Transcript The immunology of virus infection in asthma

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
Resp infection by virus
Common cold
 Pharyngitis
 Tracheobronchitis
 Croup
 Bronchiolitis
 pneumonia

Table-1
Virus type
Serotype
Common
cold
Asthma
Exacerbation
pneumonia
bronchitis
bronchiolitis
Rhinovirus
1 100+
+++
+++
+/-
+
+
Coronaviru
s
229E
OC4
3
++
++
Influenza
A.B.C
+
+
++
+
Parainfluen
za
1.2.3.4
+
+
+/-
++
+
RSV
A.B
+
+
+
+
+++
adenovirus
1 43
+
+
++
+
+
Resp infection by virus
Localized to the resp tract
RSV infant bronchiolitis
 Generalized sys illness
mealses or chickenpox

Resp infection by virus
Host factor :
Age previous infection and
immunization ,pre-existing resp or sys
disease and immunosuppression or
immunocompromise

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

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

Asthma
Trigger factors
environmental allergens
animals, moulds, pollens, mites, cold,
exercise and drugs

Asthma
In 1950s
bacterial allergy
 Now
viral rather than bacterial infection

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

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

The antiviral immune response
Cytokines for the immunoregulatory or
antiviral actions
 Body fluids for neutrolizing viral infections

The antiviral immune response

1.
2.
3.
Specific immunity
Antibodies by B-lymphocytes and
cytotoxic T-cells
Dentritic cells
Memory for re-infection
The antiviral immune response

1.
2.
3.
4.
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
The antiviral immune response

1.
2.
T-cell
Production of chemokines
Alterations in the expression of adhesion
molecules on the endothelium of
inflammed tissues
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

The antiviral immune response

1.
2.
3.
4.
5.
6.
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
The antiviral immune response

1.
2.
Secondary infection
Rapid mobilization of B and T cell for
specific immunity
Earlier T-cell peak with NK cell peak at
day 3-4
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
Epedimiology
Studies showed an increased rate of virus
detection in individuals suffering from the
asthma attacks and 10-85% in children ,1044% 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

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
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
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
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

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

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?

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)
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

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

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 classI with B7-1 and B7-2

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 complementmediated damage such C3a and C5a
increased in influenza A infection

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

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

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

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
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
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 TNFa IFN-a and IFN-B (influenza-A)

Dentric cells
As the antigen presentation both allergen
and pathogen
 Induce the primary immune responces
 Regulations of the T-cell-mediated response

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

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

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

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

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

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

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 HLAA,B,C,and CD94/NKG2A receptor that
interact with HLA-E to recognize MHC
classI cell

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
B-lymphocytes and interaction of
virus with immunoglobulin –Edependent mechanisms
1.allergic-specific Ig-Eare features of
extrinsic or atopic asthma
2.increasing in specific serum IgE to
housedust or mite
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

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
Future directions
Future directions

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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