TORCH (TOwards a Revolution in COPD Health

1
Is COPD an Autoimmune Disease ? Professor Bill
MacNee E.L.E.G.I. / Colt Laboratories MRC Centre
for Inflammation Research University of
Edinburgh and the Royal Infirmary of
Edinburgh Scotland, UK
2
Is COPD an Autoimmune
Disease ?

• Persistent inflammation in the absence of
  smoking
• What evidence is needed to prove an autoimmune
  aetiology
• in a disease ?
• Evidence of an autoimmune inflammatory response
  in
• COPD ?
• Implications for treatment

3

• The pathogenesis of Chronic Obstructive Pulmonary
  Disease (COPD) is not well understood.
• Established facts are
• Tobacco smoking is the main risk factor for the
  development of COPD, but only a percentage of
  smokers (so-called susceptible smokers) develop
  the disease2.
• Tobacco smoking elicits an inflammatory
  response in the lungs of all smokers, but this is
  enhanced and fails to resolve after quitting
  smoking in those who develop COPD3-6.
• This clearly indicates that the regulation of
  the inflammatory response is abnormal in COPD.
• What is not known is (are) the mechanism(s)
  underlying this abnormal regulation
• Important for the development of
  future
• treatment
  strategies

1..Celli B, MacNee W et al ER.J 2004 23932
2.Hogg et al N EJ M 2004 3502645. 3.Retamales
et al 2001. AJRCCM 2004164469. 4. Willemse et
al. ERJ 2005 26835. 6. Rutgers et al. Thorax
20005512.
4
Standards for the diagnosis and treatment of
patients with COPD a summary of the ATS/ERS
position paper
Definition Chronic obstructive pulmonary disease
(COPD) is a preventable and treatable disease
state characterised by airflow limitation that is
not fully reversible. The airflow limitation is
usually progressive and is associated with an
abnormal inflammatory response of the lungs to
noxious particles or gases, primarily caused by
cigarette smoking. Although COPD affects the
lungs, it also produces significant systemic
consequences.
5
The inflammatory responses in COPD D
Innate Immune Response
Acquired Immune Response
Hogg et al. N Engl J Med 2004242645
6
ABNORMAL REGULATION OF INFLAMMATION IN COPD
Impaired resolution
Enhanced Response
Not discussed in this presentation
Innate immunity
Acquired Immunity
7
ABNORMAL REGULATION OF INFLAMMATION IN COPD
Impaired resolution
Enhanced Response
Innate immunity
Acquired Immunity
Epigenetic mechanisms
Enhanced Oxidative Stress
8
The nature of small-airway obstruction in COPD
These studies suggest a response to an antigen
Innate Immune Response
Acquired Immune Response
Hogg et al. N Engl J Med 2004242645
9
ABNORMAL REGULATION OF INFLAMMATION IN COPD
Impaired resolution
Enhanced Response
Innate immunity
Acquired Immunity
Epigenetic mechanisms
Self-antigen (autoimmunity)
Non-self antigen (bacteria, virus, particles)
Enhanced oxidative Stress
10
Pathogenesis of COPD

• Does infection of the lower respiratory
• tract result in and enhanced adaptive
• immune response ?
• Hogg et al NEJM 2004242645
  
  
• Is there an Autoimmune component
• which enhances airspace inflammation
• in COPD ?
• Agusti, MacNee, Donaldson and Cosio Thorax 2003
  , Barnes and Cosio PLoS Med 2004

11
LATENT ADENOVIRUS INFECTION IN THE PATHOGENISIS
OF COPD
Inflammation
No COPD COPD EIA PCR
Ave density ratio 0.48?0.17
1.49 ?0.94
plt0.002
Matuse et al ARRD 1992146177
12
Bacterial colonisation of the airways is
associated with Neutrophilic inflammation in ex
smoking COPD patients
Sethi et al AJRCCM 2006173991
13
Is COPD an Autoimmune
Disease ?

• Persistent inflammation in the absence of
  smoking
• What evidence is needed to prove an autoimmune
  aetiology
• in a disease ?
• Evidence of an autoimmune inflammatory response
  in
• COPD ?
• Implications for treatment

14
Evidence of autoimmunity in clinical
diseaseWitebskys Postulates

• Direct proof
• Transfer of disease by Autoantibody
• Experimental
• Maternal
• To animals
• Indirect proof
• Transfer of disease by cells to SCID mice
• Induction of disease in animals by autoantigen
• Identification with lesions of AB / T-cells
• Transfer of disease by lymphocytes in
  experimental models
• Genetic models
• Auto-antibodies or self-reactive T cells
• Circumstantial evidence from clinical clues

15
Increased susceptibility to pulmonary emphysema
among HIV-seropositive smokers
Age 34 yrs, 16 pack yrs, HIV ve
Age 30yrs, 9 pack yrs,HIV ve
Diaz et al. Ann Intern Med 2000132369
16
The rate of annual decline in FEV1 and DLCO
during the 5-year follow-up period in COPD
patients with or without Hepatitis C virus
response to INF
Kanazawa, H. et al. Chest 2003123596-599
17
Inflammatory cell profile in the lungs of
nonsmokers (NS), smokers without anatomic
emphysema (SNE), and smokers with emphysema (SE)
Cosio, M. G. et al. Chest 2002121160-165S
18
Correlation between emphysema (expressed as the
density of alveolar walls Vv1 ALV) and the
numbers of neutrophils (PMN), T lymphocytes, and
alveolar macrophages per mm3 in the alveolar
walls of 6 nonsmokers and 15 smokers
Cosio, M. G. et al. Chest 2002121160-165S
19
Phenotypic characterisation of T-lymphocytes in
COPD Abnormal CD4CD25 regulatory T-lymphocytes
in response to tobacco smoke

• Regulatory T-lymphocytes have important
  anti-inflammatory
• and immunmodulatory effects

CD4CD25 cells are identified as (bright)
regulatory T-lymphocytes
CD4CD25 are increased in BAL In smokers but
not in COPD
Barcelo et al ERJ 2008
20
Phenotypic characterisation of T-lymphocytes in
COPD Abnormal CD4CD25 regulatory T-lymphocytes
in response to tobacco smoke

• Suggestive of
• a final maturationactivation state of CD8
  T-lymphocytes in COPD
• a blunted regulatory T-cell response to
  tobacco smoking in COPD
• supports a potential involvement of acaquired
  immune system in COPD

Barcelo et al ERJ 2008
21
T-regulatory cell expression of activation and
memory markers In BAL in COPD
Smyth, L. J. C. et al. Chest 2007132156-163
22
An animal model of autoimmune emphysema
Levels of antibodies in serum in rats immunised
with human umbilical vein EC (HUVEC) or human
pulmonary artery smooth muscle cells (HPASMC)
HUVEC
Control
Rat lungs develop emphysema following IP
injection of HUVECs (d), but not HPASCs (e)
HPASC
Taraseviciene-Stewart et al. AJRCCM 2005171734
23
An animal model of autoimmune emphysema
Adoptive transfer of CD4 lymphocytes from
HUVECimmunised rats develop airspace
enlargement
Control CD4
Taraseviciene-Stewart et al. AJRCCM 2005171734
24
Oligoclonal CD4 T cells in the lungs of patients
with severe emphysema

• Blasting of lung T cells from subjects with
  emphysema and normalsubjects after 2 weeks in
  culture with interleukin (IL) 2.
• Light microscopy of lung tissue

(B) Forward- versus side-scatter density plots
are shown for representative emphysema
(left panel) and control (right panel)
lung tissue culture. Blasting lymphocytes
are found within the upper gate with the
resting lymphocytes in the lower gate.
(C) A density plot of CD4 versus CD8
expression on CD3 T cells from a representative
subject with emphysema after in vitro culture in
the presence of IL-2 is shown.
Sullivan et al AJRCCM 2005172590
25
Anti-elastin autoimmunity ( peripheral blood T
and B cell responses to elastin peptides )in
emphysema
Seung-Hyo Lee Nature Medicine 2007
26
Autoantibodies in COPD
Feghali-Bostwick et al AJRCCM 2007177156
27
Autoantibodies in COPD
Compliment (C3)deposition COPD
Normal subject
Auto antibodies associated with clinical COPD
phenotype
Incubation of airway epithelial cells with COPD
plasma enhances allogeneic cytotoxicity
Feghali-Bostwick et al AJRCCM 2007177156
28
Autoimmune diseases

• Therapeutic approaches
• Alteration of thresholds of immune activation
• Blockade of costimulatory factors
• Antagonism of inflammatory cytokines or
  protective cytokines
• Inhibition of signaling cascades by small
  molecules
• Modulation of antigen-specific cells
• Induction of regulatory cells (intravenous,
  subcutaneous, or oral delivery of antigen)
• Alteration of peptide ligands
• Formation of complexes of peptide and
  major-histocompatibility-complex molecules
• Development of T-cell receptor vaccines
• Induction of B-cell tolerance
• Immune deviation from type I to type 2 helper T
  cells
• Reconstitution of the immune system
• Bone marrow ablation with autologous stem cells
• Bone marrow ablation with donor stem cells
• Bone marrow ablation without stem cells

Davidson et al. N Engl J Med 20013455340
29
Evidence of autoimmunity in clinical
diseaseWitebskys Postulates

• Direct proof
• Transfer of disease by Autoantibody
• Experimental
• Maternal
• To animals
• Indirect proof
• Transfer of disease by cells to SCID mice
• Induction of disease in animals by autoantigen
• Identification with lesions of AB / T-cells
• Transfer of disease by lymphocytes in
  experimental models
• Genetic models
• Auto-antibodies or self-reactive T cells
• Circumstantial evidence from clinical clues

30
Conclusions

• There is good direct and indirect evidence of
• autoimmunity as a pathogenic mechanism in COPD
• Proof of concept therapeutic trials are
  necessary
• to support test this hypothesis

31
Anti-elastin autoimmunity ( peripheral blood T
and B cell responses to elastin peptides )in
emphysema
Seung-Hyo Lee Nature Medicine 2007
32
EFFECT OF SMOKING AND COPD ON CYTOPLASMIC HDAC2
LEVELS IN LUNG TISSUE
Compared with non-smokers, Plt0.05
plt0.01 Compared with healthy smokers, Plt0.05
Szulakowski et al AJRCCM 200617141
33
HDAC2 expression and activity following cigarette
smoke exposure in vitro (alveolar epithelial
cells) and in vivo (rat lungs)
Marwick J et al AJRCCM 200431633-642
Post-translational modification of proteins by
oxidants in cigarette smoke ? targets of
proteolytic degradation
Smoke exposed alveolar epithelial cells