The immunology of virus infection in asthma

1. The immunology of virus infection in asthma SD.Message,S.L.Johnston Eur Respir J 2001:18:1013-1025 73 morning meeting by R2 陳信宏 91-5-29

2. Resp infection by virus • Common cold • Pharyngitis • Tracheobronchitis • Croup • Bronchiolitis • pneumonia

3. Table-1

4. Resp infection by virus • Localized to the resp tract RSV infant bronchiolitis • Generalized sys illness mealses or chickenpox

5. Resp infection by virus • Host factor : Age previous infection and immunization ,pre-existing resp or sys disease and immunosuppression or immunocompromise

6. Resp infection by virus • Nature and serverity of disease : direct harmful effects host immune response the ideal immune response was the early elimination of the virus with minimum harm to the host

7. Asthma • The multifaceted syndrome atopy bronchial hyperreactivity IgE and non-IgE mediated acute and chronic immune response • The asthmatic airway is an infiltrate of the eosinophils and T-lymphocytes with type2 cytokine and IL-3,4,5

8. Asthma • Trigger factors environmental allergens animals, moulds, pollens, mites, cold, exercise and drugs

9. Asthma • In 1950s bacterial allergy • Now viral rather than bacterial infection

10. The antiviral immune response • The typical response involves a combination of nonspecific (innate ) and specific immunity • Nonspecific elements: Phagocytes neutrophils and macrophages to engulf and destroy virus

11. The antiviral immune response • Natural killer cells : Recognize and destroy virus-infected cells on the basis of alterations to normal cell surface proteins • Cells including the NK cell neutrophils macrophages mast cells basophils and epithelial cells to release cytokines

12. The antiviral immune response • Cytokines for the immunoregulatory or antiviral actions • Body fluids for neutrolizing viral infections

13. The antiviral immune response • Specific immunity • Antibodies by B-lymphocytes and cytotoxic T-cells • Dentritic cells • Memory for re-infection

14. The antiviral immune response • Primary infection • Peak virus level at day 2 • Type 1 interferons at day 3 and undetectable at day 8 • INF can activate NK cell which detected at day 3 and peak at day 4 • NK cells can destroy the infected cell and release cytokines

15. The antiviral immune response • T-cell • Production of chemokines • Alterations in the expression of adhesion molecules on the endothelium of inflammed tissues

16. The antiviral immune response • Viral antigen locally in regional lymph nodes by the dentritic cells and it can be presented to T cells • CD 4+ T-cell at day 4 and CD 8+ T-cell at day 6 and CD8+ cytotoxic T-cell at day 7 ; decline and undetectable at day 14 • Memory CD4+ and CD 8+ responses persist for life

17. The antiviral immune response • B-cells • Mucosal Ig A at day 3 • Serum Ig M at day 5-6 • Serum Ig G at day 7-8 • All for a period of 2-3 weeks • IgA was undectable after 3-6 months • Serum IgG remain for life

18. The antiviral immune response • Secondary infection • Rapid mobilization of B and T cell for specific immunity • Earlier T-cell peak with NK cell peak at day 3-4

19. Epidemiology • Viral URI are a major cause of wheezing in infants and adult patients with asthma • Molecular biological techniques such as PCR or RT-PCR for the detection of viral infection in the asthma exacerbations • Indirect evidence from the population studies seasonal variation in wheezing episodes in young children and adult with asthma

20. Epedimiology • Studies showed an increased rate of virus detection in individuals suffering from the asthma attacks and 10-85% in children ,10-44% in adults • Asymtomatic individuals is only 3-12% • A study of transtracheal aspirates in adult asthmatics with AE had sparse bacterial culture but no correlation to clinical illness

21. Epedimiology • Most viruses with asthmatics areRVs,,RSVs and parainfluenza virus • RV is detected in 50% of virus-induced asthma attacks • Adenovirus enterovirus and coronavirus are less • Influenza is only during annual epidemics • RV is important in COPD with the decline of lung function

22. Experimental virus infection • Limited by the concerns of safety • RV in the allergic rhinitis ,mild asthmatics or normal control subjects for study • RV infection in asthma are relatively mild and do not mimic exactly the events after a natural common cold • It suggests that requires a more complex model and may be a synergistic interaction between virus infection and allergen exprosure

23. Experimental virus infection • Allergic rhinitis patients with 3 high dose allergen challenges produce the protect against a RV cold with delayed nasal leukocytosis with cytokines IL-6 and IL-8 and less severe clinical course • Limited high dose may not reproduce the effects of chronic low dose allergen exposure and it can product the anti-inflammatory mediators as IL-10 IFN-r and INF-r

24. Rhinovirus infection of the lower airway • If RV can stay in low airway ? Due to the RV culture at 33c rather than 37c • But replication occur at lower airway temperature noted in the use of in situ hybridization of the bronchial biopsy • So RV infection in lower airway and is the pathogenesis of asthma exacerbations

25. Physiological effects of experimental rhinovirus infection • Reduction of peak flow and FEV1 with RV 16 infection • Enhance the sensitivities to histamine and allergen challenge • RV16 increased asthma symptoms by the bronchoconstrictive response to methacholine < 15days after infection

26. Interactions between virus infected and asthmatic airway inflammation • Viral pathology or asthmatic pathology ? • Through the different mechanisms with the same end effects on function or by sharing the same pathogenetic mechanism in an addictive or even in a synergic fashion?

28. Effects of viruses on airway epithelial cell • Intercellular adhesion molecule(ICAM-1) in the major group RVs and low density lipoprotein receptor in minor group RVs • Influenza binds the sialic acid residues via haemaglutinin • Upregulation of ICAM-1 increases the severity of RV infection • Involving the transcription factor and nuclear factor (NF-kB)

29. Effects of viruses on airway epithelial cell • Inhibition of the upregulation of ICAM-1 can improve the course of RV infection • Corticosteroid can inhibit NF-kB and inhibit RV16-induced increases in ICAM-1 surface expression (mRNA )and promotor activation

30. Effects of viruses on airway epithelial cell • Influenza causes extensive necrosis in epithelial cell and RV causes little or only pathy damage • It increases the epithelial permeability and penetration of irritants and allergens and exposure of the extensive network of afferent nerve fibers which causes the bronchial hyperresponsiveness

31. Effects of viruses on airway epithelial cell • Epithelium acts as a physical barrier and regulatory roles with immune reponse by cytokines and chemokines • Epithelium acts as antigen-presenting cells and major histocompatibility complex class-I with B7-1 and B7-2

33. Effects of viruses on airway epithelial cell • Initial trigger of the inflammatory reactions is an epithelial cell-virus interaction • Bradykinin from the plasma precursor in nasal secretions of RV infected individuals and it can cause the sorethroat and rhinitis • Some virus caused the complement-mediated damage such C3a and C5a increased in influenza A infection

34. Effects of viruses on airway epithelial cell • Nitric oxide (NO) is produced by epithelial endothelial and smooth muscle cells and it can relax the airway smooth muscle • Parainfluenza infection decreased the NO and NO reacts with superoxide anion can generate peroxynitrite in the inflammed tissue

35. Effects of viruses on airway epithelial cell • IL-1 enhances the adhesion of the inflammatory cells to endothelium to chemotaxis • TNF-a is a potent antiviral cytokine • IL-6 stimulates IgA-mediated immune response

36. Effects of viruses on airway epithelial cell • IL-11 in virus –induced asthma causes bronchoconstriction by the direct effect on smooth muscle • IL-11 is elevated in nasal aspirates from children with colds or with the presence of wheezing

37. Effects of virus on airway smooth muscle cells • RV-16 exposure on the smooth muscle cells results in increased contractility to acetycholine and impaired relaxation to isoproterenol

38. The cellular immune response to virus infection in the lower airway • Monocytes and macrophages • Dentrtic cells • Lymphocytes • Mast cells and basophils • Eosinophis • Neutrophils • Natural killer cells • B-lymphocytes and interaction of virus with immunoglobulin –E-dependent mechanisms

39. Monocytes and macrophages • 90% alveolar macrophages in the lower airway for the early phagocytosis of virus particles and as the antigen presentation to T-cells and mediators • infection can stimulate the monocytes to make the IL-8 TNF-a(RV) IL-6 IL-1b TNF-a IFN-a and IFN-B (influenza-A)

40. Dentric cells • As the antigen presentation both allergen and pathogen • Induce the primary immune responces • Regulations of the T-cell-mediated response

41. lymphocytes • RV infection causes the increasing CD3+ CD4+and CD8+ in epithelium and submucosa • CD4+T-cell by the T-helper 1 type(IFN-r cytokine) to virus • INF-r for the increasing basophils and mast cell histamine releasing to inhibit the expression type 2 cytokines

42. lymphocytes • Asthma is the Th-2 type inflammation • Many studies have demonstrated mutual inhibition of Th1 and Th2 cells • In RV-16 infection with allergic rhinitis or asthma ,the balance of airway Th1 and Th2 cytokines in sputum induced by virus was related to clinical S/S

43. lymphocytes • CD8+T cell can polarize the cytokine production by cytotoxic T cell (Tc) • CD8+Tcell can regulate CD4+ Th1/Th2 balance • CD8+ caused the IL-5 production and the induction of the airway eosinophil

44. Mast cells and basophils • stimulate histamine release • Basophil IgE-mediated histamine release increased but the role in asthma is controversial • Leukotrine C4 is one of the maior mediators for the late phase of bronchospasm • LTC4 LTD4 PGF2aLTB2 can cause airway constriction

45. Eosinophil • Persisted up to 6weeks in asthmatic subiects • Increased the eosinophil cationic protein in RV infection sputum • GM-CSF is the eosinophil production in the bone marrow and in prolonging the eosinophil survival

46. Neutrophil • IL-8 production • Prominent in severe asthma • Day 4 in sputum with natural cold and day 2or day 9 in RV16 –infection sputum • In acute phase elevated the IL-8 and neutrophil in children • Levels of neutrophil myeloperoxidase correlated with symptom servirity

47. Natural killer cell • In the innate immune response • By natural killing ,antibody-dependent cellular cytotoxicity or apoptotic killing of Fas-positive target cell • Ig-like receptors that recognize HLA-A,B,C,and CD94/NKG2A receptor that interact with HLA-E to recognize MHC classI cell

48. Natural killer cell • Production of the IFN-r for the macrophages and dentritic cells and epithelial cells and also for the CD4+Th1 and CD8+T cl cell

49. B-lymphocytes and interaction of virus with immunoglobulin –E-dependent mechanisms 1.allergic-specific Ig-Eare features of extrinsic or atopic asthma 2.increasing in specific serum IgE to housedust or mite

50. Future directions • Resp virus are important triggers of the wheezing illness or asthma • RV is common in all ages and RSV is most in infants and young children • RSV and influenza are capable of causing extensive epithelial necrosis but RV is less destruction