Download The adaptive immune system, autoimmunity and COPD: lessons

COPD: op het kruispunt van
infecties en auto-immuniteit
Guy Brusselle, MD, PhD
Universitair Ziekenhuis Gent
Gent, Belgium
Immunology of COPD: Overview
Introduction
Innate immunity
Dendritic cells
Adaptive immunity
Auto-immunity in COPD?
Respiratory infections in COPD
Conclusion
Definition of COPD
Chronic obstructive pulmonary disease (COPD) is
a disease state that is
– characterized by airflow limitation:
not fully reversible
usually progressive
– associated with an abnormal inflammatory response
of the lungs to noxious particles or gases.
COPD is a preventable and treatable disease with some
significant extrapulmonary effects.
Comorbidities and exacerbations contribute to the
severity in individual patients.
COPD: epidemiology
Bousquet J. et al, Eur Respir J 2010; 36: 995-1001.
Bronchiolitis
Emphysema
Diagnosis of COPD
EXPOSURE TO RISK
FACTORS
SYMPTOMS
cough
sputum
dyspnea
tobacco
occupation
indoor/outdoor pollution

SPIROMETRY
: FEV1/FVC < 70%
Post bronchodilatation!
COPD: accelerated decline in lung function
FEV1 (% of value at
age 25)
100
Never smoked
75
Smoked regularly
and susceptible
to its effects
50
Stopped at 45
Disability
25
Stopped at 65
Death
0
25
50
75
Age (years)
Fletcher & Peto, 1977
COPD: impaired lung growth and/or
accelerated decline in lung function
Guy Brusselle, New Engl J Med 2009.
Local and systemic effects of COPD
BAL / LUNG INFLAMMATION
INNATE
ADAPTIVE
LOCAL
(PULMONARY)
EFFECTS
SYSTEMIC INFLAMMATION
BLOOD
Leukocytosis
LYMPHOID FOLLICLES
SERUM
TNF
CRP
ATHEROSCLEROSIS
EMPHYSEMA
MUSCLE WEAKNESS
AIRWAY WALL REMODELING
SYSTEMIC
EFFECTS
OSTEOPOROSIS
Innate and adaptive immunity in COPD
Brusselle G. et al, Lancet 2011; 378: 1015-26.
Immunology of COPD: Overview
Introduction
Innate immunity
Dendritic cells
Adaptive immunity
Auto-immunity in COPD?
Respiratory infections in COPD
Conclusion
Chronic CS-exposure in mice is
a relevant model of human COPD
COPD patients Smoking mice
Etiology
Duration
Genetic
predisposition
Pulmonary
inflammation
Cigarette
smoke
chronic
Cigarette
smoke
chronic
20% of smokers straindependent
innate 
adaptive
immune cells
innate 
adaptive
immune cells
Time course of cigarette smoke-induced BAL inflammation in mice
D’Hulst A et al, Eur Resp J 2005; 26: 204-213.
CS-induced increase in innate inflammatory cells in BAL
of wild type Balb/c and scid mice
D’Hulst A et al, Resp Research 2005.
CS-induced increase in adaptive immune cells in lungs
of wild type Balb/c and scid mice
D’Hulst A et al, Resp Research 2005.
CS-induced emphysema in Balb/c and scid mice
Air
CS (Cigarette Smoke)
WT
scid
D’Hulst A et al, Resp Research 2005.
Innate immune responses in COPD
ROS
I) sensing cigarette smoke and
danger signals
bacteria
viruses
cell death
(apoptotic,
necrotic)
PAMPs
DAMPs
RAGE
P2X7
P2Y2
TLRs
IL-1R
TLRs
P2X7
NF-KB
NLRPs
pro
caspase-1
INFLAMMASOME
caspase-1
II) effector phase
TNF-α
CXCL8
pro IL-1β
mature IL-1β
Pro-inflammatory
cytokines and chemokines
(TNF-α, IL-1β, CXCL8,…)
ROS
Proteolytic enzymes
(NE, MMP-9, MMP-12,…)
IL-1β
secretion
Sensing of cigarette smoke components and
Damage Associated Molecular Patterns (DAMPs) in COPD
Brusselle G. et al,
Lancet 2011.
Immunology of COPD: Overview
Introduction
Innate immunity
Dendritic cells
Adaptive immunity
Auto-immunity in COPD?
Respiratory infections in COPD
Conclusion
Function of dendritic cells (DC)
Vermaelen K et al, AJRCCM 2005.
Time course of the effect of cigarette smoke exposure
on dendritic cell number in BAL
D’Hulst A et al, Eur Resp J 2005; 26: 204-213.
Accumulation of Langerin+ dendritic cells
in small airways of COPD patients
Never smoker
“Healthy” Smoker
COPD GOLD I
COPD GOLD II
COPD GOLD III
COPD GOLD IV
Demedts I. et al, Am J Respir Crit Care Med. 2007.
Air
MHC II
CD86
Smoke
Dendritic cells
in BAL fluid of
CS-exposed mice
show increased
expression of
MHC class II and
costimulatory molecules.
CD80
D’Hulst A et al,
Eur Resp J 2005;
26: 204-213.
CD40
Pulmonary dendritic cells express MMP-12 mRNA
Bracke K. et al, Int Arch Allergy Immunol 2005.
Dendritic cells drive CD4+ T helper cell
differentiation
Brusselle G. et al, Lancet 2011; 378: 1015-26.
Immunology of COPD: Overview
Introduction
Innate immunity
Dendritic cells
Adaptive immunity
Auto-immunity in COPD?
Respiratory infections in COPD
Conclusion
Adaptive immune responses in COPD
Brusselle G. et al, Lancet 2011; 378: 1015-26.
Lymphoid follicles in patients with severe COPD
Hogg J et al, NEJM 2.004; 350:2645-53.
Lymphoid (B-cell) follicles in murine lung
tissue after 2-6 months smoke exposure
The development of B-cell follicles is progressive with time and
correlates with the increase in airspace enlargement.
Correlation  causal association?
Van der Strate B. et al, AJRCCM 2006; 751-758.
CS-induced increase in lymphoid follicles
Air
CS
Lm: wild type:
Air: 38.1 µm
CS: 41.6 µm
p<0.01
WT
Air
CS
Lm: scid:
Air: 38.3 µm
CS: 41.4 µm
p<0.05
Scid
D’Hulst A et al, Eur Resp J 2005; 26: 204-213.
______________________________________
______
____________________________________________
ERJ 2009; 34:219-30.
Drivers of adaptive immune responses in COPD?
+
+
-
Cigarette smoke components (eg tobacco
glycoprotein)?
Bacterial colonization (eg H. influenzae)
Viral infections (eg adenovirus)
Breakdown products of extracellular matrix
(eg elastin fragments)
Autoimmunity? Self (neo)antigens?
Immunology of COPD: Overview
Introduction
Innate immunity
Dendritic cells
Adaptive immunity
Auto-immunity in COPD?
Respiratory infections in COPD
Conclusion
Autoimmune disease: definition
A chronic inflammatory process leading to
progressive tissue damage
Induced by an interaction of a genetic
predisposition and exogenic factors
Persistent even when the initial inciting agent
has disappeared (eg smoking cessation)
Mediated by adaptive immune mechanisms
(auto-antibodies, autoreactive T cells)
 Sequence of events!
Pathogenesis of rheumatoid arthritis
I. Mcinnes and G. Schett, Nature Reviews Immunology 2007.
Autoantibodies before SLE
Arbuckle M. et al, NEJM 2003.
_____________________________________________
_________________________________
Nat Med 2007; 13: 567-69.
Innate and adaptive immune responses in COPD
Lee S. et al, Nature medicine 2007.
_____________
C. Greene et al, AJRCCM 2010; 181: 31-35.
AntiNuclear Antibodies (ANA) in COPD
Nunez B. et al, AJRCCM 2011; 183: 1025-31.
AntiTissue Antibodies (AT) in COPD
Nunez B. et al, AJRCCM 2011; 183: 1025-31.
The paradigm of autoimmune disease
Gene
environment
autoantibody
Disease
The paradigm of autoimmune disease
Gene
environment
Specific autoantibody
Disease
Non-specific autoantibody
What constitutes a specific autoantibody?
Non-Specific
Cross-reactive
Present in other
autoimmune diseases
Low titre (2-3 x normal)
Of little clinical use
Results from tissue injury
or polyclonal activation
Heterogeneous antigens
Specific
Antigen-specific
Disease or subset
specific
High titre (>10x normal)
Used in clinical diagnosis
Likely to be involved in
pathogenesis.
Family of biologically
related proteins
Immunology of COPD: Overview
Introduction
Innate immunity
Dendritic cells
Adaptive immunity
Auto-immunity in COPD?
Respiratory infections in COPD
Conclusion
M. Hilty et al, Plos One 2010; 5: e8578.
Distribution of common bacterial phyla and
genera in normal and diseased bronchi
M. Hilty et al,
Plos One 2010; 5: e8578.
Pathogen Associated Molecular Patterns (PAMPs) and
Pattern Recognition Receptors (PRR) in COPD
Defective macrophage phagocytosis
of bacteria in COPD
A. Taylor et al, ERJ 2010; 35: 1039-47.
Macrolides stimulate phagocytosis of
bacteria by macrophages
A. Taylor et al, ERJ 2010; 35: 1039-47.
Mucosal IgA switching and secretory IgA
(sIgA) epithelial transcytosis via pIgR
Cerutti A. Nat Rev Immunol 2008; 8: 421-34.
Bronchial secretory IgA deficiency in COPD
Polosukhin V. et al, AJRCCM 2011; 184: 317-27.
Deficiency of secretory IgA (SIgA)
in BAL fluid of COPD
Polosukhin V. et al, AJRCCM 2011; 184: 317-27.
Vicious-circle hypothesis of infection
and inflammation in COPD
PAMPs
DAMPs
S. Sethi and T. Murphy, NEJM 2008; 359: 2355-65.
Azithromycine ter preventie van
exacerbaties bij COPD
Albert R. et al, NEJM 2011; 689-98.
Experimental rhinovirus infection in subjects
with COPD causes exacerbations
Mallia P. et al, AJRCCM 2011; 183: 734-42.
Experimental rhinovirus infection in subjects
with COPD causes exacerbations
Mallia P. et al, AJRCCM 2011; 183: 734-42.
Immunology of COPD: Overview
Introduction
Innate immunity
Dendritic cells
Adaptive immunity
Auto-immunity in COPD?
Respiratory infections in COPD
Conclusion
Immunology of COPD: conclusions (1)
Cigarette smoke activates innate
immune cells (macrophages, neutrophils
and epithelial cells) by triggering
Pathogen Recognition Receptors:
– directly (e.g. LPS, oxidative stress) or
– indirectly (via DAMPs).
Defective macrophage phagocytosis of
bacteria and apoptotic cells in COPD.
Immunology of COPD: conclusions (2)
Dendritic cells accumulate in the lungs of CSexposed mice and in the small airways of
patients with (severe) COPD.
Chronic adaptive immune responses
(Th1 and Th17 CD4+ cells, cytotoxic CD8+ cells
and B cells) lead to the development of
lymphoid follicles.
Immunology of COPD: conclusions (3)
Autoantibodies are present in a subgroup of
patients with severe COPD (emphysema):
pathogenic?
The sequence of events in the pathogenesis of
RA (rheumatoid arthritis) and COPD is different:
– RA: auto-antibodies  articular inflammation
and destruction
– COPD: pulmonary inflammation and
destruction  auto-antibodies?
Immunology of COPD: conclusions (4)
Viral and bacterial infections of the
respiratory tract:
– cause acute exacerbations of COPD
(proof of concept: Rhinovirus)
– amplify and perpetuate chronic
inflammation in stable COPD
(via PAMPs).
Deficiency of bronchial secretory IgA in
COPD.
ACKNOWLEDGMENTS: Lab for Translational Research of
Obstructive Pulmonary Disease
Department of Respiratory Medicine
Ghent University, Ghent, Belgium
Guy Brusselle
Leen Seys
Eliane Castrique
Guy Joos
Griet Conickx
Ann Neesen
Karim Vermaelen
Fien Verhamme
Indra De Borle
Ken Bracke
Lisa Dupont
Philippe De Gryze
Tania Maes
Sharen Provoost
Ellen Lanckacker
Lies Lahousse
Nele Pauwels
Ingel Demedts
An D’Hulst
Geert Van Pottelberge
Chris Van Hove
Yannick van Durme
Tine Demoor
Katrien Moerloose
Katleen De Saedeleer
Marie-Rose Mouton
Greet Barbier
Anouck Goethals
Christelle Snauwaert
Acknowledgments
Prof Dr B Stricker
Prof Dr A Hofman
Prof A Uitterlinden
Prof C Van Duijn
Prof H Hoogsteden
Dr A Ikram
Dr M Vernooij
Dr J Heeringa
Dr L Lahousse
Dr Y van Durme
Dr D Loth
Dr J Aerts
Dr K Verhamme
Dr M Eijgelsheim
Lic F van Rooij
Mevr J verkroost
And all other colleagues and researchers at
the Erasmus University / Ommoord research centre (ERGO);
the CHARGE consortium: ARIC, CHS, FHS and RS.
Immunopathology of COPD
P. Barnes, Nat Rev Immunol 2008.