ARTICLE
Auteur(s) : Catherine Duez,
Philippe Gosset, André-Bernard Tonnel
Institut National de la Santé et de la Recherche Médicale U416,
IFR17, Institut Pasteur de Lille, 1 rue du Pr Calmette, BP 245,
59019 Lille, France
accepté le 22 Juillet 2005
Both innate and adaptive immunity are involved in the host defence
against external agents. Adaptive immunity involves the selection
of antigen-specific T and B cell clones and the development of an
immunological memory. Innate immunity arose earlier in species
evolution: this ancestral form of the host defence exists in
invertebrates and plants [1]. In contrast to adaptive immunity,
which is able to respond specifically to millions of different
antigenic motifs, innate immunity involves receptors able to detect
a limited set of conserved molecular patterns that are unique to
the microbial world and invariant among entire classes of pathogens
(Gram-positive and -negative bacteria, fungi and viruses) and are
called Pathogen-Associated Molecular Patterns (PAMP). Pattern
Recognition Receptors (PRR) detect PAMP, and are able to signal
rapidly to the host the presence of an infectious process.The
Toll-like Receptor (TLR) family is the best characterized class of
signalling PRR in mammalian species [2]. TLR are transmembrane
proteins including multiple copies of leucine–rich repeats in the
extracellular domain and a cytoplasmic Toll/IL-1 (interleukin-1)
receptor homology domain (TIR). This TIR domain has the ability to
bind and activate signalling molecules including MyD88, TIR
containing adaptor protein (TIRAP), TIR containing adaptor inducing
IFN-β (TRIF) and TRIF related adaptor molecule (TRAM). This leads
to the stimulation of several important signalling pathways such as
mitogen associated protein (MAP) kinases, Signal Transducer and
Activator of Transcription (STAT)-1 and nuclear factor (NF)-κB (
(figure 1) )[3,
4]. So far, 11 TLR have been described in mammals. They recognize
distinct structural components displayed by microorganisms (table
1). TLR1, 2, 4, 5 and 6 are mainly specialized in the detection of
bacterial products from extracellular pathogens such as
lipoproteins from Gram-positive bacteria (TLR2 associated with TLR1
or TLR6), lipopolysaccharide (LPS) from Gram-negative bacteria
(TLR4) and flagellin from flagellate bacteria (TLR5). TLR3, 7, 8
and 9, localized in intracellular compartments, are susceptible to
respond to the presence of intracellular pathogens like viruses and
to recognize nucleic acids [3, 5]. TLR11 has only been described in
the mouse. This receptor fails to respond to known TLR ligands but
instead activates cells specifically in response to uropathogenic
bacteria [6]. Moreover, a pathogen-induced immune response can
concomitantly involve several TLR: for example, Gram-negative
flagellate bacteria may involve at least TLR4 and TLR5.
TLR variations in allergic asthma
( Table 1 )Genes encoding for TLR
exhibit high variability between human populations, but the link
between these genetic variations (polymorphisms) and the frequency
of allergic diseases remains to be elucidated. The ALEX study
(jointly conducted in Arizona, Germany, Austria and Switzerland)
analyzed polymorphisms on a single nucleotide from the TLR2 gene.
Close linking was detected between TLR2/-16934 polymorphism and
asthma in farm children exposed to several microbial products, but
this relationship was not evidenced in children from the same rural
community who did not live on a farm [7].
Results obtained with TLR4 polymorphisms are more complex. 29
single nucleotide polymorphisms identified in the TLR4 locus were
analyzed in 2 different cohorts but none was found to be associated
with asthma [8]. Another study found that asthmatic people with the
D299G polymorphism have an increased severity of atopy [9].
However, if the impact of TLR4 polymorphisms on asthma development
is related to the levels of endotoxin detected in house dust,
conclusions are different: in a non-carrier group of the D299G
polymorphism, the prevalence of asthma was significantly increased
with elevated endotoxin levels in the house dust, whereas the
carrier group showed a non-significant trend to have a lower risk
of asthma [10]. These observations lead to the following
conclusion: 3 factors appear determinant for the development of
asthma: the genetic background (for example: TLR4 polymorphism),
the presence of allergen (house dust mite) and the natural
environment (levels of endotoxins). Therefore TLR polymorphisms
will remain difficult to interpret if clinical context is not taken
into account. These contradictory results may also have to be
related to the differential effect of endotoxin depending on its
levels, on the prevention or development of asthma. Exposure to
endotoxins early in life protects from subsequent sensitization to
household allergens: endotoxin concentration in house dust is
inversely proportional to house dust mite sensitization in children
at high risk [11]. In a study analyzing the time spent on the farm
(in stables) by the mother and her new-born, the levels of
endotoxin exposure during the first year of life were found to be
inversely correlated to the frequency of allergic diseases [12,
13]. However LPS exacerbates existing asthma, probably by
increasing the extent of airway inflammation [14].
TLR9 polymorphisms have been less extensively studied. In a
study on a small cohort, TLR9 polymorphism (C allele at -1237) was
associated with increased risk of asthma among European Americans
[15].
Table 1 TLR and their ligands
|
Receptors
|
Ligands
|
|
TLR2/TLR1 or 6 (or TLR10 probably)
|
- Lipoproteins
- Glycophosphatidylinositol (Trypanosoma cruzi)
- Lipoarabinomannan (Mycobacterium tuberculosis)
- Porins (Neisseria meningitides, Klebsiella pneumoniae)
- Zymosan (yeast cell-wall component: Saccharomyces
cerevisiae)
- Macrophage-activating lipopeptide 2 (for TLR2/6)
|
|
TLR3
|
Double-stranded RNA
|
|
TLR4
|
- Lipopolysaccharide (also involves CD14, MD2 molecules)
- Heat shock proteins (HSP)
- F protein (from the RhinoSyncicial Virus)
|
|
TLR5
|
Flagellin
|
|
TLR7, TLR8
|
- Guanosine and uridine-rich single-stranded RNA
- Imidazoquinoline (anti-viral compounds)
|
|
TLR9
|
- Bacterial and viral DNA
- CpG DNA (synthetic oligonucleotides containing unmethylated CpG
dinucleotides)
|
DC in allergic asthma
TLR are expressed by a variety of cells involved in the allergic
reaction: mast cells, T lymphocytes, mononuclear phagocytes and in
particular dendritic cells (DC). DC play a key role in the
initiation of the immune response. Derived from bone marrow
precursors, DC colonize peripheral tissues like skin and intestinal
or bronchial mucosa, where they form a tight surveillance network
for the immune system. Increased numbers of DC have been detected
in nasal or bronchial epithelium from allergic patients. After
allergen capture and processing, DC mature, migrate towards lymph
nodes through the expression of CC chemokine Receptor (CCR) 7, and
induce a T cell response in the draining lymph nodes [16]. DC are
crucial to the T cell polarization: the expression of costimularory
molecules like CD86 or OX40-ligand by DC favours a Th2 profile,
whereas a Th1 profile involves IL-12 production and costimulatory
molecules like CD80 [17, 18]. Development of T regulatory (Treg)
cells is dependent upon ICOS activation by DC-expressed ICOS-ligand
and IL-10 production [19]. Several reports demonstrated the key
role of myeloid DC (mDC) in the induction and control of the Th2
response and the inflammatory reaction in asthmatic patients, but
also in the mouse experimental models [18, 20]. T cell polarization
is also influenced by another DC subset, plasmacytoid DC (pDC).
Indeed, in physiological conditions, pDC are clearly involved in
the development of tolerance towards inhaled antigen in mice [21].
However, in allergic asthma, pDC from patients sensitized to house
dust mite induce Th2 polarization after activation with Derp1
(Dermatophagoïdes pteronyssinus major allergen), which might
reflect an intrinsic defect of pDC in allergic patients [22].
DC activation through TLR
DC express different TLR depending on the DC subset (table 2( Table 2 )) [23]. TLR engagement following
exposure to allergen contaminants or to infectious agents may
modulate DC functions and in this way, either favours or prevents
the development of the allergic reaction.
Again, LPS plays a double game: in a mouse model of
sensitization, low levels of inhaled LPS signalling through TLR4
are necessary to induce Th2 responses to inhaled antigen. DC are
involved in TLR4-induced Th2 response as DC maturation and
migration to the draining lymph nodes is diminished in TLR4
deficient mice [24, 25]. LPS-induced suppression of airway Th2
responses does not require IL-12 production by DC [26]. In
contrast, inhalation of high levels of LPS with antigen results in
a Th1 response, suggesting that the level of LPS exposure can
determine the type of inflammatory response generated. Consistent
with this observation, bone marrow-derived DC produce IL-12 in
response to high, but not low doses of LPS in vitro [25]. These
apparently conflicting data might reflect differential responses
depending on the cell type activated through TLR4. Indeed, TLR4 is
expressed and activates CD4+CD25+ Treg cells,
and therefore may decrease the allergic response [27]. The TLR
signalling pathway is also crucial to the orientation of allergic
asthma regulation. The common TLR adaptor protein MyD88 has been
found to be essential for the induction of adaptive Th1 immunity.
Conversely, innate control of adaptive Th2 immunity has been shown
to occur in a MyD88-independent manner. Bone marrow-derived DC from
MyD88-deficient mice retains the capacity to upregulate MHC class
II and B7 costimulatory molecules, and to induce a Th2 response. In
contrast, activation of pulmonary DC requires MyD88, which is
related to the loss of Th2 responses elicited by intranasal antigen
administered with a low dose of LPS in MyD88 deficient mice [28].
Therefore, the type and localization of DC is also of major
importance for the role of TLR-induced regulation of Th2
immunity.
Paradoxical effects have also been shown for TLR2. In vitro
stimulation of human monocyte-derived DC with TLR2 ligands failed
to produce IL-12 p70 and interferon-γ inducible protein (IP)-10 but
resulted in the release of the IL-12 inhibitory p40 homodimer,
producing conditions that are predicted to favour Th2 development
[29]. Indeed in a mouse model of ovalbumin (OVA) sensitization,
TLR2 synthetic ligand Pam3Cys, given at the time of sensitization,
increases Th2 responses and leads to aggravation of the asthmatic
phenotype. In parallel, Pam3Cys increased bone marrow-derived DC
maturation and their production of Th2-associated cytokines like
IL-13, GM-CSF and IL-1β [30]. Similarly, exposure to ovalbumin
associated with peptidoglycan leads to airway hypersensitivity
responses [31], although the involvement of TLR2 in the effect of
this PAMP is now discussed. However, when given before
sensitization, TLR2 agonists (peptidoglycan from Staphylococcus
aureus and PamCys) were recently shown to decrease additional
allergen-induced parameters of inflammation in mice [32]. Moreover,
the lipoprotein I (OprI) derived from Pseudomonas aeruginosa
enhances the abilities of mouse DC to induce the development of Th1
cells both in vitro and in vivo. Intranasal co-administration of
OVA and Opr1 significantly decreases airway eosinophilia and Th2
cytokine production. These effects are mediated by TLR2 and TLR4
[33]. It is therefore not excluded that TLR4 engagement, alone or
concomitant to TLR2 engagement, might be responsible for the
decrease of the allergic reaction. The timing of TLR agonist
administration also seems crucial to the modulation of the allergic
response by non-antigen dependent stimuli.
In contrast, concordant and interesting results have been found
following TLR9 activation. Synthetic immunostimulatory sequence
(ISS) oligodeoxynucleotides (also known as CpG ODN) have been shown
to exhibit anti-allergic activities in mouse models [34-36]. CpG
ODN can not only prevent allergen-induced airway inflammation, even
to a recall antigen challenge [34, 35], but also reverse
Th2-associated allergic airway responses. The downregulation of Th2
responses is accompanied by an increased CD80 and decreased CD86
mRNA expression in lung tissues [36]. Activation of TLR9 induces
immediate high levels of indoleamine 2,3-dioxygenase (IDO), the
rate-limiting enzyme of tryptophan catabolism, in the lungs. IDO
activity expressed by resident lung cells, rather than by pulmonary
DC, suppresses lung inflammation and airway hyperreactivity.
However the long term protective effect might be mediated by
DC-induced IDO activity, which elicits effector and memory Treg
responses [37]. Treatment with CpG ODN given during the course of
immunotherapy also reverses established allergic airway reaction in
mice partially through redirecting a Th2 to a Th1 response [38].
Moreover, CpG in vitro treatment of pDC from allergic patients
reverses their capacity to favour the development of a Th2 response
and induces a Th1 profile [39]. In ragweed sensitive patients,
preliminary results using CpG ODN are promising: immunotherapy
using purified Amb a 1 from short ragweed proteins, covalently
linked to a CpG ODN, reduces nasal inflammation and symptoms in the
long term [40, 41].
Table 2 TLR on human DC subsets (from [23])
|
Freshly isolated mDC
|
Freshly isolated pDC
|
Monocyte-derived DC (in vitro differentiated with IL-4 +
GM-CSF)
|
|
TLR1
|
++
|
+
|
++
|
|
TLR2
|
++
|
–
|
++
|
|
TLR3
|
++
|
–
|
++
|
|
TLR4
|
–
|
–
|
++
|
|
TRL5
|
+
|
–
|
+/–
|
|
TLR6
|
++
|
++
|
++
|
|
TLR7
|
+/–
|
++
|
–
|
|
TLR8
|
++
|
–
|
++
|
|
TLR9
|
–
|
++
|
–
|
|
TLR10
|
+
|
+
|
ND
|
|
TLR11
|
ND
|
ND
|
ND
|
TLR activation and other cells of the allergic response
All these studies highlight the complexity of TLR-induced
regulation of allergic asthma. Even though DC are at the crossroads
between innate and adaptive immunity, and therefore participate to
a large extent in the initiation and the regulation of allergic
diseases, the physiological impact of TLR activation is not solely
dependent upon them. Indeed, TLR are expressed by numerous cells
involved in the pathogenesis of asthma or its resolution, including
epithelial cells, T and B cells, mast cells and eosinophils, which
makes it difficult to predict the overall answer to a TLR agonist.
Moreover microbial products are more likely to contain ligands for
several TLR, increasing the complexity of the response.
The discovery of TLR and their signalling pathways provides an
immunological basis for the hygiene hypothesis. The hygiene
hypothesis is based on the observation, in industrialized
countries, of an inverse association between an increased
prevalence of allergic diseases and a decreased microbial exposure
in early life, leading to a defect in the immunoregulatory
mechanisms. However, some TLR agonists have the capacity to trigger
allergen sensitization, at least in the experimental models, and
increase the inflammation associated with allergic asthma. One may
also wonder to what extent TLR might be involved in non-allergic
asthma. Like allergic asthma, non-allergic asthma exhibits
eosinophils and Th2 cell pulmonary infiltration; however,
non-allergic asthma develops in the absence of a family and
clinical context of atopy. Among etiological factors, the
implication of still unidentified allergens, auto-immunity, or of
bacterial or viral infection has been suspected, although their
involvement has not yet been proved with certainty. Non-allergic
asthma is often associated with prior viral (rhinovirus,
coronavirus) [42] or bacterial infections, which suggests that TLR
might be involved in this other form of asthma.
In conclusion, although DC undeniably play an important role in
the control of the allergic reaction, at least in part through TLR
engagement, grey areas remain in this field. Understanding how some
microbial agents increase and others decrease the immune response
is one of the future challenges and might allow the development of
new therapeutic strategies in allergic diseases.
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