and neonatal factors on bronchopulmonary dysplasia development. Rev Assoc Med Bras. 2011;57(4):391–6.
  44. Marra F, Lynd L, Coombes M, Richardson K, Legal M, Fitzgerald JM, Marra CA. Does antibiotic exposure during infancy lead to development of asthma?: a systematic review and metaanalysis. Chest. 2006;129(3):610–8.
  45. Magnus MC, Håberg SE, Stigum H, Nafstad P, London SJ, Vangen S, Nystad W. Delivery by Cesarean section and early childhood respiratory symptoms and disorders: the Norwegian mother and child cohort study. Am J Epidemiol. 2011;174(11):1275–85.
  46. Smith GC, Wood AM, White IR, Pell JP, Cameron AD, Dobbie R. Neonatal respiratory morbidity at term and the risk of childhood asthma. Arch Dis Child. 2004;89(10):956–60.
  47. Sly PD, Kusel M, Holt PG. Do early-life viral infections cause asthma? J Allergy Clin Immunol. 2010;125(6):1202–5.
  48. Whitrow MJ, Moore VM, Rumbold AR, Davies MJ. Effect of supplemental folic acid in pregnancy on childhood asthma: a prospective birth cohort study. Am J Epidemiol. 2009;170(12):1486–93.
  49. Håberg SE, London SJ, Stigum H, Nafstad P, Nystad W. Folic acid supplements in pregnancy and early childhood respiratory health. Arch Dis Child. 2009;94(3):180–4.
  50. Bekkers MB, Elstgeest LE, Scholtens S, Haveman-Nies A, de Jongste JC, Kerkhof M, et al. Maternal use of folic acid supplements during pregnancy, and childhood respiratory health and atopy. Eur Respir J. 2012;39(6):1468–74.
  51. Dunstan JA, West C, McCarthy S, Metcalfe J, Meldrum S, Oddy WH, et al. The relationship between maternal folate status in pregnancy, cord blood folate levels, and allergic outcomes in early childhood. Allergy. 2012;67(1):50–7.
  52. Miyake Y, Sasaki S, Tanaka K, Hirota Y. Maternal B vitamin intake during pregnancy and wheeze and eczema in Japanese infants aged 16–24 months: the Osaka Maternal and Child Health Study. Pediatr Allergy Immunol. 2011;22(1 Pt 1):69–74.
  53. Magdelijns FJ, Mommers M, Penders J, Smits L, Thijs C. Folic acid use in pregnancy and the development of atopy, asthma, and lung function in childhood. Pediatrics. 2011;128(1):e135–144.
  54. Kiefte-de Jong JC, Timmermans S, Jaddoe VW, Hofman A, Tiemeier H, Steegers EA, et al. High circulating folate and vitamin B-12 concentrations in women during pregnancy are associated with increased prevalence of atopic dermatitis in their offspring. J Nutr. 2012;142(4):731–8.
  55. Martinussen MP, Risnes KR, Jacobsen GW, Bracken MB. Folic acid supplementation in early pregnancy and asthma in children aged 6 years. Am J Obstet Gynecol. 2012;206(1):72.e71–77.
  56. Litonjua AA, Rifas-Shiman SL, Ly NP, Tantisira KG, Rich-Edwards JW, Camargo CA, et al. Maternal antioxidant intake in pregnancy and wheezing illnesses in children at 2 y of age. Am J Clin Nutr. 2006;84(4):903–11.
  57. Granell R, Heron J, Lewis S, Davey Smith G, Smith GD, Sterne JA, et al. The association between mother and child MTHFR C677T polymorphisms, dietary folate intake and childhood atopy in a population-based, longitudinal birth cohort. Clin Exp Allergy. 2008;38(2):320–8.
  58. Brown SB, Reeves KW, Bertone-Johnson ER. Maternal folate exposure in pregnancy and childhood asthma and allergy: a systematic review. Nutr Rev. 2014;72(1):55–64.
  59. Tatum AJ, Shapiro GG. The effects of outdoor air pollution and tobacco smoke on asthma. Immunol Allergy Clin North Am. 2005;25(1):15–30.
  60. David GL, Romieu I, Sienra-Monge JJ, Collins WJ, Ramirez-Aguilar M, del Rio-Navarro BE, et al. Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase and glutathione S-transferase M1 polymorphisms and childhood asthma. Am J Respir Crit Care Med. 2003;168(10):1199–204.
  61. Careau E, Proulx LI, Pouliot P, Spahr A, Turmel V, Bissonnette EY. Antigen sensitization modulates alveolar macrophage functions in an asthma model. Am J Physiol Lung Cell Mol Physiol. 2006;290(5):L871–879.
  62. Dalle-Donne I, Aldini G, Carini M, Colombo R, Rossi R, Milzani A. Protein carbonylation, cellular dysfunction, and disease progression. J Cell Mol Med. 2006;10(2):389–406.
  63. Haque R, Umstead TM, Ponnuru P, Guo X, Hawgood S, Phelps DS, et al. Role of surfactant protein-A (SP-A) in lung injury in response to acute ozone exposure of SP-A deficient mice. Toxicol Appl Pharmacol. 2007;220(1):72–82.
  64. Mikerov AN, Umstead TM, Gan X, Huang W, Guo X, Wang G, et al. Impact of ozone exposure on the phagocytic activity of human surfactant protein A (SP-A) and SP-A variants. Am J Physiol Lung Cell Mol Physiol. 2008;294(1):L121–130.
  65. Wang G, Umstead T, Phelps D, Al-Mondhiry H, Floros J. The effect of ozone exposure on the ability of human surfactant protein a variants to stimulate cytokine production. Environ Health Perspect. 2002;110(1):79–84.
  66. Mikerov AN, Umstead TM, Huang W, Liu W, Phelps D, Floros J. SP-A1 and SP-A2 variants differentially enhance association of Pseudomonas aeruginosa with rat alveolar macrophages. Am J Physiol Lung Cell Mol Physiol. 2005;288:L150–L158.
  67. Mikerov AN, Gan X, Umstead TM, Miller L, Chinchilli VM, Phelps DS, et al. Sex differences in the impact of ozone on survival and alveolar macrophage function of mice after Klebsiella pneumoniae infection. Respir Res. 2008;9:24.
  68. Haque R, Umstead TM, Freeman WM, Floros J, Phelps DS. The impact of surfactant protein-A on ozone-induced changes in the mouse bronchoalveolar lavage proteome. Proteome Sci. 2009;7:12.
  69. Floros J, Phelps DS. Pulmonary surfactant protein A; structure, expression, and its role in innate host defense. In: Surfactant-Update of Intensive Care Medicine. Volume 6, edn. Edited by Nakos G, Lekka ME. Ioannina, Greece: University of Ioannina; 2002;87–102.
  70. Floros J, Wang G, Mikerov AN. Genetic complexity of the human innate host defense molecules, surfactant protein A1 (SP-A1) and SP-A2–-impact on function. Crit Rev Eukaryot Gene Expr. 2009;19(2):125–37.
  71. Kann S, Huang MY, Estes C, Reichard JF, Sartor MA, Xia Y, et al. Arsenite-induced aryl hydrocarbon receptor nuclear translocation results in additive induction of phase I genes and synergistic induction of phase II genes. Mol Pharmacol. 2005;68(2):336–46.
  72. Fahy O, Sénéchal S, Pène J, Scherpereel A, Lassalle P, Tonnel AB, et al. Diesel exposure favors Th2 cell recruitment by mononuclear cells and alveolar macrophages from allergic patients by differentially regulating macrophage-derived chemokine and IFN-gamma-induced protein-10 production. J Immunol. 2002;168(11):5912–9.
  73. Kim H, Herbert R, Landrigan P, Markowitz SB, Moline JM, Savitz DA, et al. Increased rates of asthma among World Trade Center disaster responders. Am J Ind Med. 2012;55(1):44–53.
  74. Colilla S, Nicolae D, Pluzhnikov A, Blumenthal MN, Beaty TH, Bleecker ER, Lange EM, Rich SS, Meyers DA, Ober C et al. Evidence for gene-environment interactions in a linkage study of asthma and smoking exposure. J Allergy Clin Immunol. 2003;111(4):840–6.
  75. Larsson ML, Frisk M, Hallström J, Kiviloog J, Lundbäck B. Environmental tobacco smoke exposure during childhood is associated with increased prevalence of asthma in adults. Chest. 2001;120(3):711–7.
  76. Cross CE, Traber M, Eiserich J, van der Vliet A. Micronutrient antioxidants and smoking. Br Med Bull. 1999;55(3):691–704.
  77. Rahman I, MacNee W. Role of transcription factors in inflammatory lung diseases. Thorax. 1998;53(7):601–12.
  78. Francus T, Klein RF, Staiano-Coico L, Becker CG, Siskind GW. Effects of tobacco glycoprotein (TGP) on the immune system. II. TGP stimulates the proliferation of human T cells and the differentiation of human B cells into Ig secreting cells. J Immunol. 1988;140(6):1823–9.
  79. Umetsu DT, McIntire JJ, Akbari O, Macaubas C, DeKruyff RH. Asthma: an epidemic of dysregulated immunity. Nat Immunol. 2002;3(8):715–20.
  80. Murk W, Risnes KR, Bracken MB. Prenatal or early-life exposure to antibiotics and risk of childhood asthma: a systematic review. Pediatrics. 2011;127(6):1125–38.
  81. McRae WM, Wong CS. Asthma, allergy and the hygiene hypothesis. In., vol. 29. Continuing Medical Education; 2002:31–7.
  82. Gern JE, Busse WW. Association of rhinovirus infections with asthma. Clin Microbiol Rev. 1999;12(1):9–18.
  83. McIntire JJ, Umetsu DT, DeKruyff RH. TIM-1, a novel allergy and asthma susceptibility gene. Springer Semin Immunopathol. 2004;25(3–4):335–48.
  84. Tripathi P, Awasthi S, Husain N, Prasad R, Mishra V. Increased expression of ADAM33 protein in asthmatic patients as compared to non-asthmatic controls. Indian J Med Res. 2013;137(3):507–14.
  85. Reijmerink NE, Bottema RW, Kerkhof M, Gerritsen J, Stelma FF, Thijs C, et al. TLR-related pathway analysis: novel gene-gene interactions in the development of asthma and atopy. Allergy. 2010;65(2):199–207.
  86. Papoutsakis C, Priftis KN, Drakouli M, Prifti S, Konstantaki E, Chondronikola M, Antonogeorgos G, Matziou V. Childhood overweight/obesity and asthma: is there a link? A systematic review of recent epidemiologic evidence. J Acad Nutr Diet. 2013;113(1):77–105.
  87. Dietert RR. Maternal and childhood asthma: risk factors, interactions, and ramifications. Reprod Toxicol. 2011;32(2):198–204.
  88. Miller RL, Ho SM. Environmental epigenetics and asthma: current concepts and call for studies. Am J Respir Crit Care Med. 2008;177(6):567–73.
  89. Tagaya E, Tamaoki J. Mechanisms of airway remodeling in asthma. Allergol Int. 2007;56(4):331–40.
  90. Holgate ST. Pathogenesis of asthma. Clin Exp Allergy. 2008;38(6):872–97.
  91. Yoshimura A, Wakabayashi Y, Mori T. Cellular and molecular basis for the regulation of inflammation by TGF-beta. J Biochem. 2010;147(6):781–92.
  92. Costa R, Marques C, Rios R, Silva H, Carneiro N, Cana Brasil T, et al. Are TGF-β gene polymorphisms associated with asthma risk? In., vol. 1. OA Immunology; 2013: 5.
  93. Tran DQ. TGF-β: the sword, the wand, and the shield of FOXP3(+) regulatory T cells. J Mol Cell Biol. 2012;4(1):29–37.
  94. Prakash YS, Martin RJ. Brain-derived neurotrophic factor in the airways. Pharmacol Ther. 2014;143(1):74–86.
  95. Murdoch JR, Lloyd CM. Chronic inflammation and asthma. Mutat Res. 2010;690(1–2):24–39.
  96. Balhara J, Gounni AS. The alveolar macrophages in asthma: a double-edged sword. Mucosal Immunol. 2012;5(6):605–9.
  97. Madore AM, Perron S, Turmel V, Laviolette M, Bissonnette EY, Laprise C. Alveolar macrophages in allergic asthma: an expression signature characterized by heat shock protein pathways. Hum Immunol. 2010;71(2):144–50.
  98. Hohlfeld JM, Erpenbeck VJ, Krug N. Surfactant proteins SP-A and SP-D as modulators of the allergic inflammation in asthma. Pathobiology. 2002;70(5):287–92.
  99. Silveyra P, Floros J. Genetic variant associations of human SP-A and SP-D with acute and chronic lung injury. Frontiers in Bioscience. 2012;17:407–29.
  100. Wang G, Phelps DS, Umstead TM, Floros J. Human SP-A protein variants derived from one or both genes stimulate TNF-alpha production in the THP-1 cell line. Am J Physiol Lung Cell Mol Physiol. 2000;278(5):L946–54.
  101. Phelps DS. Surfactant regulation of host defense function in the lung: a question of balance. Pediatr Pathol Mol Med. 2001;20(4):269–92.
  102. Brinker KG, Martin E, Borron P, Mostaghel E, Doyle C, Harding CV, et al. Surfactant protein D enhances bacterial antigen presentation by bone marrow-derived dendritic cells. Am J Physiol Lung Cell Mol Physiol. 2001;281(6):L1453–63.
  103. Brinker KG, Garner H, Wright JR. Surfactant protein A modulates the differentiation of murine bone marrow-derived dendritic cells. Am J Physiol Lung Cell Mol Physiol. 2003;284(1):L232–41.
  104. Jäkel A, Clark H, Reid KB, Sim RB. The human lung surfactant proteins A (SP-A) and D (SP-D) interact with apoptotic target cells by different binding mechanisms. Immunobiology. 2010;215(7):551–8.
  105. Madan T, Kishore U, Singh M, Strong P, Clark H, Hussain EM, et al. Surfactant proteins A and D protect mice against pulmonary hypersensitivity induced by Aspergillus fumigatus antigens and allergens. J Clin Invest. 2001;107(4):467–75.
  106. Madan T, Reid KB, Clark H, Singh M, Nayak A, Sarma PU, Hawgood S, Kishore U. Susceptibility of mice genetically deficient in SP-A or SP-D gene to invasive pulmonary aspergillosis. Mol Immunol. 2010;47(10):1923–30.
  107. Saxena S, Madan T, Shah A, Muralidhar K, Sarma PU. Association of polymorphisms in the collagen region of SP-A2 with increased levels of total IgE antibodies and eosinophilia in patients with allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol. 2003;111(5):1001–7.
  108. Wang G, Guo X, Diangelo S, Thomas NJ, Floros J. Humanized SFTPA1 and SFTPA2 transgenic mice reveal functional divergence of SP-A1 and SP-A2: formation of tubular myelin in vivo requires both gene products. J Biol Chem. 2010;285(16):11998–2010.
  109. Wang G, Myers C, Mikerov A, Floros J. Effect of cysteine 85 on biochemical properties and biological function of human surfactant protein A variants. Biochemistry. 2007;46(28):8425–35.
  110. Wang G, Bates-Kenney SR, Tao JQ, Phelps DS, Floros J. Differences in biochemical properties and in biological function between human SP-A1 and SP-A2 variants, and the impact of ozone-induced oxidation. Biochemistry. 2004;43(14):4227–39.
  111. Huang W, Wang G, Phelps DS, Al-Mondhiry H, Floros J. Human SP-A genetic variants and bleomycin-induced cytokine production by THP-1 cells: effect of ozone-induced SP-A oxidation. Am J Physiol Lung Cell Mol Physiol. 2004;286(3):L546–53.
  112. Tagaram HR, Wang G, Umstead TM, Mikerov AN, Thomas NJ, Graff GR, et al. Characterization of a human surfactant protein A1 (SP-A1) gene-specific antibody; SP-A1 content variation among individuals of varying age and pulmonary health. Am J Physiol Lung Cell Mol Physiol. 2007;292(5):L1052–63.
  113. Wang Y, Voelker DR, Lugogo NL, Wang G, Floros J, Ingram JL, et al. Surfactant protein A is defective in abrogating inflammation in asthma. Am J Physiol Lung Cell Mol Physiol. 2011;301(4):L598–606.
  114. Phelps D, Umstead T, Silveyra P, Hu S, Wang G, Floros J. Differences in the alveolar macrophage proteome in transgenic mice expressing human SP-A1 and SP-A2. Journal of Proteomics and Genomics Research; 2013;1:2–26.
  115. Phelps DS, Umstead TM, Quintero OA, Yengo CM, Floros J. In vivo rescue of alveolar macrophages from SP-A knockout mice with exogenous SP-A nearly restores a wild type intracellular proteome; actin involvement. Proteome Sci. 2011;9:67.
  116. Wright AL. Epidemiology of asthma and recurrent wheeze in childhood. Clin Rev Allergy Immunol. 2002;22(1):33–44.
  117. Hanson LA, Adlerberth I, Carlsson B, Zaman S, Hahn-Zoric M, Jalil F. Antibody-mediated immunity in the neonate. Padiatr Padol. 1990;25(5):371–6.
  118. Cabrera-Rubio R, Collado MC, Laitinen K, Salminen S, Isolauri E, Mira A. The human milk microbiome changes over lactation and is shaped by maternal weight and mode of delivery. Am J Clin Nutr. 2012;96(3):544–51.
  119. Schulman ES. Development of a monoclonal anti-immunoglobulin E antibody (omalizumab) for the treatment of allergic respiratory disorders. Am J Respir Crit Care Med. 2001;164(8 Pt 2):S6–11.
  120. Schwarzer M, Repa A, Daniel C, Schabussova I, Hrncir T, Pot B, et al. Neonatal colonization of mice with Lactobacillus plantarum producing the aeroallergen Bet v 1 biases towards Th1 and T-regulatory responses upon systemic sensitization. Allergy. 2011;66(3):368–75.