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3rd Jack Pepys Workshop on Asthma in the
Workplace (Montreal, May 17-19 2007)
An ATS/ERS report: 100 key questions and
needs in occupational asthma (ERJ 2006;
27:607-14)
PHYSIOPATHOLOGY AND MECHANISMS
Questions 47-60
Cristina E. Mapp
University of Ferrara, Italy
Question 47: is asthma heterogeneous?
YES, both between and within individuals
Phenotypic classification of Adult-onset asthma:
• etiologic factors
• clinical characteristics of the disease
Each method is largely descriptive and is a gross
oversemplification
More recently, classification of asthma according
to the nature of the underlying airway inflammation
has been suggested
Four distinct phenotypes:
• eosinophilic
• neutrophilic
• mixed inflammatory
• paucigranulocytic asthma
Non-eosinophilic asthma
by using IS, BP, BW, and BAL
• absence of airway eosinophilia
• normal subepithelial layer thickness
• a poor short-term response to treatment with
inhaled corticosteroids
Berry MA et al. Thorax 2007; Mar 13
Neutrophilic asthma
Increased expression of the innate immune
receptors toll-like receptor (TLR)2,TLR4 and
CD14, and inflammatory cytokines IL-8, IL1β
in induced sputum
Innate immune activation
Simpson JL et al. Thorax 2007; 62:211-8
Contiguos innate and
physically) in
adaptive immunity (temporally and
asthma
Purple arrows =
unidirectional
connections
Red arrows=
continual dialog
Dashed arrow=
inflammatory
stimuli
Sabroe I et al. AJRCCM 2007; 175:306-11
Question 48: timing of A, AHR, and inflammation
baseline ventilation heterogeneity is a strong predictor of AHR,
independent of airway inflammation in asthmatics, its relationship
persists following anti-inflammatory therapy
a= baseline
b= following treatment
closed circles =ICS treatment; open circles = no ICS treatment;
triangles= CFC-BDP treated; squares= HFA-BDP treated subjects
Downie SRT et al. Thorax published online 20 Feb 2007
Dual asthmatic responders: the increase in AHR persists 7 d after allergen
challenge
Changes from baseline in FEV1 (A) and methacholine PC20 24 h and 7 d after allergen
challenge
The 24 h increase in
airway wall inflammation
resolves by 7 d,
whereas
the increase in markers
of remodeling persist
A: tenascin, B: procollagen III, procollagen I cells, HSP-47+ fibroblasts, E: eosinophils,
F: macrophages, G: CD3+ T cells, H: neutrophils, at baseline, 24 h and 7 d after allergen
challenge
Kariyawasam HH et al. AJRCCM 2007; 175:896-904
• AHR can be dissociated from cellular
inflammation
• whilst remaining associated with sustained
airway remodeling
Measuring the degree of inflammation does
not allow insight into disease severity in
terms of AHR
Time course of exhaled NO after
specific inhalation test (SIT)
180
**
SIT +
—

NO ppb
120
Exposure

*
SIT -
*
*
*
60
0
Time
• Ferrazzoni S. et al. ERS 2005
* p<0.05 ** p<0.01
• Barbinova L. Int Arch Environ Health 2006;
79:387 : eNO increase 22 h after isocyanate challenge
After specific bronchial challenge
with TDI
Eosinophils in IS: ↑ 8-24 h ↓ 48 h
in BP ↑ 48 h
CD8+ in blood: ↑ 8 h ↑ 48 h (not all
subjects)
AHR: ↑ 8-24 h
↓ 1-4 wk
1in 4 asthmatics have PAO and uncontrolled symptoms at 4 to 6 wk postviral exacerbation; the phenomenon does not involve the influx of inflammatory cells into the lower airways during exacerbation
Induced-sputum samples during an acute exacerbation
Wood et al. Chest 2007; 131:415-23
Question 49: what is the additional value of other
procedures (to determine the influence of
confounders in the interpretation of cytology) on
top of clinical history taking in subjects who
perform induced-sputum?
• clinical history
• statistical analysis
Particular attention in the presence of
neutrophilic airway inflammation
Questions 50 and 57: role of neutrophils
sputum neutrophils are usually elevated
• during asthma exacerbation
• in severe asthma
• in older asthmatics
• in smoking asthma patients
In OA
• at diagnosis
• after cessation of exposure in subjects with no
improvement
IgE could influence
biological function
of neutrophils
In vitro IgE can
delay programmed
cell death of
neutrophils from
allergic asthmatics
and this may
possibly contribute
to neutrophilic
inflammation in
atopic asthma
Neutrophils from AAs express FcRI and carry surface-bound IgE. Freshly isolated neutrophils from two
(nos. 1 and 2) were analyzed for expression of FcRI (A), surface-bound IgE (B), and CD16 (C) by FACS.
Figure is representative of eight separate experiments. Saffar AS et. J Immunol 2007; 178:2535-41
Neutrophils fit both in allergic and nonallergic
asthma
Question 51: can skin absorption lead to
respiratory sensitization?
•
•
Vanoirbeek JA et al. Toxicol Sci 2004; 80:310-21(TDI)
Plitnick LM et al. Toxicology 2005; 207:487-99
(isocyanates)
•
Selgrade M et al. Toxicol Sci 2006; 94:108-17 (DNCB,
isoc.)
Vanoirbreek JA et al. J Allergy Clin Immunol 2006; 117:
1090-7 (TMA, DNCB)
Tarkowski M et al. Am J Physiol Lung Cell Mol Physiol
2007; 292:L207-14 (TDI)
Sun LZ ert al. Scand J Immunol 2007; 65:118-25 (TDI)
•
•
•
dermal exposure causes respiratory
hypersensitivity
• isocyanate skin exposure can occur at work
• it is likely that such exposure can contribute to the
development of isocyanate asthma, presumably by
inducing systemic sensitization
Bello D et al. Environ Health Perspect 2007; 115:328-35
a reasonable advice: avoid skin contact with
chemical sensitizers in the workplace to prevent
chemical-induced asthma
Vanoirbreek JA et al. J Allergy Clin Immunol 2006; 117:1090-7
….. a provocative hypothesis
dermal contact with polyurethane-containing
medical materials in early life may be involved
in dysregulation of the neonatal immune system
and could predispose infants to the development
of childhood asthma
Krone CA et al. Med Sci Monit 2003; 9:HY39-43
Question 52:
are animal models useful in understanding the
pathogenesis of OA?
animal models are useful, but at the moment, they
do not provide enough information to predict the
ability of a chemical to act as a sensitizer and to
fully understand the mechanims involved in OA
Animal models of chemical-induced asthma
• Th2 or mixed Th1 and Th2 responses
• stimulatory effects on bronchial epithelial
cells
• production of proinflammatory cytokines
and chemokines
• a protective role of PPARgamma
JACI 2006; 117;1090-7 Exp Lung Res 2006; 32:245-62
J Immunol 2006; 177:5248-57
• The PPARgamma is a ligand-activated
transcription factor belonging to the
nuclear hormone receptor superfamily
• Is expressed on dendritic cells,
eosinophils, macrophages, and T cells
• PPAR ligands are thought to exert antiinflammatory effects by negatively
regulating the expression of proinflammatory genes
• PPAR agonists to prevent and treat asthma
Question 53: many questions (outcome, pH, tolerance…..)
IS is a feasible, repeatable, non-invasive method to
measure airways pH (with a cut-off value of 7.3: sensitivity
72.1% and specificity 100% to distinguish asthmatics from
healthy subjects)
Correlation between the levels of control of asthma (ACQ score) and
pH and percentage of eosinophils
Kodric M et al. Am J Respir Crit Care Med 2007; 175:905-10
Questions 53-54: LMWA and the immune system
One example: diisocyanates
although many authors have focused their
research on the mechanisms involved in LMWAinduced OA
many questions such as: the outcome
when inhaled, how long do stay in the airways,
how does the immune system recognizes a
LMWA and generates a specific response, can
tolerance occur, are still incompletely understood
Diisocyanate-induced asthma is a
non IgE-mediated disease at least
in subjects in whom specific IgE
antibodies to diisocyanates are
undectable
Jones MG et al. JACI 2006; 117:663-9
Question 55: is appropriate the concept of “united
airways”?
YES
• upper and lower airways may be considered a
unique entity
• allergic rhinitis is a risk factor for the occurrence
and severity of asthma
• rhinoconjunctivitis is a risk factor for HMWAinduced OA
Rhinitis - Sinusitis
Eosinophils
IL-5
Basophils
Mast cells
degranulation
Nasal allergen
challenge
Loss of
filtration
efficiency
Allergen
Postnasal
drip
Reflex
Nose-bronchi
Precursors
Cytokines
Bone marrow
Viral
infection
Eosinophils
ICAM-1
VCAM-1
Bronchial allergen
challenge
Asthma
There is a gradient of T-cell activation (blood and
induced sputum)
• ENA: a decrease of Th1, an increase of Th2 and
Treg after SIT (tolerating profile)
• OA: an increase of both Th1 and Th2, a decrease
of Treg cells after SIT (inflammatory profile)
• OR: an increase of Th2 cells, absence of Th1
activation and of Treg cell decrease after SIT
(intermediate profile)
Mamessier E et al. Allergy 2007; 62:162-9
Questions 56-58: role of cells….. Dendritic cells are crucial for sensitization to inhaled Ag
and in established inflammation; plasmacytoid DCs: tolerance; myeloid DCs: immunity
Immune regulation by DCs in the lung. Under steady-state conditions (A), in the absence of accompanying danger
signals in the lung, inhaled antigens are picked up by mDCs and pDCs, which take the antigen to the mediastinal
nodes. Here partially mature mDCs induce a short-lived boost of division in antigen-specific T cells, but these T cells
fail to differentiate into effector cells and die. Some T cells might also differentiate into Tregs. Plasmacytoid DCs in the
draining node influence the generation of T effector cells from dividing T cells, probably by giving negative signals
(indoleamine 2,3-dioxygenase [IDO] and programmed death ligand [PDL] 1) to T cells and mDCs. At the same time, they
also generate Tregs. Under inflammatory conditions (B), mDCs arrive in the draining node as fully mature cells.
Antigen-specific T cells undergo proliferation, this time generating effector cells. On the other hand, pDCs also acquire
a mature phenotype and prime antigen-specific T cells to become effector cells as well. ICOSL, Inducible costimulator
ligand.
Hammad H and Lambrecht BN. J Allergy Clin Immunol 2006;118:331-6
By using BAL in allergic asthmatics, both myeloid
and plasmacytoid DCs accumulate in the airway
lumen 24 hours after allergen challenge
Bratke K, et al. Thorax 2007; 62: 168-75
By using IS it is possible to analyze human airway
DCs (0.5% of viable sputum cells, HLA-DR+)
McCarthy NE et al. Clin Exp Allergy 2007; 37:72-82
Several studies indicate that CD8 T cells
• do not exhibit a fixed phenotype
• can differentiate into functionally distinct
subsets
• uptake by DCs is sufficient for their initial
proliferative response to protein allergens
• sustained expansion and functional maturation
of the CD8 response most likely requires signals
from CD4 T cells or Toll-like receptor ligation
CD8 and occupational asthma
• Animal and human data show a mixed
Th1/Th2 activation with implication of the
CD8+ T cells in OA
• In OA subjects, specific inhalation challenge
induces a mixed Th2/Th1 response and CD8+
cells are the main producers of IFN-gamma
Allergy 2007; 62:162-9
Questions 59-60: specific to compounds
(diisocyanates)
• Physiologic levels of GSH protect against HDI
exposure
• Type I hypersensitivity mechanism in 44% of TDI
asthma by using vapor TDI-albumin conjugates
• Autoantibodies to CK18 and CK19 as serologic
markers in TDI asthma
Clin Exp Allergy 2005; 35:352-7
J Allergy Clin Immunol 2006; 118:885-91
Yonsei Med J 2006; 47:773-81
Isocyanate asthma and oxidative stress
• glutathione S-transferase polymorphisms
• protective role of airway GSH
• protective role of PPARgamma agonists
• PPARgamma modulates reactive oxygen
species (ROSs) generation and activates
the redox-sensitive transcription factor
nuclear-kappaB and hypoxia-inducible
factor 1alpha
Question 60: asthma and hairdressers
• sensitization is more related to individual
hypersusceptibility
• an immunologic mechanism is strongly
suggested but not definitely demonstrated
• diagnosis is based on standardized SIC
Moscato G and Galdi E. Curr Opion Allergy Clin Immunol
2006; 6:91-5
Certain, or a large body of
evidence
Uncertain or limited evidence
• asthma is heterogeneous
skin and respiratory sensitization
• timing of OA, AHR and AI
is different
usefulness of animal models
• neutrophils fit both in allergic
and nonallergic asthma
mechanisms of recognition of LMWA
by the immune system
• upper and lower airways as a
unique entity
role of GSH and a low pH in asthma
• role of DCs in asthma
• CD8+ T cells exhibit different
phenotypes
• CD8+ T cells play a role in OA