ARTICLE
Auteur(s) :, Pierre SAINT-MEZARD1, Aurore
ROSIERES1, Maya KRASTEVA1, Frédéric
BERARD1,3, Bertrand DUBOIS2, Dominique
KAISERLIAN2, Jean-François NICOLAS1,3,*
1INSERM U 503, IFR 128 Bioscience Lyon-Gerland,
21, avenue Tony Garnier 69007 Lyon
2INSERM U 404, IFR 128 Bioscience Lyon-Gerland, 21,
avenue Tony Garnier 69007 Lyon
3Clinical Immunology and Allergy Unit, CH Lyon-Sud,
69495 Pierre-Benite Cedex, France.
*J.F. Nicolas, Fax: (+33) 478 861 528. E-mail:
jean-francois.nicolas@chu-lyon.fr
accepté le 15 Avril 2004
Contact dermatitis is one of the most common skin diseases, with a
great socio-economic impact [1]. As the outermost barrier of the
human body, the skin is the first to encounter chemical and
physical factors from the environment. According to the
pathophysiological mechanisms involved, two main types of contact
dermatitis may be distinguished. Irritant contact dermatitis is due
to the pro-inflammatory and toxic effects of xenobiotics able to
activate the skin innate immunity. Allergic contact dermatitis
(ACD) requires the activation of antigen specific acquired immunity
leading to the development of effector T cells which mediate the
skin inflammation.ACD is a T-cell-mediated inflammatory reaction
occurring at the site of challenge with a contact allergen in
sensitized individuals. It is characterized by redness, papules and
vesicles, followed by scaling and dry skin [2]. Knowledge of the
pathophysiology of ACD is derived chiefly from animal models in
which the skin inflammation induced by hapten painting of the skin
is referred to as contact sensitivity (CS) or contact
hypersensitivity (CHS). ACD and CS (CHS) are thus considered as
synonymous and define a hapten-specific T cell-mediated skin
inflammation [3]. The skin and the draining lymph nodes (LN) play a
central role in the induction and triggering of a CS reaction.
Three elements are necessary for the development of a CS reaction:
antigen presenting dendritic cells (DC), hapten-specific T-cells,
and the hapten itself.
Haptens - contact allergens
The origin and nature of the compounds able to induce a CS reaction
are very diverse, but they share some common features: contact
allergens are low molecular weight chemicals named haptens, that
are not immunogenic by themselves and need to bind to epidermal
proteins. These then act as carrier proteins to form the
hapten-carrier complex that finally acts as the antigen. Most
haptens bear lipophilic residues, which enable them to cross
through the corneal barrier, and electrophilic residues, which
account for covalent bonds to the nucleophilic residues of
cutaneous proteins [4-6].
Haptens often derive from unstable chemicals, named prohaptens,
which require an additional metabolization step in vivo in
the epidermis to be converted into an electrophilic hapten endowed
with antigenic properties. This is the case of urushiol (poison
ivy) [7] and of photosensitizers, which must be activated by
UV-light in order to bind to epidermal proteins. Metal salts do not
bind covalently to cutaneous proteins but form complexes with these
proteins through weak interactions. Some metal salts also undergo
chemical conversions in the skin, such as hexavalent chromium
salts, which are turned into trivalent chromium, a highly reactive
form binding to cutaneous proteins [8]. Evidence that the
conversion of the parent compound into a reactive metabolite is
necessary for the development of CS was recently demonstrated for
the polyaromatic hydrocarbon (PAH) dimethylbenz(a)anthracene
(DMBA). CS to DMBA only occurred in strains of mice that could
metabolize the compound and inhibitors of PAH metabolism reduced
the magnitude of the reaction. Furthermore, among the PAHs, only
those that could induce aryl hydrocarbon hydroxylase, the
rate-limiting enzyme in the PAH metabolic pathway, were immunogenic
[9]. The implications of these experiments are that at least for
some contact allergens, the metabolic status of the host is a key
determinant of individual susceptibility to the development of
allergic contact dermatitis.
Recent studies from several laboratories have shown that T cells
recognize haptens as structural entities bound covalently to, or by
complexation to, peptides anchored in the grooves of major
histocompatibility (MHC) class I and class II molecules. Thus the
contact allergen is a chemical but the antigen able to activate
hapten-specific T cells is a haptenated peptide [10].
Pathophysiology of contact sensitivity
Knowledge of the mechanisms by which a xenobiotic can induce CS
responses comes from the study of strong haptens, also known as
“experimental haptens”, since they do not exist in the usual
environment of human beings. The pathophysiology of CS consists of
two distinct phases (( Fig. 1 )) which are
summarized below:
Phase 1 - Sensitization phase (also referred to as afferent
phase or induction phase of CS)
This occurs at the first contact of skin with the hapten and leads
to the generation of hapten-specific T-cells in the LN and their
migration back to the skin. The ability of a hapten to induce
sensitization relies on two distinct properties. Through their
pro-inflammatory properties, haptens activate the skin innate
immunity and deliver signals able to induce the migration and
maturation of cutaneous dendritic cells (DC). Through their binding
to amino-acid residues they modify self proteins and allow the
expression in the skin of new antigenic determinants.
Haptens or haptenated proteins are loaded by cutaneous dendritic
cells (DC) and are expressed as haptenated peptides in the groove
of MHC class I and class II molecules at the cell surface.
Hapten-bearing DC migrate from the skin to the regional LN where
specific CD8+ and CD4+ T lymphocytes are primed in the
para-cortical area. T cells proliferate and emigrate out of the LNs
to the blood where they recirculate between the lymphoid organs and
the skin. The sensitization step lasts 10 to 15 days in
man, and 5 to 7 days in the mouse. This first step has no
clinical consequence.
The theory of the first contact of a chemical being immunogenic
for the host is true for the strong haptens but cannot be accepted
for the vast majority of haptens responsible for ACD. Indeed, ACD
to moderate or weak haptens almost never occurs after the first
contact but may take years of permanent skin exposure to
develop.
Phase 2 - Elicitation phase (also known as efferent or
challenge phase of CS)
Challenge of sensitized individuals with the same hapten leads in
24/72 hours to the apparition of ACD/CS. Haptens diffuse in
the skin and are uptaken by skin cells which express MHC I and
II/haptenated peptide complexes. Specific T lymphocytes are
activated in the dermis and the epidermis, and trigger the
inflammatory process responsible for the cutaneous lesions. Recent
studies have demonstrated that CD8+ cytotoxic T lymphocytes are the
main effector cells of CHS to strong haptens and that they are
recruited early after challenge before the massive infiltration of
leucocytes which contain the down-regulatory cells of CHS, found in
the CD4+ T cell subset.
The efferent phase of CS takes 72 hours in man, and
24 to 48 hours in the mouse. The inflammatory reaction
persists only for a few days and rapidly decreases following
down-regulatory mechanisms.
Primary allergic contact sensitivity
Although the development of CHS has been postulated to require two
spatially and temporally dissociated phases, clinical evidence has
demonstrated that ACD could develop after a single skin contact
with a strong hapten in previously unsensitized patients. This
phenomenon has been referred to as “primary ACD” [11]. We have
recently demonstrated, in a murine model, that the pathophysiology
of this primary (one step) ACD is identical to the classical (two
step) ACD reaction [12]. The afferent and efferent phases of
primary ACD can be induced after a single skin contact with haptens
due to the persistence of the hapten in the skin for long period of
time, allowing the skin recruitment and the activation of T cells
which have been primed in the lymphoid organs.
The central role of cutaneous dendritic cells
There are different subtypes of DC in the skin. Although they are
all able to uptake haptens and to present haptenated peptides to T
cells, two subsets of cutaneous DC seem crucial in the development
of CS.
The basic role of epidermal Langerhans cells (LC) has been shown
by two sets of experiments. On the one hand, animals painted with a
hapten on cutaneous sites naturally or artificially depleted in LC
are unable to mount a CS response [13, 14]. On the other hand,
sensitization of naive mice can be achieved by injection of in
vitro haptenized total epidermal cells, purified LC or FSDC
dendritic cell lines, whereas injection of total epidermal cells
depleted in LC before haptenization is inefficient in inducing
sensitization [15-17].
Dermal DC could also participate in the induction phase of CS,
even though their precise contribution and phenotype is not well
known [18]. Recent studies by Geissmann et al have brought
some insights into the turnover of macrophages and DC in the dermis
in normal and inflammatory skin. Two different subsets of monocytes
can be defined according to the expression of the chemokine
receptor CCR2 [19, 20]. CCR2- monocytes appear to be involved in
the physiological turnover of resident macrophages and DC, whereas
CCR2+ monocytes are recruited in inflammatory sites where they
could differentiate into mature DC able to present exogenous
antigens to T cells. Since hapten application is responsible for
activation of skin innate immunity, it is possible that the CCR2+
inflammatory monocytes which are recruited in the skin could uptake
the hapten and participate in the afferent phase of CHS [21].
Cutaneous DC load haptens in the skin and migrate to the
draining LN
Activation of naive specific T cell precursors occurs in the
regional draining LN upon presentation of haptenated peptides by
cutaneous migrating DC. Initial observations showed that induction
of a CS reaction requires an intact draining lymphatic system [22],
and that after skin painting with the hapten fluorescein
isothiocyanate (FITC), dendritic cells bearing the hapten, some of
which containing Birbeck granules, accumulate in the draining lymph
nodes [23, 24].
Cutaneous DC continuously migrate out of the skin at a low rate
which dramatically increases after hapten exposure [25]. This
phenomenon is the consequence of numerous factors including the
secretion of inflammatory cytokines and chemokines induced by the
pro-inflammatory properties of the hapten itself. Fifteen minutes
after hapten painting, LC start to synthesize IL-1β mRNA and to
release the protein. Then, keratinocytes are activated and release
TFN-α and GM-CSF [26]. In the epidermis, LC and keratinocytes are
firmly associated by E-cadherine/E-cadherine junctions [27].
Binding of TNF-α and IL-1β on their cognate receptors (TNF-α RII
and IL-1 RI and RII) expressed on LC, is followed by a decreased
expression of E-cadherine on the LC membrane, allowing their
disentanglement from surrounding keratinocytes [28–31].
Furthermore, IL-1β and TFN-α inhibit the expression of chemokine
receptors such as CCR1, CCR2, CCR5 and CCR6 on the LC membrane,
inducing a loss of sensitivity to their cognate ligands, in
particular to MIP-3α (CCL20), a chemokine produced by keratinocytes
[32]. In parallel, TNF-α and IL-1β induce the expression of
adhesive molecules such as CD54, α6 integrin and different isoforms
of CD44, which permit some interactions between LC and the
extracellular matrix, allowing the migration of cutaneous DC.
In order to reach the lymphatic vessels, LC have to cross the
dermo-epidermal junction and the dermis. To this end, LC secrete
different types of enzymes, such as metalloproteinase (MMP)
3 and 9 [33], which could cleave macromolecules of the
dermo-epidermal junction and of the extracellular matrix. They are
also involved in the cleavage of E-cadherin and of pro-TNF-α in its
biologically active form [34]. Once in the dermis, DC acquire
sensitivity to the chemokines MIP-3β (CCL19) and SLC (CCL21)
through the up-regulation of the chemokine receptor CCR7 [32, 35].
CCL21 is expressed on endothelial cells from lymphatic vessels and
by stromal cells from the T cell area in LN [36]. The CCL21/CCR7
interaction is crucial during the sensitization phase of CS.
Indeed, Endeman and colleagues have described a strong inhibition
of CS following injections of SLC-blocking antibodies before and
during the sensitization phase [37]. Moreover, TNF-α is able to
induce a strong up-regulation of CCL21 on the endothelial cells of
skin lymphatic vessels. The over-expression of CCL21 is of critical
importance in the migratory properties of peripheral DC and is able
to increase, by a factor of 10, the number of cutaneous DC able to
migrate from the skin to the LN and subsequently the magnitude of
antigen-specific T cell activation [38].
Maturation of cutaneous DC
The term “maturation” takes into account a group of morphological,
phenotypic and functional modifications which transform skin DC
into professional antigen-presenting cells able to prime naïve
specific T cell precursors. Although the different steps of DC
maturation and differentiation are well described in vitro
[18], correlation with the in vivo modifications is not yet
totally achieved. Migration and maturation of cutaneous DC are
intimately linked. Indeed, factors known to induce migration of DC
are also able to engage DC in a maturation program. Presence of
TNF-α and IL-1β in the skin leads to the up-regulation of MHC class
II molecules on DC membranes. In the first 3 hours following
application of the hapten, expression of MHC II molecules at the DC
surface first decreases [39], whereas their intracellular level
increases, which probably reflects an endocytosis process triggered
by hapten binding [40]. From the sixth hour after hapten painting,
synthesis of MHC II mRNA starts to increase to reach a maximum at
around 18 hours. This up-regulation of mRNA synthesis, plus an
increase in the half life of membrane MHC II molecules [41], is
responsible for the strong MHC class II expression observed after
24 hours. In a similar way, the expression and stability of
MHC class I molecules on DC increase.
DC maturation is also associated to the loss of capability to
internalize and process exogenous antigens. Indeed, the expression
of DC receptors such as mannose receptors or FcR receptors
decreases during DC maturation. Birbeck granules disappear from LC
and the intracellular machinery which controls macropinocytosis and
phagocytosis is blocked [42]. Although this process was clearly
demonstrated in vitro, recent in vivo data suggest,
however, that mature migratory skin DC recovered from LN may still
be able, at least for a proportion of them, to internalize, process
and present some exogenous antigen [43].
In parallel, during the maturation process, DC express
costimulatory molecules such as CD80 (B7-1), CD86 (B7-2), CD40,
CD83, adhesive molecules such as CD54 (ICAM-1) and CD58 (LFA-3) and
chemokine receptors such as CCR4, CCR7 and CXCR4, which permit them
to migrate through lymphatic vessels .
In summary, cutaneous DCs uptake haptens in the skin and migrate
to draining LNs. This migration is associated with an up-regulation
of MHC and costimulatory molecules that confer a high efficiency in
the priming of naive T cells to skin DC.
Hapten-specific T lymphocytes
Hapten specific T cell activation
CS reactions are dependant on the priming of effector T cells
during the sensitization phase. Adoptive transfer of T cells from
sensitized mice into naive recipients results in the transfer of
sensitization. Moreover, T cell depletion of sensitized mice
totally removes the CS reaction. Finally, patients with thymic
aplasia (Di George syndrome) cannot be sensitized [44].
T cell activation requires the combination of two distinct
signals. The first signal involves the interaction of TCR and the
MHC/peptide complex. The second signal requires costimulatory
molecules and/or the secretion of cytokines and chemokines by DC.
The absence of this second signal may lead to anergy or the death
of the T cell which has already engaged its TCR.
Hapten determinants for T cells provide the first signal
T lymphocytes usually recognize hapten-modified peptides in the
groove of MHC molecules [45]. Most of the results were obtained
with the strong hapten TNP (trinitrophenyl) in mouse models. In
vitro experiments have shown that for MHC class I [10, 46] as
well as MHC class II restricted determinants [47, 48], T cells
react to MHC-associated TNP-peptides and not to covalently
TNP-modified MHC molecules, whereas TCR would interact mainly with
the hapten TNP and parts of the MHC molecule [45]. However, metal T
cell recognition may be different from the general scheme described
above for non-metal chemicals. Indeed, Weltzien and co-workers have
recently shown that nickel may behave like a superantigen and could
directly link TCR and MHC outside the groove of the MHC molecule,
in a peptide-independent manner [49].
The special nature of haptens may explain the different routes
of processing that they could follow in antigen-presenting cells.
Haptens could bind to extracellular and cell surface proteins which
are internalized and processed into peptides via the
endosomal/lysosomal compartments where they bind to the MHC class
II groove. These haptenated peptides can eventually be recognized
by class II-restricted CD4+ T cells. In addition, since most
haptens are lipid soluble molecules they may also enter the cell,
conjugate with intracytoplasmic proteins, and after processing in
the endogenous route may be presented to MHC class I-restricted
CD8+ T cells. Alternatively, direct binding of haptens, without
processing, to a peptide in the groove of either MHC class I or
class II molecules may also contribute to recognition by CD8+ or
CD4+ T cells, respectively [50]. These different routes of hapten
presentation have been demonstrated for the haptens TNP [51],
urushiol [52] and arsonate [53]. These data point to the existence
of both hapten-specific class I-restricted CD8+ T cells and class
II-restricted CD4+ T cells.
The second signal is provided by mature DC
During their maturation, DC up-regulate the expression of CD80 and
CD86, two ligands of CD28, constitutively expressed on T cells [54,
55]. CD28 ligation is mandatory for the development of CS since
mice deficient for the CD28 molecule present a strong reduction of
CS [56]. CD86 seems to be the CD28 ligand involved in the second
signal [57]. Indeed, injection of anti- CD86 blocking antibodies
inhibits the activation of both CD4+ and CD8+ T cells and the
development of CS.
TCR engagement induces the activation of the nuclear factor
NF-AT which regulates the IL-2 gene transcription. The instability
of the IL-2 mRNA limits the production of this cytokine, which is
essential for the proliferation and activation of T cells. One of
the effects of CD28 engagement is to stabilize the IL-2 mRNA,
leading to a 20 to 30 fold increase in IL-2 production
[58]. Moreover through the activation of AP-1 and NF-kB, CD28
engagement induces an increase in IL-2 and anti apoptotic Bcl-XL
gene transcription, which both protect T cells from the apoptotic
signals received after TCR engagement [59].
Circulating CD4+ and CD8+ T cells penetrate in the paracortical
area of LNs through the post capillary high endothelial venules
(HEV) in response to the chemokine DC-CK1, secreted by resident DC
of this zone [60]. The rare specific T cell precursors are
activated by presentation of haptenated peptides by skin derived DC
and start a program of clonal expansion and differentiation. This
process is initiated by physical contact between T cells and DCs
which implicate cell membrane remodeling, allowing the engagement
of TCR/MHC-peptide complexes and costimulatory molecules with their
cognate ligands. This membrane juxtaposition, associated with
transmission of the information, presents some analogy with the
neural synapse and is called immune synapse.
The plasmic membrane of mature DC expresses a high level of
adhesive molecules which are essential for T cell activation. It
comprises integrins such as CD54 and CD58 and the lectin DC-SIGN.
These molecules interact respectively with LFA-1 (CD11a/CD18), a β2
integrin, CD2 and ICAM-3/2 molecules which are expressed on T
cells [61]. In seconds following the T/DC interaction, a small
number of TCR engagements leads to cytoskeleton rearrangement by
actine polymerisation, and activation of ZAP-70 and the adaptative
protein Vav-1 [62]. These modifications generate a central zone,
rich in MHC-peptide /TCR complex surrounded by an integrin ring
called SMAC (for supramolecular activation cluster). In this zone,
CD4+ and CD8+ molecules are progressively replaced by CD28 and
CTLA-4 [63].
Other couplings of costimulatory molecules from the TNF-TNF
family receptors such as CD40/CD40-L or RANK/RANK-L participate in
T cell activation. Their interactions lead to the up-regulation of
OX40-L on DC membranes. Interaction between OX40-L and OX40,
expressed on activated T cells, induces an over expression of CD80
and CD86 and thus a better T cell activation which is of relevance
for CS because mice deficient for OX40-L display a dramatic
decrease in CS reaction to oxazolone, DNFB, and FITC. This poor CS
response was due to deficient T cell priming, as shown by decreased
T cell proliferation induced by DC from OX40-L deficient mice
[64].
T cell polarization and constitution of CD4+ and CD8+ T cell
populations
Classically, two distinct roles have been attributed to CD4+ and
CD8+ T cell subsets in immunological responses. CD4+ T cells, or T
helper (Th) cells, are considered as sources of cytokines and help
the establishment of specific B and T specific responses. CD8+ T
cells are associated to cytotoxic functions, cleaning of
potentially dangerous cells, and produce mainly IFN-γ and TNF-α.
However, more recent studies on T cells subsets have revealed that
CD8+ T cells can synthesize a pattern of cytokines as large as that
produced by CD4+ T cells [65]. Moreover, CD4+ T cell functions are
not restricted to T cell help or cytokine secretion and may
comprise cytotoxicity [66].
Depending on the pattern of cytokine secretion, different
functional subpopulations of T lymphocytes serve to determine the
qualitative aspects of the adaptative immune response. CD4+ Th1
cells produce IFN-γ, IL-2 and TNF-α, and CD4+ Th2 cells produce
IL-4, IL-10, IL-13, and IL-5. Similarly, Tc1 cells produce type
1 cytokines (IFN-γ, IL-2 and TNF-α) and Tc2 cells type
2 cytokines (IL-4, IL-10, IL-13, and IL-5). However, Tc2 cells
could also produce TNF-α in some conditions [65]. A simplification
of the nomenclature is the use of “type 1” and “type 2” cytokine
pattern for either CD4+ and CD8+ T cells.
For CD4+ and CD8+ T cells, orientation through one or the other
subtype is dependent on comparable environmental factors [67].
In vitro treatment of APC/T cells mixtures with IL-4 plus
anti-IFN-γ mAb polarizes T cells to a type 2 phenotype,
whereas IL-12 plus anti-IL-4 mAb treatment polarizes T cells to a
type 1 phenotype. However, the mechanisms implicated during
the T cell-DC dialogue in vivo which are responsible for the
polarization of T cells are still poorly understood.
Two hypotheses have been recently proposed to explain the basis
of the dichotomy of T cell responses. The first hypothesis
postulates the existence of distinct DC subpopulations (DC1
versus DC2) involved in the polarization of the immune
response (type 1 versus type 2). After CD40 triggering, one
subpopulation of DC, derived from monocytes in humans or expressing
CD8α in mouse (myeloid), referred to as DC1, would provoke a type
1 response by producing high amounts of IL-12. The other
subpopulation, derived from plasmacytoïd DC in human and CD8α neg
in mouse (lymphoid) and defined as DC2, produces few IL–12 and
might be able to induce a type 2 response [68]. However, CD8α
neg cells can prime both type 1 and type 2 responses
depending on the activation signal they received [69, 70],
demonstrating that the phenotype of a given DC subset cannot be
considered as a marker of functionality for the activation of type
1 versus type 2 T cells. The second hypothesis considers
that environmental factors will influence the maturation process of
a given DC enabling it to prime for type 1 or type 2 T
cells [71]. Along this line, Soumelis et al have reported
that human epithelial cells produce a cytokine, thymic stromal
lymphopoietin (TSLP), that binds to specific receptors on CD11c+DCs
[72]. This induces the production of Th2-attracting chemokines and
primes naïve T cells for a Th2 phenotype.
Polarization of type 1 T cells is crucial to the
development of specific effector T cell populations and optimal CS
reaction. CS to DNFB is due to CD8+ effector type 1 T cells
and is regulated by CD4+ type 2 T cells [73, 74]. Type
1 polarization by injection of IL-12 at the time of
sensitization favors CD8+ T cell differentiation and increases the
CS reaction [75]. On the contrary, type 2 polarization using
IL-4 (or anti-IFNγ mAbs) leads to a diminished CS response
associated with an altered CD8+ T cell priming [75].
Need for CD4+ help in hapten-specific CD8+ responses?
CS to strong haptens is mediated by CD8+ T cells and regulated by
CD4+ T cells. More importantly, CD8+ effectors can develop in the
absence of CD4+ T cells. This has been demonstrated by different
sets of experiments: i) mice depleted in CD8+ T cells or deficient
in CD8+ T cells (MHC class I-KO mice) cannot develop CS responses;
ii) mice depleted in CD4+ T cells or genetically deficient in CD4+
T cells (MHC class II-KO mice) develop an enhanced CS response;
iii) DC recovered from MHC class I-deficient mice cannot sensitize
for CS in transfer experiments whereas DC recovered from MHC class
II-deficient mice are able to induce a normal CS reaction [73,
76–82].
That CD4+ T cell help is not necessary for development of CHS is
in keeping with recent studies showing that antigen-specific
cytotoxic lymphocyte (CTL) responses can be induced in the absence
of help provided that i) the immunogen has intrinsic
proinflammatory properties (e.g. endotoxins and pathogenic
microorganisms) able to generate a danger signal to the DC [83];
ii) the affinity of TCR for MHC/peptide complexes is high; iii) the
frequency of specific CD8+ T cell precursors is high [85]. Contact
sensitizing haptens have two important properties that may explain
their immunogenicity in the absence of CD4+ help. First, they are
proinflammatory xenobiotics through induction of chemokine and
cytokine production by skin cells [3]. Second, covalent binding of
haptens, such as DNFB or TNCB, on amino acid residues of proteins
generates a high number of haptenated peptides allowing activation
of high numbers of CTL precursors [85].
Migration of specific T cells in the blood and in the skin
Once activated, T cells emigrate from the LN through the efferent
lymphatic vessels and then circulate in the blood. Emigration of T
cells outside the LNs is associated with modifications in the
expression of chemokine and adressine receptors. Different subsets
of T cells are generated during an immune response. A subset of
activated specific T cells down-regulates the expression of CCR7
and then loses the ability to re-circulate into the LNs. The CCR7-
T cells constitute the peripheral memory T cell subsets able to
enter peripheral tissues and especially the skin. CCR7+ T cells
constitute the other memory subset called central memory T cells,
which has kept the ability to re-circulate from the blood to LN,
but which cannot be recruited in peripheral tissues [86]. Upon a
subsequent antigen challenge, peripheral memory T cells may act as
innate cells in respect to their quick and strong release of IFN-γ
and RANTES which confer an increased efficiency in the T cell
response. The central memory T cells have a role in the
preservation of relative high frequency of hapten-specific T cells.
CD4+ and CD8+ T cells found in the skin of sensitized mice,
express CCR4, α4β1 integrin and cutaneous lymphocyte antigen (CLA)
[87]. Skin-selective homing of primed T cells depends on tissue
microenvironment and more specifically on skin dendritic cells
[88]. Migration of T cells from the blood to the skin occurs at the
site of post capillary HEV through interactions of CLA and CCR4
with their respective ligands, E-, P-selectine and TARC (CCL17),
constitutively expressed on endothelial cells [89–92]. The passage
of T cells in the dermis requires the sequential interaction of
VLA-4 and LFA-1 receptors on T cells with VCAM-1 and ICAM-1 on
endothelial cells [93].
Thus, at the end of the afferent phase of CHS, specific T cells
which have been activated by hapten-bearing DC are found in the LNs
(central memory cells), in the blood and in the skin (peripheral
memory cells). The skin has a normal looking appearance. Specific T
cells will be activated directly in the skin and massively
recruited upon a subsequent skin contact with the same hapten.
Expression of contact sensitivity reaction
Hapten skin painting in sensitized individuals induces the skin
inflammatory reaction which occurs in three steps. First,
activation of the skin innate immunity recruits hapten-specific T
cells. Second, T cells are activated, produce IFN-γ and
cytotoxicity which results in the activation of skin resident cells
and in the production of new mediators of the inflammatory
reaction. Third, leucocytes (polymorphonuclears, monocytes, T
cells) are recruited and progressively induce the morphological
changes typical of contact dermatitis (Figs. 2 and 3).
T cell recruitment
Skin contact with the hapten induces, as during the sensitization
phase, the release of TNF-α and IL-1β [94, 95], followed by the
production of cytokines and chemokines. This first signal induces
the recruitment of hapten specific T cells from the blood to the
dermis and the epidermis. One of characteristic features of CS
consists in the early recruitment of type 1 CD8+ effector T
cells followed by a late arrival of the CD4+ T cell population
which contains the regulatory T cells responsible for the
resolution of the inflammation [96].
That CD8+ and CD4+ T cells are recruited at different times
after hapten painting may be explained by the differential
expression of chemokine receptors by T cell subsets as well as by
the sequential production of chemokines during the development of
the skin inflammation. Even if it is still unclear which chemokines
drive the initial influx of T cells, the recruitment of activated
CD8+ T cells seems to be under the control of the IP-10/CXCR3
chemokine/chemokine receptor pathway [97–99]. The contribution of
IP-10 (CXCL10) has been recently suggested by a study showing that
IP-10 deficient mice present a deficient skin recruitment in IFN-γ
producing T cells and a diminished CS reaction [100]. The
recruitment of CD4+ T cells is possibly under the control of the
MDC (CCL22) and TARC (CCL17) chemokines and their receptor CCR4
expressed on activated CD4+ T cells [92]. These two chemokines are
up regulated in the skin around 12 hours after hapten exposure
concomitantly with the infiltration of mononuclear cells. Another
recently described chemokine, CTACK (CCL27) and its receptor CCR10,
is also important in the traffic of activated T cells in the skin
[101, 102]. This chemokine is constitutively expressed by
keratinocytes and its synthesis is up-regulated following IL-1β and
TNF-α exposure.
In parallel to chemokines and chemokine receptors, adhesion
molecules (CLA, VLA-4 and LFA-1) are involved in the infiltration
of T cells in the skin. Under the influence of TNF-α, endothelial
cells up-regulate their respective ligands (E-, P-selectine, VCAM-1
and ICAM-1) allowing a direct interaction with T cells and their
extravasation in the dermis.
Characterization of effector T cells
During the 1980s, studies from Cher and colleagues clearly
established that classical delayed-type hypersensitivity (DTH) to
nominal protein antigens was mediated by CD4+ T cells [103]. The
over-representation of CD4+ T cells in established ACD lesions and
the presence of hapten-specific CD4+ T cells in the blood of
sensitized patients [104, 105], have led to the wrong conclusion
that CS was mediated by CD4+ T cells.
Animals models have contributed to elucidate the nature of the
effector T cell population in CS. Mice deficient in CD8+ T cells,
following the invalidation of the MHC class I β2 microglobulin
gene, or mice depleted in CD8+ T cells, are unable to develop a CS
reaction to experimental haptens [73]. However, lack of CD8+ T
cells in these mice does not affect the classical DTH to proteins.
Alternatively, mice deficient in CD4+ T cells, following the
invalidation of the MHC class II Aβ gene, or mice depleted in CD4+
T cells, develop a stronger and sustained CS reaction, suggesting a
regulatory function for the CD4+ T cell compartment [73]. Thus CS
appears as very different from classical DTH reactions in term of T
cell subset involved in the effector pro-inflammatory functions.
Recent studies on nickel ACD have confirmed that the
pathophysiology of ACD in humans was similar to that of CS in mice
and involved CD8+ effector T cells and CD4+ regulatory T cells
[106].
IFN-γ production by CD8+ T cells
Once in the skin, type 1 CD8+ T cells recognize
hapten-modified peptides presented by cutaneous cells. In part due
to their chemical properties, haptens are able to cross through
plasmic cell membranes, to bind to intracellular proteins and are
then presented in an MHC class I context by resident skin cells. It
is certainly by this mechanism, or by a direct binding to external
MHC I/peptide complexes, that haptenated peptides are presented to
CD8+ T cells [10, 51].
TCR engagement induces the release of type 1 cytokines such
as IFN-γ, which in turn is responsible for the increased production
in the skin of IP-10, IP-9 and Mig, of IL-1, IL-6, TFN-α, GM-CSF
and MIP-2 (CXCL8). This complex cytokine and chemokine production
amplifies the inflammatory response initiated by the hapten (IL-1,
TNF-α) and is responsible for the massive infiltration of
leukocytes. Recruited cells comprise polynuclear neutrophils, T
cells and inflammatory monocytes able to differentiate into
macrophages and dendritic cells.
Resident mast cells have been recently proposed to be key
regulators of the amplification phase of the skin inflammation
[107]. Indeed, following CD8+ T cell activation, mast cells produce
TNF-α and MIP-2 which are both needed for the recruitment of
neutrophils constitutively expressing CXCR1 and 2.
Cytotoxic activity of CD8+ T cells
IFN-γ release by CD8+ T cells is not sufficient for the full
development of the CS reaction, since CS is only moderately
impaired in mice deficient for IFNγ receptors [108]. Recent studies
have shown that CD8+ T cell cytotoxicity was mandatory for the
development of CS responses since mice deficient in the two
cytotoxic pathways, i.e. Fas/Fas-L and perforin, were unable to
develop a CS reaction although IFN-γ producing CD8+ T cells were
detected at the site of hapten challenge [109]. Moreover, the two
CD8+ CTL pathways are redundant since abrogation of CS occurs only
when the 2 pathways are inactivated in the same animal. Thus,
the CD8+ T cells are effectors of CHS through cytotoxicity.
Keratinocytes are the main targets of the cytotoxic effect of
hapten specific CD8+ T cells [110]. Keratinocyte apoptosis
coincides with CD8+ T cell arrival in the epidermis and increases
proportionally with the number of infiltrating CD8+ T cells [96].
These epidermal damages facilitate the penetration of haptens
present on the skin which may increase the inflammation [111].
Finally, perforin release by CD8+ T cells is associated to the
production of RANTES, MIP-1α and MIP-1β, which mediate the
recruitment of CCR1+ and CCR5+ monocytes and granulocytes
[112].
In summary, hapten-specific type 1 T cell activation leads
to the production of a cascade of cytokines and chemokines by skin
cells which induce a massive recruitment of leukocytes responsible
for the cutaneous changes typical of CS. After a peak obtained at
24/48 hours, the inflammation starts to resolve slowly by
active down-regulatory mechanisms which limit the tissular damages
and maintain the skin integrity.
Regulation of contact sensitivity
Down-regulation of CS was initially attributed to clearance of the
hapten from the skin in the few days following hapten painting.
However, recent studies have shown that a hapten could stay in the
epidermis for as long as two weeks after a single skin contact
[12]. In parallel, several groups have reported that the
down-regulation of CS was an active immune phenomenon mediated by a
subset of suppressor/regulatory CD4+ T cells [73, 81, 113]. Several
CD4+ T cell subsets with down-regulatory activities have been
described in murine models and in human diseases, among which are
Th2 cells, Th3 cells, Tr1 cells, CD4+25+ cells, which could be
involved in the resolution of the CS reaction [114].
The regulation of CS could be divided into two phases, a central
and peripheral phase [115, 116]. The central regulatory phase
controls the expansion and differentiation of CD8+ effector T cells
in the LNs while the peripheral phase limits the inflammatory
process generated in the skin. CD4+CD25+ natural regulatory T cells
seem to be involved in the first phase. Indeed, a recent study has
shown that CD4+CD25+ T cells are necessary in the oral tolerance
phenomenon to haptens through the total inhibition of the clonal
expansion of hapten-specific CD8+ T cells [114, 117]. Moreover,
mice treated with an IL-2-IgG2b fusion protein, showed a decreased
CS reaction associated with an increase in the CD4+CD25+ T cell
subset [118]. Finally, depletion of CD4+25+ T cells by in
vivo treatment of mice with an anti-CD25 mAb at the time of
sensitization led to an enhanced CS reaction and an increased CD8+
T cell priming (Dubois B and Kaiserlian D, unpublished data).
The mechanisms by which CD4+ T cells (CD4+25+ and/or CD4+25- T
cells) limit the skin inflammatory reaction are still not
understood and may involve IL-10 and other immunosuppressive
cytokines [106]. The immunosuppressive effect occurs through the
inhibition of production of IFN-γ, IL-6, IL-1, GM-CSF and TNF-α.
IL-10 plays a crucial role in the down-regulation of CS reactions
inasmuch as IL-10-deficient mice mount an exaggerated CS reaction
to oxazolone, increased in both magnitude and duration as compared
to wild type mice. Moreover, IL-10 injection before challenge
totally abrogated the CS response [119]. Finally, resolution of CS
is associated with the recruitment in the skin of a regulatory
CCR8+ T cell population which produces a large amount of IL-10
around 24 hours post-challenge [120]. The production of IL-10
is not restricted to T cells and can be supplied locally by other
cells such as keratinocytes which synthesize the cytokine by
48/72 hours after hapten painting [121].
Other regulatory mechanisms may be involved in the resolution of
CS. As an example, in the presence of a large quantity of IFN-γ,
endothelial cells down-regulate the expression of E and P
selectins, thereby limiting the arrival of new infiltrating
leucocytes in the dermis [122].
Clinical hallmarks
In a sensitized individual, ACD appears 24 to 96 hours
after contact with the causative allergen. Its initial localization
is at the site of contact [2]. The edges of the lesions may be well
demarcated, but unlike irritant contact dermatitis it may propagate
in the immediate vicinity or to distant unrelated sites. In its
acute phase, ACD is characterized by erythema and edema, followed
by the appearance of papules, closely set vesicles, oozing and
crusting. In the chronic stages, the involved skin becomes
lichenified, fissured and pigmented, but new episodes of oozing and
crusting may occur, usually as a consequence of a new exposure to
the causative allergen. ACD is usually accompanied by intense
pruritus. Systemically induced eczema or hematogenous contact
dermatitis is induced by oral or parenteral application of certain
contact allergens in previously sensitized individuals. The best
known example is the “flare-up” phenomenon at sites of previous
eczematous skin changes following an experimental challenge by oral
or parenteral application. Substances most often implicated in
inducing hematogenous contact eczema are metal salts and drugs.
Histopathology of allergic contact dermatitis
The histopathologic findings are different in acute and chronic
contact dermatitis and are dependent on the severity of the
inflammatory reaction. The most common histologic feature is
spongiosis, which results from intercellular edema. It is often
limited to the lower epidermis but, if the reaction is severe, it
may affect the upper layers. The clinical expression of intense
fluid accumulation in the acute stage is the formation of vesicles
that may rupture at the epidermal surface. The papillary vessels
are dilated, with perivascular lymphohistiocytic infiltrate, and
the upper dermis is edematous. The lymphohistiocytic infiltrate
extends in the epidermis (exocytosis) and accumulates in the
spongiotic vesicles. In subacute and chronic ACD the spongiotic
pattern gradually fades out, the epidermis becomes hyperplastic,
and parakeratosis develops.
Diagnosis
The site and clinical appearance of the lesions frequently suggest
the etiologic factor when the patient is first seen. Thus sharply
delineated geometric lesions are evocative of sensitivity to rosin
in adhesive tape [123]. Dermatitis at the site of contact with
jewelry, blue jeans buttons, wrist watches, and other metallic
objects are seen in nickel dermatitis. It is important to know the
location of the initial skin changes and to try to establish a list
of possible contactants that may have caused them. If the
dermatitis has taken a chronic course, the patient’s observations
about factors causing relapses may be helpful. A search for
possible sources should concentrate on occupation, hobbies,
clothing and personal objects, home environment, and past and
previous treatment. Inhalents, dust exposure and ingestion have to
be considered. A family history or a past history of atopy and
psoriasis may be decisive particularly when a diagnosis of hand
eczema is discussed.
Patch testing is the universally accepted method for the
detection of the causative contact allergens. The positive patch
test reproduces an experimental contact dermatitis on a limited
area of the skin. A good patch test indicates contact sensitization
of past or present relevance and produces no false-positive
reaction. Based on the principles of evidence-based medicine, patch
testing is cost-effective only if patients are selected on the
basis of a clear-cut clinical suspicion of contact allergy and only
if patients are tested with chemicals relevant to the problem
[124]. Finn chambers and several other tape methods are currently
in use [125]. Most allergens used in patch testing are well-defined
chemical substances. To save place and time, mixes of chemically
related chemicals may be used. The most frequently encountered
contact allergens have been selected by various international
contact dermatitis groups and included in standard patch test
series [126]. There are additional series aimed towards specific
occupations and other spheres of activities. Most commercially
available allergens supplied in syringes are incorporated in
petrolatum. Considerable efforts have been made to standardize the
concentration of the allergens to ensure comparable results
worldwide. Great care must be taken in testing with non
standardized chemicals not found in commercially available kits
because testing with irritant concentrations may result in false
positive reactions [127].
Patch tests are usually applied for 48 hours on the upper
half of the back. Patches are read at least 20 minutes after
their removal.
The method of recording recommended by the European and North
American contact dermatitis groups is as follows [128]:
- + weak positive reaction: erythema, infiltration, possibly
papules
- ++ strong positive reaction: erythema, infiltration, papules,
vesicles
- +++ extreme positive reaction: intense erythema and
infiltration, coalescing vesicles, bullous reaction.
- ? doubtful reaction (weak erythema only)
- IR irritant reaction of different types
- NR negative reaction
- NT not tested
It is recommended to perform a second reading 24 or
48 hours after patch test removal. In doing only a single
reading, a large number of delayed reactions will be missed, while
others due to early irritant effects will be considered as allergic
[127]. The type of positive reaction that can safely be interpreted
as indicating allergic contact sensitivity exhibits erythema,
edema, and small vesicles extending slightly beyond the patch
border. Pruritus and reactivation of previous eczematous skin
lesions at the time of testing indicate allergy.
When a positive patch test is considered to reveal a genuine
contact sensitivity, a decision has to be taken as to its
relevance. Current relevance is related to “current clinical
symptoms, occurring in the last few days or weeks”; past relevance
refers to older clinical events [129]. The major prerequisites for
a contact allergy to be clinically relevant are: i) exposure
to the sensitizer; ii) presence of a dermatitis which is
understandable and explainable with regard to the exposure, on the
one hand, and type, localization and course of the dermatitis, on
the other hand [130].
Common causes of allergic contact dermatitis
Metals
Nickel is the most common cause of ACD in women in almost all
countries. The greater exposure of women to high-nickel content
jewelry is a predisposing factor. Ear piercing is considered to be
the principal inducer of nickel contact dermatitis. Hand eczema in
nickel sensitive patients is often of the dyshidrotic type and may
be aggravated by nickel ingestion. A threshold of
0.5 microgram of nickel/cm2/week has been
established to which only a small number of nickel-sensitive
patients will react [131]. The Danish nickel exposure regulation
and the nickel directive (European union) regulating nickel content
in objects which are in direct and prolonged contact with the skin
have resulted in a significant decrease in nickel sensitization in
young patients [132, 133].
Chromate is the most common contact allergen in men and
sensitization to it is usually occupational. Occupational exposure
is most frequent in construction workers who handle cement. Other
common sources are chrome-tanned leather, bleaching agents, paints,
and printing solutions.
Cosmetics and skin care products
Compulsory ingredient labeling of cosmetic products (excluding
perfumes) has greatly facilitated the diagnosis and treatment of
cosmetic contact dermatitis. Positive patch tests are found most
frequently to preservatives, perfumes, active or category-specific
ingredients, excipients/emulsifiers and sunscreens [134]. The
relevance of the positive patch tests is confirmed if the contact
dermatitis disappears upon discontinuation of the use of the
product. Most allergic reactions are caused by cosmetics that
remain on the skin: “stay-on” or “leave-on” products [135].
Dermatitis from clothes and shoes
Contact dermatitis to clothes is usually located in the axillae,
which is due to the release of allergens from the textile under the
action of sweat and friction. Clothing dermatitis from formaldehyde
is rare nowadays. Textile dye dermatitis is usually related to
disperse dyes [136]. Leather articles contain several substances
that may cause ACD: chrome, adhesives (paratertiary butyl phenol
formaldehyde resin), and dyes. A number of accelerators and
antioxidants used in the production of synthetic rubber may also
cause contact dermatitis.
Drug dermatitis
Drug dermatitis may be elicited by the active ingredient of a
topical drug, by the vehicle or by a preservative. Contact
sensitization to antibiotics, antiseptics, and anesthetics is
relatively frequent, especially in leg ulcer patients. ACD from
topical corticosteroids has been reported with increasing frequency
[137, 138]. Systemic application of a drug to which an individual
has been sensitized by a previous cutaneous exposure may cause
systemic contact dermatitis.
Plant dermatitis
Plant dermatitis can manifest itself in a variety of ways,
depending upon the plant and the means of exposure. Airborne
contact dermatitis mimicking photodermatitis may be caused by
sesquiterpene lactones found in the Compositae family, while
contact dermatitis to plants from the Liliaceae and
Alstroemeriaceae families may present as a dry painful
dermatitis of the fingers in bulb growers, called “tulip fingers”.
Urushiol, present in poison ivy and poison oak is the most common
cause of ACD in the United States, with 50% of the adult population
clinically sensitive to it.
Treatment
The only available etiologic treatment of ACD is elimination of the
contact allergen. The patients should be informed about the
identity of the offending agent and the possible sources of the
sensitizer. Cross-reacting substances should be listed.
Topical steroids are used in the acute stage and are gradually
replaced by ointments and cold creams as the skin lesions withdraw.
If ACD is widespread and severe, systemic corticosteroids may be
indicated for a short period of time.
Reducing the total body load of nickel has been attempted in
nickel eczema by means of a nickel-restricted diet and by treatment
with disulfiram. Trials have yielded conflicting results as regards
the clinical effect of the treatment and the application of the
metal-chelator disulfiram was limited by serious side effects
[139].
Oral hyposensitization to urushiol and nickel has been attempted
but is not performed in practice.
Conventional immunosuppressive therapy is not appropriate in the
management of ACD. New immunomodulating macrolactams have been
successfully tested in clinical trials [140–142]. Perspectives in
pharmacological intervention include new classes of
immunosuppressors, inhibitors of cellular metabolic activity,
inhibitors of cell adhesion molecules, targetted skin application
of regulatory cytokines and neutralization of pro-inflammatory
cytokines (antisense oligonucleoides, anticytokine antibodies,
soluble cytokine receptors).
Conclusion
Recent advances in knowledge of the mechanisms by which haptens can
generate a specific T cell activation leading to ACD have
reinforced the importance of hapten presentation by Langerhans
cells to specific T cells. The induction of ACD depends on the
production by epidermal cells, within minutes or hours following
hapten application, of a rather specific pattern of cytokines. This
cytokine milieu seems necessary for efficient hapten handling by LC
and for T cell priming in the regional draining lymph nodes. More
recently, it was demonstrated that LC have a dual function in the
pathophysiology of ACD. On the one hand, LC activate effector cells
which mediate the inflammatory reaction aimed at eliminating the
potentially harmful haptens. On the other hand, LC are able to
activate regulatory cells which limit the skin inflammation. These
regulatory cells are extremely important for the outcome of ACD,
since their absence will lead to a chronic skin inflammation with
major tissue damage. Although CD4+ T cells have been shown to
comprise regulatory cells in ACD, the molecular mechanisms by which
they exert their regulatory properties are presently unknown.
Ongoing studies will undoubtedly provide more information on how
CD4+ regulatory T cells could be specifically activated and thus
provide new ways of treating ACD.
Acknowledgments
This work was supported by the Region Rhône Alpes Grant 8HC07H
and by Institutional Grants from INSERM. Pierre Saint-Mezard is
supported by Laboratoire BIODERMA, 75 Cours Albert Thomas,
69003 Lyon, France.
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