The immunology of virus infection in asthma

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The immunology of virus infection in asthma

• SD.Message,S.L.Johnston
• Eur Respir J 2001181013-1025
• 73 morning meeting by R2 ??? 91-5-29

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Resp infection by virus

• Common cold
• Pharyngitis
• Tracheobronchitis
• Croup
• Bronchiolitis
• pneumonia

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Table-1
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Resp infection by virus

• Localized to the resp tract
• ?RSV infant bronchiolitis
• Generalized sys illness
• ?mealses or chickenpox

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Resp infection by virus

• Host factor
• Age previous infection and immunization
  ,pre-existing resp or sys disease and
  immunosuppression or immunocompromise

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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

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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

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Asthma

• Trigger factors
• ?environmental allergens
• ?animals, moulds, pollens, mites, cold, exercise
  and drugs

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Asthma

• In 1950s
• ?bacterial allergy
• Now
• ?viral rather than bacterial infection

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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

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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

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The antiviral immune response

• Cytokines for the immunoregulatory or antiviral
  actions
• Body fluids for neutrolizing viral infections

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The antiviral immune response

• Specific immunity
• Antibodies by B-lymphocytes and cytotoxic T-cells
• Dentritic cells
• Memory for re-infection

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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

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The antiviral immune response

• T-cell
• Production of chemokines
• Alterations in the expression of adhesion
  molecules on the endothelium of inflammed tissues

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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 lt
  15days after infection

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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?

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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Dentric cells

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

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lymphocytes

• RV infection causes the increasing CD3 CD4and
  CD8 in epithelium and submucosa
• CD4T-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

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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

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lymphocytes

• CD8T cell can polarize the cytokine production
  by cytotoxic T cell (Tc)
• CD8Tcell can regulate CD4 Th1/Th2 balance
• CD8 caused the IL-5 production and the induction
  of the airway eosinophil

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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

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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

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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

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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

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Natural killer cell

• Production of the IFN-r for the macrophages and
  dentritic cells and epithelial cells and also for
  the CD4Th1 and CD8T cl cell

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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

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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

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Future directions

• Virally-infected epithelial cell is an important
  component of the antiviral immune response
• Efficient clearance of a virus is by the
  antibodies and T-cells producing type 1 cytokines
• Asthmatic airway is rich in type 2 cytokines
  which results in virus specific T-cells with
  type2 cell or mixed type1 /type 2 character?an
  inefficient antiviral immune response

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Future directions
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Future directions

• Current Tx for virus-induced asthma exacerbation
  is limited to high- dose inhaled and oral
  corticosteroid or the purely sumptomatic Tx with
  bronchodilators
• Antiviral therapy exists for influenza
• Vaccine is difficult for RV due to many serotypes
  and the subsequent enhanced immunopathology
• Virus-induced inflammation can be treated by
  promoting type 1 response in individuals with
  excessive type 2 response