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Pulmonary adaptive responses against bacterial pathogens
J S BrownReader in Respiratory Infection
Centre for Respiratory Research
Department of Medicine
University College London
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• incidence: overall 0.25%? admissions 50/100,000 per year > 65 years
• 50 - 80% mild - outpatient treatment
• 50 - 20% admitted - 10 - 20% severe / ITU- mortality 5 – 10% (20% UK audit)- 65000 deaths per year in UK
• who gets CAP?- elderly: but only 50% cases >65 years- smokers: attributable risk 51%- comorbidities: attributable risk 14%(lung /cirrhosis / renal disease / diabetes CNS
disease)
Adult community acquired pneumonia: CAP
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Causes of adult community acquired pneumonia [CAP] (Lim et al. Thorax 2001)
UK hospitalised patients
Unknown
48%
13%
13%
20%
Haemophilus influenzae
Gram negative bacilli 1.4%
Staphylococcus aureus 1.5%
Moraxella catarrhalis 2%
7%
4%
Legionella 3%
Mycoplasma pneumoniae 3%
Chlamydia pneumoniae
other viruses
influenza
Streptococcus pneumoniae
20% no pathogen identified
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Causes of CAP worldwide (JSBrown Respirology 2009)
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Streptococcus pneumoniae infections2nd commonest bacterial cause of death
pneumonia0 to 75 per 100,000
colonisations
aspiration
nasopharyngeal commensal
10% adults 50% infants
Septicaemia1 in 25
mortality 20%
otitis mediamortality 0%
meningitismortality 20%
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Health Protection Agency, United Kingdom, 2008
Streptococcus pneumoniae infection epidemiology- suggests adaptive immunity to colonisation is important?- waning of adaptive immunity with age?
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Immune response to S. pneumoniae pneumonia
2. Early lung infection
3. Established pneumonia
1. NP colonisation 4. Septicaemia
Ke
y im
mu
ne
eff
ect
ors
1. inflammatory exudate 2. phagocytes
3. CD4 and CD8 lymphocytes?
1. physical defences
2. mucosal proteins
3. alveolar macrophages
1. Complement
2. RE system
3. Circulating phagocytes
1. physical defences
2. mucosal proteins
3. lymphocytes
4. phagocytes
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Mechanisms of adaptive immunity
Th1
Th17
B-cellAntibody
IFN-gamma
IL-22Mucosal repair
Antimicrobial peptides
Chemokine release
Phagocyterecruitment
IL-17
Phagocyte
CD4 T-cell
Th2
CD8 T-cell Cytotoxicity v. intracellular pathogens
Hyper IgE syndrome
Antibody deficiencies
TAP syndrome?
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ScavengerReceptors
Mannose receptor / lectins
ComplementReceptors
Fc gamma Receptors
Toll LikeReceptors
• First-line phagocyte in lung
• Large range of receptors for - direct interactions with bacteria- Indirect interactions
• Airway lining fluid opsonins:- surfactant - complement - IgA and IgG
Alveolar macrophages (AMs)
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+
+
All bacteria killed
Bacterial phagocytosis by AMs can be saturated
1 hour
1 hour 1 hour
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EFFICIENT BACTERIAL CLEARANCE
NO PNEUMONIA / BRONCHITIS
• low inoculum• low virulence strain
• intact epithelium• efficient alveolar macrophages
BACTERIAL FACTORS HOST FACTORS
Do IgG and IgA improve S. pneumoniae opsonisation in
airways??
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• significant levels in IgG, IgA and IgM in airway lining fluid
• IgG predominant x5 that of IgA
• efficacy of IgG at promoting alveolar macrophage activity:
• efficacy of IgA / IgM not clear……
Antibody and alveolar macrophages:
Gordon et al.Infect Immun 2000
IgG effect
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• 1er and 2er IgG deficiency recurrent lung infections
• therefore IgG essential for preventing lung infection
• role of IgA unclear - IgA deficiency 1 in 400, only a subset
develop recurrent lung infections
• deficiency IgM also only sometimes associated with
recurrent lung infection
Antibody and prevention pneumonia:
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• mice protected v pneumoniaafter vaccination with:- protein antigens- conjugated capsule antigen- unconjugated capsule antigen- dead or live whole cells
• but few data on mechanism(s)
Anti IgG, alveolar macrophages, and S. pneumoniae: mouse data
Bacterial lung CFU inversely correlate with Ab level to Cps Ag
Jakobsen Infect Immun 1999
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• 23 valent unconjugated Pneumovax
- protects against septicaemia
- no evidence protects against pneumonia
• conjugated vaccine
- 7 to 13 valent
- protects children against pneumonia (25%:)
directly??
- not used in adults yet
- major issue serotype with coverage:
<30% CAP strains covered by Prevenar?
S. pneumoniae capsular polysaccharide vaccines and protection against CAP:
IgG response too weak (unconjugated)?
Host response poor due to comorbidity / age?
Serotype coverage too restricted to detect effects?
Wrong antigens?
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Failure of clearance of initial S. pneumoniae infection neutrophilic consolidation
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IL17 dependent immunity
IL-22
Invading S. pneumoniae
increased mucosal:- chemokine release- antimicrobial peptides- mucosal repair
IL-17
Primed Th17 CD4 cells
Neutrophil recruitment
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Hyper IgE (Job’s) syndrome and pneumonia
• triad of: raised IgE, abscesses, and pneumonia
• infections with S. pneumoniae
• mutations of STAT3, regulates cytokine responses
• specifically causes a defect in CD4 Th17 response
• demonstrates probable role for Th17 v. lung infection
Milner Nature 2008
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IL-17 dependent adaptive immunity and S. pneumoniae
• required for immunity v. nasopharyngeal colonisation:- after colonisation (Zhang J Clin Inv 2009)
- after vaccination with whole cell vaccine (Lu PLoS Pathogens)
• mechanism: - neutrophil-dependent- increases neutrophil recruitment and efficacy
• We don’t know whether protects against pneumonia….
• Antigen targets unknown…… (lipoprotein?)
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Target antigens for natural adaptive responses to S. pneumoniae
Lipsitch, Plos Medicine, 2005
serotype dependent incidence in children with increasing age• capsule target for vaccine
adaptive responses
• may not be for natural responses:- wide range protein antigens- acquired immunity seems
independent of capsule serotype- anti-protein response to
colonisation often dominant
• protein antigens maybe cross-protective
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Summary and conclusions re. lung adaptive immunity v. S.pneumoniae
• Antibody via improved alveolar macrophage and neutrophil phagocytosis v. important
• Th-17 mechanisms also could be helpful
• Natural adaptive immune responses can be directed against protein antigens
• Need to aim for vaccination strategy that:- boosts S. pneumoniae clearance from the lungs therefore alveolar macrophage efficacy key- can protect against wide-range of strains protein antigens need to be considered
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Acknowledgments• UCL Institute of Child Health
– Dr Helen Baxendale– Prof David Goldblatt– Prof Nigel Klein– Lindsey Ashton
• UCL Centre for Respiratory Research
– Dr Jonathan Cohen– Dr Suneeta Khandavilli– Dr Catherine Hyams– Dr Emilie Camberlein– Dr Jose Yuste– Dr Alejandro Ortiz Stern – Steve Bottoms
• Erasmus Medical Centre, Rotterdam– Prof Alex van Belkum– Dr Corné de Vogel
• UCL Biological Services Unit
• UCL Dept Immunology– Dr Claudia Mauri– Dr Natalie Carter
• Intercell AG, Vienna– Dr Carmen Giefing– Dr Eszter Nagy