Current Allergy and Asthma Reports

, Volume 13, Issue 5, pp 462–468 | Cite as

Identification of Innate Immune Response Endotypes in Asthma: Implications for Personalized Medicine



Asthma is an idiopathic disease characterized by episodic inflammation and reversible airway obstruction triggered by exposure to environmental agents. Because this disease is heterogeneous in onset, exacerbations, inflammatory states, and response to therapy, there is intense interest in developing personalized approaches to its management. Of focus in this review, the recognition that a component of the pathophysiology of asthma is mediated by inflammation has implications for understanding its etiology and individualizing its therapy. Despite understanding how Th2 polarization mediates asthma exacerbations by aeroallergen exposure, we do not yet fully understand how RNA virus infections produce asthmatic exacerbations. This review will summarize the explosion of information that has revealed how patterns produced by RNA virus infection trigger the innate immune response (IIR) in sentinel airway cells. When the IIR is triggered, these cells elaborate inflammatory cytokines and protective mucosal interferons whose actions activate long-lived adaptive immunity and limit organismal replication. Recent work has shown the multifaceted way that dysregulation of the IIR is linked to viral-induced exacerbation, steroid insensitivity, and T helper polarization of adaptive immunity. New developments in quantitative proteomics now enable accurate identification of subgroups of individuals that demonstrate activation of IIR (“innate endotype”). Potential applications to clinical research are proposed. Together, these developments open realistic prospects for how identification of the IIR endotype may inform asthma therapy in the future.


Asthma Multivariate adaptive regression splines Innate immune response (IIR) Respiratory syncytial virus Interferon (IFN) Nuclear factor-κB (NFκB) Interferon response factor (IRF) Pattern recognition receptors Toll-like receptors (TLRs) Retinoic acid like helicases (RLH) Personalized medicine Endotypes Innate immune response endotypes 


Papers of particular interest, published recently, have been highlighted as: • of importance •• of major importance

  1. 1.
    Busse WW, Lemanske RF. Asthma. N Engl J Med. 2001;344:350–62.PubMedCrossRefGoogle Scholar
  2. 2.
    Johnston NW, Sears MR. Asthma exacerbations · 1: Epidemiology. Thorax. 2006;61:722–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Bardin PG, Johnston SL, Pattemore PK. Viruses as precipitants of asthma symptoms. II. Physiology and mechanisms. Clin Exp Allergy. 1992;22:809–22.PubMedCrossRefGoogle Scholar
  4. 4.
    Corne JM, Holgate ST. Mechanisms of virus induced exacerbations of asthma. Thorax. 1997;52:380–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Gern JE, Busse WW. Relationship of viral infections to wheezing illnesses and asthma. Nat Rev Immunol. 2002;2:132–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Brasier AR, Calhoun WJ. Proteomic Insights Into Inflammatory Airway Diseases. Current Proteomics. 2011;8:84–96.CrossRefGoogle Scholar
  7. 7.
    Pillai RR, Divekar R, Brasier A, Bhavnani S, Calhoun WJ. Strategies for Molecular Classification of Asthma Using Bipartite Network Analysis of Cytokine Expression. Curr Allergy Asthma Rep. 2012;12:388–95.PubMedCrossRefGoogle Scholar
  8. 8.
    Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008;372:1107–19.PubMedCrossRefGoogle Scholar
  9. 9.
    Bhavnani SK, Victor S, Calhoun WJ, Busse WW, Bleecker E, Castro M, et al. How cytokines co-occur across asthma patients: from bipartite network analysis to a molecular-based classification. J Biomed Inform. 2011;44 Suppl 1:S24–30.PubMedCrossRefGoogle Scholar
  10. 10.
    Akira S, Uematsu S, Takeuchi O. Pathogen Recognition and Innate Immunity. Cell (Cambridge MA). 2006;124:783–801.CrossRefGoogle Scholar
  11. 11.
    Liu P, Jamaluddin M, Li K, Garofalo RP, Casola A, Brasier AR. Retinoic Acid-Inducible Gene I Mediates Early Antiviral Response and Toll-Like Receptor 3 Expression in Respiratory Syncytial Virus-Infected Airway Epithelial Cells. J Virol. 2007;81:1401–11.PubMedCrossRefGoogle Scholar
  12. 12.
    Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature (London). 2006;441:101–5.CrossRefGoogle Scholar
  13. 13.
    Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol. 2004;5:730–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Sun Q, Sun L, Liu HH, Chen X, Seth RB, Forman J, et al. The specific and essential role of MAVS in antiviral innate immune responses. Immunity. 2006;24:633–42.PubMedCrossRefGoogle Scholar
  15. 15.
    O'Neill LAJ, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol. 2007;7:353–64.PubMedCrossRefGoogle Scholar
  16. 16.
    Hernandez ML, Harris B, Lay JC, Bromberg PA, Diaz-Sanchez D, Devlin RB, et al. Comparative airway inflammatory response of normal volunteers to ozone and lipopolysaccharide challenge. Inhal Toxicol. 2010;22:648–56.PubMedCrossRefGoogle Scholar
  17. 17.
    Reed CE, Milton DK. Endotoxin-stimulated innate immunity: A contributing factor for asthma. J Allergy Clin Immunol. 2001;108:157–66.PubMedCrossRefGoogle Scholar
  18. 18.
    Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16(225–60):225–60.PubMedCrossRefGoogle Scholar
  19. 19.
    Brasier AR: The NF- k B Signaling Network: Insights from systems approaches. In: Cellular Signaling And Innate Immune Responses To RNA Virus Infections. Edited by Brasier AR, Lemon SM, Garcia-Sastre A: American Society for Microbiology 2008: 119–135.Google Scholar
  20. 20.
    Hiscott J. Triggering the Innate Antiviral Response through IRF-3 Activation. J Biol Chem. 2007;282:15325–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Pitha PM, Au WC, Lowther W, Juang YT, Schafer SL, Burysek L, et al. Role of the interferon regulatory factors (IRFs) in virus-mediated signaling and regulation of cell growth. [Review] [50 refs]. Biochimie (Paris). 1998;80:651–8.CrossRefGoogle Scholar
  22. 22.
    Zhang Y, Luxon BA, Casola A, Garofalo RP, Jamaluddin M, Brasier AR. Expression of respiratory syncytial virus-induced chemokine gene networks in lower airway epithelial cells revealed by cDNA microarrays. J Virol. 2001;75:9044–58.PubMedCrossRefGoogle Scholar
  23. 23.
    Tian B, Brasier AR. The Nuclear Factor- k B (NF- k B) Gene Regulatory Network. In: Microarrays and Transcription Factor Networks. Austin, TX: Landes Bioscience; 2005.Google Scholar
  24. 24.
    Garrood T, Lee L, Pitzalis C. Molecular mechanisms of cell recruitment to inflammatory sites: general and tissue-specific pathways. Rheumatology. 2006;45:250–60.PubMedCrossRefGoogle Scholar
  25. 25.
    Pulendran B, Smith JL, Caspary G, Brasel K, Pettit D, Maraskovsky E, et al. Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc Natl Acad Sci U S A. 1999;96:1036–41.PubMedCrossRefGoogle Scholar
  26. 26.
    Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3:673–80.PubMedCrossRefGoogle Scholar
  27. 27.
    Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–41.PubMedCrossRefGoogle Scholar
  28. 28.
    Johnston SL. Innate Immunity in the Pathogenesis of Virus-induced Asthma Exacerbations. Proc Am Thorac Soc. 2007;4:267–70.PubMedCrossRefGoogle Scholar
  29. 29.
    Contoli M, Message SD, Laza-Stanca V, Edwards MR, Wark PA, Bartlett NW, et al. Role of deficient type III interferon-lambda production in asthma exacerbations. Nat Med. 2006;12:1023–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Brasier AR, Tian B, Jamaluddin M, Kalita MK, Garofalo RP, Lu M. RelA Ser276 phosphorylation-coupled Lys310 acetylation controls transcriptional elongation of inflammatory cytokines in respiratory syncytial virus infection. J Virol. 2011;85:11752–69.PubMedCrossRefGoogle Scholar
  31. 31.
    Bartlett NW, Slater L, Glanville N, Haas JJ, Caramori G, Casolari P, et al. Defining critical roles for NF-kappaB p65 and type I interferon in innate immunity to rhinovirus. EMBO Mol Med. 2012;4:1244–60.PubMedCrossRefGoogle Scholar
  32. 32.
    Haeberle HA, Casola A, Gatalica Z, Petronella S, Dieterich HJ, Ernst PB, et al. IkappaB kinase is a critical regulator of chemokine expression and lung inflammation in respiratory syncytial virus infection. J Virol. 2004;78:2232–41.PubMedCrossRefGoogle Scholar
  33. 33.
    Wark PA, Johnston SL, Bucchieri F, Powell R, Puddicombe S, Laza-Stanca V, et al. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J Exp Med. 2005;201:937–47.PubMedCrossRefGoogle Scholar
  34. 34.
    • Brasier AR, Victor S, Ju H, Busse WW, Curran-Everett D, Bleecker E, et al. Predicting intermediate phenotypes in asthma using bronchoalveolar lavage-derived cytokines. Clin Transl Sci. 2010;3:147–57. This paper provides proof of principle that cytokine patterns in BAL of stable asthmatics provide information relative to dynamic airway physiology.PubMedCrossRefGoogle Scholar
  35. 35.
    Brasier AR, Victor S, Boetticher G, Ju H, Lee C, Bleecker ER, et al. Molecular Phenotyping Of Severe Asthma Using Pattern Recognition Of Bronchoalveolar Lavage-Derived Cytokines. J Allergy Clin Immunol. 2008;121:30–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Zhao Y, Tian B, Edeh CB, Brasier AR: Quantitation of the dynamic profiles of the innate immune response using multiplex selected reaction monitoring-mass spectrometry. Molecular & cellular proteomics : MCP (2013):Google Scholar
  37. 37.
    Zhao Y, Brasier AR. Methods for Biomarker Verification and Assay Development. Current Proteomics. 2011;8:138–52.CrossRefGoogle Scholar
  38. 38.
    Zhao Y, Brasier AR: Applications Of Selected Reaction Monitoring (SRM)-Mass Spectrometry (MS) For Quantitative Measurement Of Signaling Pathways. Methods (2013):Google Scholar
  39. 39.
    Spratt H, Ju H, Brasier AR: A structured approach to predictive modeling of a two-class problem using multidimensional data sets. . Methods (2013):in press.Google Scholar
  40. 40.
    Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A. 2001;98:5116–21.PubMedCrossRefGoogle Scholar
  41. 41.
    Friedman JH. Multivariate Adaptive Regression Splines. Ann Stat. 1991;19:1–67.CrossRefGoogle Scholar
  42. 42.
    Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol. 2002;109:410–8.PubMedCrossRefGoogle Scholar
  43. 43.
    •• Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365:1088–98. This study demonstrates that stratification on the basis of Th2 bioactivity identifies subjects that respond to neutralizing antibody therapy. It is a demonstration of personalized medicine in asthma. PubMedCrossRefGoogle Scholar
  44. 44.
    Brasier AR. Expanding Role of Cyclin Dependent Kinases in Cytokine Inducible Gene Expression. Cell Cycle. 2008;7:1–6.CrossRefGoogle Scholar
  45. 45.
    Tian B, Zhao Y, Kalita M, Edeh C, Paessler S, Casola A, Teng M, Garofalo R, Brasier AR: CDK9-dependent transcriptional elongation in the innate ISG response to RSV infection in airway epithelial cells. Journal of Virology in press (2013):Google Scholar
  46. 46.
    Nowak DE, Tian B, Jamaluddin M, Boldogh I, Vergara LA, Choudhary S, et al. RelA Ser276 Phosphorylation Is Required for Activation of a Subset of NF-{kappa}B-Dependent Genes by Recruiting Cyclin-Dependent Kinase 9/Cyclin T1 Complexes. Mol Cell Biol. 2008;28:3623–38.PubMedCrossRefGoogle Scholar
  47. 47.
    Luecke HF, Yamamoto KR. The glucocorticoid receptor blocks P-TEFb recruitment by NF{kappa}B to effect promoter-specific transcriptional repression. Genes Dev. 2005;19:1116–27.PubMedCrossRefGoogle Scholar
  48. 48.
    Shapiro GI. Preclinical and Clinical Development of the Cyclin-Dependent Kinase Inhibitor Flavopiridol. Clin Cancer Res. 2004;10:4270s–5s.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Institute for Translational Sciences, Department of Internal Medicine, Sealy Center for Molecular Medicine, 8.128 Medical Research BuildingUniversity of Texas Medical BranchGalvestonUSA

Personalised recommendations