European Respiratory Society International Congress,

London, September 3-7, 2016

Immunity in COPD Time for questions? (session 688)

The immune system in COPD: guilty as

charged?
Wim Timens, MD, PhD
Professor and Chair
Dept. Pathology and Medical Biology,
University Medical Center Groningen, The Netherlands

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 Disclosures

Advisory Boards for Merck Sharp & Dohme, Pfizer, Roche/Ventana.

Lectures / courses for Bristol-Myers Squibb, GSK, Biotest, Chiesi,

Lilly Oncology, Merck Sharp & Dohme, Novartis, Pfizer,
Roche/Ventana.

(not related to this presentation; no personal fees, all fees to Institution)

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 Overview
Inflammation in COPD

Ongoing inflammation after stopping smoking in COPD

Innate Immunity / Adaptive immunity in COPD

Role of Autoimmunity

Conclusion: the Immune system in COPD: Foe or Friend?

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Barnes. Nature Rev Immunol 2008
 Seemungal et al. AJRCCM2015

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 Smoking cessation and ongoing
airway inflammation in COPD

Groningen Research Institute for

Asthma and COPD

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 Inflammatory cell levels in ex-smokers
with COPD (>1 year of smoking cessation)
Neutrophils Lymphocytes Eosinophils
P=0.0001 P=0.0161 P=0.0083 Patients with COPD
100 10
Healthy controls
90
Sputum Neutrophils

80 8

Sputum Lymphocytes
and Eosinophils (%)
70
60 6
(%)

50

40 4

30
20 2
10
0 0

Subjects with COPD who do not currently smoke have

increased numbers of inflammatory cells Rutgers et al. Thorax. 2000;55:12-18.
 Sputum inflammation 1 yr after stopping
smoking
p<0.05 p<0.05 p<0.05
15
300
neutrophils in sputum

IL-8 in sputum (ng/ml)

100

10 80
(106/ml)

60

40
5
20

0
start 1 year start 1 year
0
start 1 year start 1 year COPD+ COPD-
COPD+ COPD-

p<0.05
5
macrophages in sputum

4
(106/ml)

2
* Willemse et al.:
1
ERJ 2004, 23:464-476; ERJ 2004,
0 24:391-6; ERJ 2005, 26: 835-845;
start 1 year start 1 year Respir. Res. 2005, 6: 38; Chest 2005,
COPD+ COPD- 128:3685-87

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 Relation between duration of smoking cessation
and bronchial inflammation in COPD

Lapperre et al, Thorax 2006

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 Why ongoing inflammation after
smoking cessation?
Colonisation with bacteria and/or viruses in the lower airways

COPD may have auto-immune features:

Auto-antibodies may be directed to:
particles/antigens in cigarette smoke itself

protein fragments of the extra-cellular matrix, generated by smoke-induced lung injury

Acquired somatic mutations caused by carcinogens in cigarette smoke could

contribute to the ongoing inflammation in COPD by amplification of
inflammatory signal transduction cascades

Cellular inflammation is a negative consequence of smoke exposure,

but is also an integrative part of a repair process, taking place after
smoking cessation.

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 Inflammatory cells in tissue repair

MacLeod et al. Adv Wound Care 2015

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 Pro-inflammatory factors affect promote repair

Broekman et al. Resp Res. 2016

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 Inflammatory cells in tissue repair

Wynn et al, Immunity 2016

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 Adaptive Immunity in COPD
Lung compartments
small airways
central airways
parenchyma

Role for B- and T-cells

Anti-microbial
Anti-tobacco smoke
Anti-ECM
(non-specific)

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 Lymphoid follicles in patients with severe
COPD

Hogg et al, NEJM 2004

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 B-cell follicles in COPD: Vh-gene analysis,

airways

parenchyma
phylogenetic tree:
ongoing mutations -> oligoclonal proliferation
CD20
Van der Strate et al, AJRCCM 2006

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 Blood; Active smoking induces memory B
cell response, which differs in COPD
Class switched memory B cells
80

of total B cells
60

% CD27+IgM-
*
40 Brandsma et al, ERJ 2012
20

0
------COPD------ ------Healthy------
smoker ex-smoker smoker ex-smoker never smoker

IgG positive memory B cells IgA positive B cells in peripheral blood

% IgG of CD20+ CD27+ B cells

40 * 4 *

% IgA positive cells

30 3

20 2

10 1

0 0
------COPD------ ------Healthy------ ------COPD------ ------Healthy------
smoker ex-smoker smoker ex-smoker never smoker smoker ex-smoker smoker ex-smoker never smoker

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 Lung; active smoking induces IgG memory B
cells and more memory B cells in COPD

IgG memory B cells in lung tissue Memory B cells in lung tissue

current smokers vs ex- and never smokers

% CD20CD27 of lymphocytes
50 * 8 *
% IgG of CD20CD27

40 6

30
4
20

2
10

0 0
Current Smokers Ex- and never smokers
COPD non-COPD

Brandsma et al, ERJ 2012

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 Auto-antibodies in COPD

Antinuclear antibodies (ANAs) in Frequency of cationic amino acids (shown

patients with COPD and controls in %) in the CDR3 region of antibodies
sequenced from lung-infiltrated B cells.

Bonarius et al, Thorax 2011

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 BAFF and follicles in severe COPD

Polverino et al., AJRCCM 2010 and 2015

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 BAFF and follicles in severe COPD

Conclusion: BAFF
contributes to the
formation and expansion of
pulmonary LFs in the
severe stages of COPD
likely by promoting the
survival and proliferation of
LF B cells by inhibiting
activation of NF-kB.
Polverino et al., AJRCCM 2015

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 BAFF and follicles in COPD

Seys et al. AJRCCM 2015

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 Role of IL17 in lymphoid neogenesis in
COPD via CXCL-12

Roos et al. , AJRCCM 2015

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 A1AT COPD: neutrophils /
macrophages

Baraldo et al. AJRCCM 2015

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 A1AT COPD: Lymphoid follicles also
showing clonality

Baraldo et al. AJRCCM 2015

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 A1AT COPD: adaptive immune cells

Conclusions: An important adaptive immune inflammation, comprising B,

CD41, and CD81 lymphocytes, and LFs, is a prominent feature in AATD.
These results change the paradigm of the mechanism of AATD-induced
emphysema from a pure elastaseantielastase imbalance to a much more
complex one involving the adaptive immune system, similarly to what
occurs in usual COPD.
Baraldo et al. AJRCCM 2015

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 Correlation gene expression
network in patients with
emphysema

Faner et al. AJRCCM 2016

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 Correlation gene
expression network in
patients with bronchiolitis.

Faner et al. AJRCCM 2016

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 Anti-microbial?
remarkably similar histology in mice and men

no presence of mycoplasma, chlamydia, adenovirus, or

pneumocystis jiroveci (real-time PCR frozen tissue)
no evidence for specific bacterial pathogens
Real-time PCR analysis with broad-range primers reactive
with 16S RNAs from prokaryotes: no reactivity above baseline
levels
In mice
specified pathogen free conditions
not in non-smoking littermates
-> not (full) explanation
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 ECM in immune response in COPD

Lee et al, Nature Med 2007, 13: 567

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 Anti-ECM: humoral anti-elastin
response

Lee et al, Nature Med 2007

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 Anti-ECM: cellular anti-elastin
response (PBL)

Lee et al, Nature Med 2007

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 Autoreactive T-cell responses to elastin fragments (EFs)
in current smokers correlates with progression of
emphysema (CT).

Bhavani et al. AJRCCM 2015

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 Role of IL17 in COPD exacerbations

Roos et al. , AJRCCM 2015

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 Brusselle & Bracke, AnnalsATS 2014

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 Conclusions 1
Ongoing inflammation:

The lack of resolution -or even increase- of inflammation in lungs of

ex-smokers with COPD when compared to non-COPD may be due to a
combination of autonomous perpetuation of inflammation and long-
term repair events

Therefore: not all inflammation is detrimental; research should include

dissection of detrimental and beneficial effects of inflammation

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 Conclusions 2
Adaptive Immunity:
Antigen specific immune response: candidates:
Microbes; viral/bacterial colonization/infection of the airways
Cigarette smoke components or derivatives
Neo-antigens; e.g. degradation products of ECM or modified self
proteins (induced by smoking and/or inflammatory environment)
More pronounced in severe COPD (emphysema) than in mild
(bronchitis)
Still unclear whether and to what extent this contributes to tissue damage
or is a secondary bystander effect

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 Conclusions 3
Autoimmune response in COPD?
The antigen specific adaptive immune response may lead to breakdown of
tolerance autoimmunity:
Increased levels of autoantibodies in COPD (but: problems:
reproducibility, heterogeneity of COPD population, home made assays)
Increased BAFF in follicles
Auto-immune T-cell responses
Only in subset of COPD
So:
Autoimmune component/contribution in COPD is likely
Not a true full autoimmune disease

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 Conclusion

The Immune system in COPD: Foe or Friend?

Partly foe, partly friend, often combined

Still often in disguise

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