The immunology of virus infection in asthma

SD.Message,S.L.JohnstonSD.Message,S.L.Johnston

Eur Respir J 2001:18:1013-1025Eur Respir J 2001:18:1013-1025 73 morning meeting by R2 73 morning meeting by R2 陳信宏 陳信宏 91-5-2991-5-29

Resp infection by virus

Common cold Common cold Pharyngitis Pharyngitis Tracheobronchitis Tracheobronchitis CroupCroup BronchiolitisBronchiolitis pneumonia pneumonia

Table-1

Virus typeVirus type SerotypeSerotype Common Common coldcold

AsthmaAsthmaExacerbationExacerbation

pneumoniapneumonia bronchitisbronchitis bronchiolitisbronchiolitis

RhinovirusRhinovirus 1 100+1 100+ ++++++ ++++++ +/-+/- ++ ++

CoronaviruCoronaviruss

229229E E OC4OC433

++++ ++++

InfluenzaInfluenza A.B.CA.B.C ++ ++ ++++ ++

ParainfluenParainfluenzaza

1.2.3.41.2.3.4 ++ ++ +/-+/- ++++ ++

RSVRSV A.BA.B ++ ++ ++ ++ ++++++

adenovirusadenovirus 1 431 43 ++ ++ ++++ ++ ++

Resp infection by virus

Localized to the resp tractLocalized to the resp tract

RSV infant bronchiolitis RSV infant bronchiolitis Generalized sys illnessGeneralized sys illness

mealses or chickenpoxmealses or chickenpox

Localized to the resp tractLocalized to the resp tract

RSV infant bronchiolitis RSV infant bronchiolitis Generalized sys illnessGeneralized sys illness

mealses or chickenpoxmealses or chickenpox

Resp infection by virus

Host factor :Host factor :

Age previous infection and Age previous infection and immunization ,pre-existing resp or sys immunization ,pre-existing resp or sys disease and immunosuppression or disease and immunosuppression or immunocompromiseimmunocompromise

Resp infection by virus

Nature and serverity of disease :Nature and serverity of disease :

direct harmful effectsdirect harmful effects

host immune responsehost immune response

the ideal immune response was the early the ideal immune response was the early elimination of the virus with minimum elimination of the virus with minimum harm to the hostharm to the host

Asthma

The multifaceted syndrome The multifaceted syndrome

atopy bronchial hyperreactivity atopy bronchial hyperreactivity

IgE and non-IgE mediated acute and IgE and non-IgE mediated acute and chronic immune responsechronic immune response

The asthmatic airway is an infiltrate of the The asthmatic airway is an infiltrate of the eosinophils and T-lymphocytes with type2 eosinophils and T-lymphocytes with type2 cytokine and IL-3,4,5cytokine and IL-3,4,5

Asthma

Trigger factors Trigger factors

environmental allergensenvironmental allergens

animals, moulds, pollens, mites, cold, animals, moulds, pollens, mites, cold, exercise and drugsexercise and drugs

Asthma

In 1950sIn 1950s

bacterial allergy bacterial allergy Now Now

viral rather than bacterial infection viral rather than bacterial infection

The antiviral immune response

The typical response involves a The typical response involves a combination of nonspecific (innate ) and combination of nonspecific (innate ) and specific immunityspecific immunity

Nonspecific elements:Nonspecific elements:

Phagocytes neutrophils and macrophages to Phagocytes neutrophils and macrophages to engulf and destroy virusengulf and destroy virus

The antiviral immune response

Natural killer cells :Natural killer cells :

Recognize and destroy virus-infected cells on Recognize and destroy virus-infected cells on the basis of alterations to normal cell the basis of alterations to normal cell surface proteinssurface proteins

Cells including the NK cell neutrophils Cells including the NK cell neutrophils macrophages mast cells basophils and macrophages mast cells basophils and epithelial cells to release cytokinesepithelial cells to release cytokines

The antiviral immune response

Cytokines for the immunoregulatory or Cytokines for the immunoregulatory or antiviral actions antiviral actions

Body fluids for neutrolizing viral infectionsBody fluids for neutrolizing viral infections

The antiviral immune response

1.1. Specific immunity Specific immunity

2.2. Antibodies by B-lymphocytes and Antibodies by B-lymphocytes and cytotoxic T-cellscytotoxic T-cells

3.3. Dentritic cellsDentritic cells

4.4. Memory for re-infection Memory for re-infection

The antiviral immune response

1.1. Primary infection Primary infection 2.2. Peak virus level at day 2Peak virus level at day 23.3. Type 1 interferons at day 3 and Type 1 interferons at day 3 and

undetectable at day 8undetectable at day 84.4. INF can activate NK cell which detected INF can activate NK cell which detected

at day 3 and peak at day 4at day 3 and peak at day 45.5. NK cells can destroy the infected cell and NK cells can destroy the infected cell and

release cytokinesrelease cytokines

The antiviral immune response

1.1. T-cell T-cell

2.2. Production of chemokines Production of chemokines

3.3. Alterations in the expression of adhesion Alterations in the expression of adhesion molecules on the endothelium of molecules on the endothelium of inflammed tissuesinflammed tissues

The antiviral immune response

Viral antigen locally in regional lymph Viral antigen locally in regional lymph nodes by the dentritic cells and it can be nodes by the dentritic cells and it can be presented to T cells presented to T cells

CD 4+ T-cell at day 4 and CD 8+ T-cell at CD 4+ T-cell at day 4 and CD 8+ T-cell at day 6 and CD8+ cytotoxic T-cell at day 7 ; day 6 and CD8+ cytotoxic T-cell at day 7 ; decline and undetectable at day 14decline and undetectable at day 14

Memory CD4+ and CD 8+ responses Memory CD4+ and CD 8+ responses persist for lifepersist for life

The antiviral immune response

1.1. B-cells B-cells

2.2. Mucosal Ig A at day 3Mucosal Ig A at day 3

3.3. Serum Ig M at day 5-6Serum Ig M at day 5-6

4.4. Serum Ig G at day 7-8Serum Ig G at day 7-8

5.5. All for a period of 2-3 weeksAll for a period of 2-3 weeks

6.6. IgA was undectable after 3-6 months IgA was undectable after 3-6 months

7.7. Serum IgG remain for lifeSerum IgG remain for life

The antiviral immune response

1.1. Secondary infection Secondary infection

2.2. Rapid mobilization of B and T cell for Rapid mobilization of B and T cell for specific immunity specific immunity

3.3. Earlier T-cell peak with NK cell peak at Earlier T-cell peak with NK cell peak at day 3-4 day 3-4

Epidemiology

Viral URI are a major cause of wheezing in infants Viral URI are a major cause of wheezing in infants and adult patients with asthmaand adult patients with asthma

Molecular biological techniques such as PCR or Molecular biological techniques such as PCR or RT-PCR for the detection of viral infection in the RT-PCR for the detection of viral infection in the asthma exacerbations asthma exacerbations

Indirect evidence from the population studies Indirect evidence from the population studies seasonal variation in wheezing episodes in seasonal variation in wheezing episodes in young children and adult with asthmayoung children and adult with asthma

Epedimiology

Studies showed an increased rate of virus Studies showed an increased rate of virus detection in individuals suffering from the detection in individuals suffering from the asthma attacks and 10-85% in children ,10-asthma attacks and 10-85% in children ,10-44% in adults 44% in adults

Asymtomatic individuals is only 3-12%Asymtomatic individuals is only 3-12% A study of transtracheal aspirates in adult A study of transtracheal aspirates in adult

asthmatics with AE had sparse bacterial asthmatics with AE had sparse bacterial culture but no correlation to clinical illnessculture but no correlation to clinical illness

Epedimiology

Most viruses with asthmatics areRVs,,RSVs and Most viruses with asthmatics areRVs,,RSVs and parainfluenza virusparainfluenza virus

RV is detected in 50% of virus-induced asthma RV is detected in 50% of virus-induced asthma attacks attacks

Adenovirus enterovirus and coronavirus are less Adenovirus enterovirus and coronavirus are less Influenza is only during annual epidemicsInfluenza is only during annual epidemics RV is important in COPD with the decline of lung RV is important in COPD with the decline of lung

function function

Experimental virus infection

Limited by the concerns of safety Limited by the concerns of safety RV in the allergic rhinitis ,mild asthmatics or RV in the allergic rhinitis ,mild asthmatics or

normal control subjects for study normal control subjects for study RV infection in asthma are relatively mild and do RV infection in asthma are relatively mild and do

not mimic exactly the events after a natural not mimic exactly the events after a natural common coldcommon cold

It suggests that requires a more complex model It suggests that requires a more complex model and may be a synergistic interaction between virus and may be a synergistic interaction between virus infection and allergen exprosure infection and allergen exprosure

Experimental virus infection

Allergic rhinitis patients with 3 high dose allergen Allergic rhinitis patients with 3 high dose allergen challenges produce the protect against a RV cold challenges produce the protect against a RV cold with delayed nasal leukocytosis with cytokines with delayed nasal leukocytosis with cytokines IL-6 and IL-8 and less severe clinical course IL-6 and IL-8 and less severe clinical course

Limited high dose may not reproduce the effects Limited high dose may not reproduce the effects of chronic low dose allergen exposure and it can of chronic low dose allergen exposure and it can product the anti-inflammatory mediators as IL-10 product the anti-inflammatory mediators as IL-10 IFN-r and INF-rIFN-r and INF-r

Rhinovirus infection of the lower airway If RV can stay in low airway ? Due to the If RV can stay in low airway ? Due to the

RV culture at 33c rather than 37cRV culture at 33c rather than 37c But replication occur at lower airway But replication occur at lower airway

temperature noted in the use of in situ temperature noted in the use of in situ hybridization of the bronchial biopsy hybridization of the bronchial biopsy

So RV infection in lower airway and is the So RV infection in lower airway and is the pathogenesis of asthma exacerbationspathogenesis of asthma exacerbations

Physiological effects of experimental rhinovirus infection Reduction of peak flow and FEV1 with RV Reduction of peak flow and FEV1 with RV

16 infection 16 infection Enhance the sensitivities to histamine and Enhance the sensitivities to histamine and

allergen challenge allergen challenge RV16 increased asthma symptoms by the RV16 increased asthma symptoms by the

bronchoconstrictive response to bronchoconstrictive response to methacholine < 15days after infection methacholine < 15days after infection

Interactions between virus infected and asthmatic airway inflammation Viral pathology or asthmatic pathology ?Viral pathology or asthmatic pathology ? Through the different mechanisms with the Through the different mechanisms with the

same end effects on function or by sharing same end effects on function or by sharing the same pathogenetic mechanism in an the same pathogenetic mechanism in an addictive or even in a synergic fashion?addictive or even in a synergic fashion?

Effects of viruses on airway epithelial cell Intercellular adhesion molecule(ICAM-1) in the Intercellular adhesion molecule(ICAM-1) in the

major group RVs and low density lipoprotein major group RVs and low density lipoprotein receptor in minor group RVsreceptor in minor group RVs

Influenza binds the sialic acid residues via Influenza binds the sialic acid residues via haemaglutinin haemaglutinin

Upregulation of ICAM-1 increases the severity of Upregulation of ICAM-1 increases the severity of RV infection RV infection

Involving the transcription factor and nuclear Involving the transcription factor and nuclear factor (NF-kB) factor (NF-kB)

Effects of viruses on airway epithelial cell Inhibition of the upregulation of ICAM-1 Inhibition of the upregulation of ICAM-1

can improve the course of RV infection can improve the course of RV infection Corticosteroid can inhibit NF-kB and Corticosteroid can inhibit NF-kB and

inhibit RV16-induced increases in ICAM-1 inhibit RV16-induced increases in ICAM-1 surface expression (mRNA )and promotor surface expression (mRNA )and promotor activation activation

Effects of viruses on airway epithelial cell Influenza causes extensive necrosis in Influenza causes extensive necrosis in

epithelial cell and RV causes little or only epithelial cell and RV causes little or only pathy damage pathy damage

It increases the epithelial permeability and It increases the epithelial permeability and penetration of irritants and allergens and penetration of irritants and allergens and exposure of the extensive network of exposure of the extensive network of afferent nerve fibers which causes the afferent nerve fibers which causes the bronchial hyperresponsiveness bronchial hyperresponsiveness

Effects of viruses on airway epithelial cell Epithelium acts as a physical barrier and Epithelium acts as a physical barrier and

regulatory roles with immune reponse by regulatory roles with immune reponse by cytokines and chemokines cytokines and chemokines

Epithelium acts as antigen-presenting cells Epithelium acts as antigen-presenting cells and major histocompatibility complex class-and major histocompatibility complex class-I with B7-1 and B7-2 I with B7-1 and B7-2

Effects of viruses on airway epithelial cell Initial trigger of the inflammatory reactions Initial trigger of the inflammatory reactions

is an epithelial cell-virus interaction is an epithelial cell-virus interaction Bradykinin from the plasma precursor in Bradykinin from the plasma precursor in

nasal secretions of RV infected individuals nasal secretions of RV infected individuals and it can cause the sorethroat and rhinitis and it can cause the sorethroat and rhinitis

Some virus caused the complement-Some virus caused the complement-mediated damage such C3a and C5a mediated damage such C3a and C5a increased in influenza A infection increased in influenza A infection

Effects of viruses on airway epithelial cell Nitric oxide (NO) is produced by epithelial Nitric oxide (NO) is produced by epithelial

endothelial and smooth muscle cells and it endothelial and smooth muscle cells and it can relax the airway smooth musclecan relax the airway smooth muscle

Parainfluenza infection decreased the NO Parainfluenza infection decreased the NO and NO reacts with superoxide anion can and NO reacts with superoxide anion can generate peroxynitrite in the inflammed generate peroxynitrite in the inflammed tissuetissue

Effects of viruses on airway epithelial cell IL-1 enhances the adhesion of the IL-1 enhances the adhesion of the

inflammatory cells to endothelium to inflammatory cells to endothelium to chemotaxischemotaxis

TNF-a is a potent antiviral cytokineTNF-a is a potent antiviral cytokine IL-6 stimulates IgA-mediated immune IL-6 stimulates IgA-mediated immune

response response

Effects of viruses on airway epithelial cell IL-11 in virus –induced asthma causes IL-11 in virus –induced asthma causes

bronchoconstriction by the direct effect on bronchoconstriction by the direct effect on smooth muscle smooth muscle

IL-11 is elevated in nasal aspirates from IL-11 is elevated in nasal aspirates from children with colds or with the presence of children with colds or with the presence of wheezing wheezing

Effects of virus on airway smooth muscle cells RV-16 exposure on the smooth muscle cells RV-16 exposure on the smooth muscle cells

results in increased contractility to results in increased contractility to acetycholine and impaired relaxation to acetycholine and impaired relaxation to isoproterenol isoproterenol

The cellular immune response to virus infection in the lower airway Monocytes and macrophagesMonocytes and macrophages Dentrtic cellsDentrtic cells LymphocytesLymphocytes Mast cells and basophilsMast cells and basophils EosinophisEosinophis NeutrophilsNeutrophils Natural killer cellsNatural killer cells B-lymphocytes and interaction of virus with B-lymphocytes and interaction of virus with

immunoglobulin –E-dependent mechanismsimmunoglobulin –E-dependent mechanisms

Monocytes and macrophages

90% 90% alveolar macrophages in the lower alveolar macrophages in the lower airway for the early phagocytosis of virus airway for the early phagocytosis of virus particles and as the antigen presentation to particles and as the antigen presentation to T-cells and mediatorsT-cells and mediators

infection can stimulate the monocytes to infection can stimulate the monocytes to make the IL-8 TNF-a(RV) IL-6 IL-1b TNF-make the IL-8 TNF-a(RV) IL-6 IL-1b TNF-a IFN-a and IFN-B (influenza-A)a IFN-a and IFN-B (influenza-A)

Dentric cells

As the antigen presentation both allergen As the antigen presentation both allergen and pathogen and pathogen

Induce the primary immune responcesInduce the primary immune responces Regulations of the T-cell-mediated responseRegulations of the T-cell-mediated response

lymphocytes

RV infection causes the increasing CD3+ RV infection causes the increasing CD3+ CD4+and CD8+ in epithelium and CD4+and CD8+ in epithelium and submucosasubmucosa

CD4+T-cell by the T-helper 1 type(IFN-r CD4+T-cell by the T-helper 1 type(IFN-r cytokine) to virus cytokine) to virus

INF-r for the increasing basophils and mast INF-r for the increasing basophils and mast cell histamine releasing to inhibit the cell histamine releasing to inhibit the expression type 2 cytokinesexpression type 2 cytokines

lymphocytes

Asthma is the Th-2 type inflammation Asthma is the Th-2 type inflammation Many studies have demonstrated mutual Many studies have demonstrated mutual

inhibition of Th1 and Th2 cells inhibition of Th1 and Th2 cells In RV-16 infection with allergic rhinitis or In RV-16 infection with allergic rhinitis or

asthma ,the balance of airway Th1 and Th2 asthma ,the balance of airway Th1 and Th2 cytokines in sputum induced by virus was cytokines in sputum induced by virus was related to clinical S/Srelated to clinical S/S

lymphocytes

CD8+T cell can polarize the cytokine CD8+T cell can polarize the cytokine production by cytotoxic T cell (Tc)production by cytotoxic T cell (Tc)

CD8+Tcell can regulate CD4+ Th1/Th2 CD8+Tcell can regulate CD4+ Th1/Th2 balancebalance

CD8+ caused the IL-5 production and the CD8+ caused the IL-5 production and the induction of the airway eosinophil induction of the airway eosinophil

Mast cells and basophils

stimulate histamine releasestimulate histamine release Basophil IgE-mediated histamine release Basophil IgE-mediated histamine release

increased but the role in asthma is increased but the role in asthma is controversialcontroversial

Leukotrine C4 is one of the maior mediators Leukotrine C4 is one of the maior mediators for the late phase of bronchospasm for the late phase of bronchospasm

LTC4 LTD4 PGF2aLTB2 can cause airway LTC4 LTD4 PGF2aLTB2 can cause airway constriction constriction

Eosinophil

Persisted up to 6weeks in asthmatic subiectsPersisted up to 6weeks in asthmatic subiects Increased the eosinophil cationic protein in Increased the eosinophil cationic protein in

RV infection sputumRV infection sputum GM-CSF is the eosinophil production in the GM-CSF is the eosinophil production in the

bone marrow and in prolonging the bone marrow and in prolonging the eosinophil survival eosinophil survival

Neutrophil

IL-8 productionIL-8 production Prominent in severe asthmaProminent in severe asthma Day 4 in sputum with natural cold and day Day 4 in sputum with natural cold and day

2or day 9 in RV16 –infection sputum2or day 9 in RV16 –infection sputum In acute phase elevated the IL-8 and In acute phase elevated the IL-8 and

neutrophil in children neutrophil in children Levels of neutrophil myeloperoxidase Levels of neutrophil myeloperoxidase

correlated with symptom serviritycorrelated with symptom servirity

Natural killer cell

In the innate immune responseIn the innate immune response By natural killing ,antibody-dependent By natural killing ,antibody-dependent

cellular cytotoxicity or apoptotic killing of cellular cytotoxicity or apoptotic killing of Fas-positive target cell Fas-positive target cell

Ig-like receptors that recognize HLA-Ig-like receptors that recognize HLA-A,B,C,and CD94/NKG2A receptor that A,B,C,and CD94/NKG2A receptor that interact with HLA-E to recognize MHC interact with HLA-E to recognize MHC classI cellclassI cell

Natural killer cell

Production of the IFN-r for the Production of the IFN-r for the macrophages and dentritic cells and macrophages and dentritic cells and epithelial cells and also for the CD4+Th1 epithelial cells and also for the CD4+Th1 and CD8+T cl celland CD8+T cl cell

B-lymphocytes and interaction of virus with immunoglobulin –E-

dependent mechanisms1.1.allergic-specific Ig-Eare features of allergic-specific Ig-Eare features of

extrinsic or atopic asthmaextrinsic or atopic asthma

2.increasing in specific serum IgE to 2.increasing in specific serum IgE to housedust or mitehousedust or mite

Future directions Resp virus are important triggers of the Resp virus are important triggers of the

wheezing illness or asthmawheezing illness or asthma RV is common in all ages and RSV is most RV is common in all ages and RSV is most

in infants and young childrenin infants and young children RSV and influenza are capable of causing RSV and influenza are capable of causing

extensive epithelial necrosis but RV is less extensive epithelial necrosis but RV is less destruction destruction

Future directions

Virally-infected epithelial cell is an important Virally-infected epithelial cell is an important component of the antiviral immune responsecomponent of the antiviral immune response

Efficient clearance of a virus is by the antibodies Efficient clearance of a virus is by the antibodies and T-cells producing type 1 cytokinesand T-cells producing type 1 cytokines

Asthmatic airway is rich in type 2 cytokines which Asthmatic airway is rich in type 2 cytokines which results in virus specific T-cells with type2 cell or results in virus specific T-cells with type2 cell or mixed type1 /type 2 charactermixed type1 /type 2 characteran inefficient an inefficient antiviral immune responseantiviral immune response

Future directions

Future directions

Current Tx for virus-induced asthma exacerbation Current Tx for virus-induced asthma exacerbation is limited to high- dose inhaled and oral is limited to high- dose inhaled and oral corticosteroid or the purely sumptomatic Tx with corticosteroid or the purely sumptomatic Tx with bronchodilatorsbronchodilators

Antiviral therapy exists for influenzaAntiviral therapy exists for influenza Vaccine is difficult for RV due to many serotypes Vaccine is difficult for RV due to many serotypes

and the subsequent enhanced immunopathologyand the subsequent enhanced immunopathology Virus-induced inflammation can be treated by Virus-induced inflammation can be treated by

promoting type 1 response in individuals with promoting type 1 response in individuals with excessive type 2 response excessive type 2 response