ARTICLE
INTRODUCTION
The biological effects of ultraviolet B (UVB) radiation have been under
extensive investigation for the last two decades, starting with its identification
as a carcinogenic agent. There is evidence from epidemiological data that
exposure to UVB increases the incidence of non-melanoma skin cancer and,
in addition, that it inhibits the cellular immune response to these highly
immunogenic tumors, thereby facilitating their outgrowth [1, 2]. Furthermore,
it has been demonstrated that UVB suppresses contact hypersensitivity
(CHS), delayed type hypersensitivity (DTH) and alloantigen responses [3-5].
This form of unresponsiveness or peripheral tolerance is, at least in
part, mediated by "suppressor" T-cells. As a consequence of the observed
impairment of cellular immunity, a reduced resistance to infections (such
as Herpes simplex, Candida albicans and Mycobacterium bovis)
has been observed [6, 7]. These deleterious effects of this environmental
factor have stimulated research on the mechanisms underlying the immunosuppressive
effect of UVB in which T-cells and the immunomodulatory functions of cytokines
appear to play an essential role.
PHOTORECEPTOR
UVB radiation is defined as electromagnetic radiation with a wavelength
ranging from 290 to 320 nm, as depicted in Figure
1. The energy load of the photons enables them to penetrate only
the epidermis and the upper layers of the dermis. Within these layers
the energy is absorbed by photoreceptors and transduced into biological
effects. Several candidate molecules have been proposed which absorb UVB
light in the skin and may mediate UVB-induced effects on cellular responses;
among them DNA and urocanic acid (UCA) have received most attention. UVB
irradiation of cellular DNA has been found to generate a large variety
of photoproducts (e.g. cyclobutyl pyrimidine dimers and 6-hydroxy-dihydropyrimidine)
as well as DNA double-strand breaks. Formation of pyrimidine dimers occurs
most frequently [8]. These mutagenic effects might result in the transcriptional
upregulation of certain cytokine genes. Indeed, induction of DNA double-strand
breaks in murine skin in vivo, by means of liposome encapsulated
endonucleases, has been shown to result in enhanced tumor necrosis factor
alpha (TNF-alpha) production by epidermal cells [9, 10].
A second candidate photoreceptor for UVB is urocanic acid, a naturally
occurring component of the superficial cornifying epidermis [11]. Upon
absorption of UVB light, urocanic acid in the stratum corneum isomerizes
from its naturally occuring trans configuration to a cis
form. Similar to the effect observed following irradiation with UVB, intravenous
injection of cis-urocanic acid suppresses the CHS response, a process
which is probably mediated by enhanced release of TNF-alpha by keratinocytes
[11, 12] (see below).
KERATINOCYTES
Within hours after UVB exposure, keratinocytes are triggered to produce
and/or release a plethora of cytokines. These mediators play an important
role in local and systemic inflammatory reactions and in the modulation
of most immune responses. As shown in Table
1, UVB modulates the transcription of a wide variety of keratinocyte-derived
cytokines. Following UVB irradiation, autocrine stimulation of keratinocytes
by interleukin (IL)-1alpha results in an enhanced production of IL-1alpha,
IL-6 and granulocyte-macrophage-colony stimulating factor (GM-CSF), whereby
IL-1alpha, IL-10 and TNF-alpha act in a paracrine manner on Langerhans
cells (see below).
In UVB irradiated skin, upregulation of the expression by keratinocytes
of IL-8 has been demonstrated [13]. The chemotactic properties of the
enhanced expression of chemokines, such as IL-8, RANTES and IFN-gamma inducible
protein 10, might contribute to the extensive infiltrates of macrophages
and neutrophils that are observed in UVB irradiated skin.
Some of the induced cytokines released upon UVB irradiation (IL-1, IL-6,
TNF-alpha and IL-10) have been detected in serum and are thought to mediate
suppression of systemic immunity by modulating the antigen-presenting
function of splenocytes (see below) [14-17]. Interestingly, upregulation
of a 40 kDa protein which inhibits the activity of IL-1 [18], and the
IL-1 receptor antagonist in the stratum corneum have been reported as
well [19]. These anti-inflammatory factors are antagonists of IL-1 and
are considered relevant mediators of immunosuppression in the skin. Recently,
it was demonstrated that UVB also affects the expression of IL-1 receptors
type I and II (IL-1RI and IL-1RII) on human keratinocytes [20]. It was
shown that within 1 hour after UVB exposure IL-1RII was upregulated and
returned to background levels within 24 hours, whereas IL-1RI expression
initially decreased and later increased. Since IL-1RII probably functions
as a scavenger for IL-1, the resulting effect of UVB is an initial unresponsiveness
to IL-1 followed by enhanced sensitivity of keratinocytes for IL-1.
The effect of UVB on the expression of intercellular adhesion molecule-1
(ICAM-1) has been studied in detail [21, 22]. ICAM-1 expression is inhibited
the first 24 hours after irradiation, followed by upregulation. This biphasic
expression is thought be to regulated by the transient expression of IL-1alpha,
IL-1RI and IL-RII [20]. Apart from ICAM-1, upregulation of E-selectin
on endothelium is observed following UVB irradiation [21]. This effect
is thought to be predominantly mediated by TNF-alpha. Upregulation of
E-selectin on endothelium is generally considered an important early event
in inflammation and is followed by infiltration of neutrophils, and macrophages
into UVB injured skin [23]. No effect on the expression of vascular cell
adhesion molecule-1 (VCAM-1) has been demonstrated [21].
LANGERHANS CELLS
In addition to direct effects originating from the non-specific release
of keratinocyte-derived cytokines, UVB irradiation also induces antigen-specific
immunosuppression. In mice exposed to a low dose of UVB, subsequent challenge
with a hapten on the same cutaneous site decreases the CHS response as
compared to nonirradiated animals, whereas application of a different
hapten mounts a normal immune response [3]. This indicates that UVB-induced
unresponsiveness is antigen-specific. Mixed leukocyte reactions, performed
with UVB irradiated epidermal cells or splenocytes as stimulator cells,
are suppressed as well, suggesting impairment of antigen-presenting functions
[4]. Indeed, Langerhans cells (LC) have been shown to be both directly
and indirectly affected by UVB irradiation. Their morphology changes from
a dendritic appearance into cells with a roundish shape, they have lost
characteristic markers (e.g. membrane ATPase) and are reduced in
numbers in the epidermis following UVB exposure [3]. Recently, a reduction
of the expression of vimentin within the cytoplasm of LC was demonstrated
in UVB irradiated mice. Circumstantial data indicate that this reduction
might correlate with disruption of the cytoskeleton and with impairment
of CHS responses [24]. This suggests one mechanism whereby UVB impairs
the antigen-presenting capacity of LC. An alternative mechanism might
be that UVB affects the expression of MHC II molecules on LC. However,
electron microscopical studies showed that UVB did not alter the density
of MHC II molecules. Furthermore, UVB irradiated LC were still able to
migrate to the draining lymph nodes and present antigen to T-cells. This
is not surprising since the observed immunosuppression following local
UVB irradiation is antigen-specific implying that the process of antigen-presentation
must have taken place. Migration of LC towards lymph nodes is increased
following UVB radiation [25], a process in which keratinocyte-derived
TNF-alpha is thought to play an essential role.
ROLE OF TNF-alpha
TNF-alpha mediates its effects by binding to two distinct TNF receptors,
one of 55 kDa (TNFR-p55) and one of 75 kDa (TNFR-p75). Soluble forms of
both receptors (sTNFR) which can be produced by proteolytic cleavage are
able to neutralize the effects of TNF-alpha [26]. UVB irradiation initially
decreases TNFR-p55 expression by keratinocytes, but later expression is
increased [27]. This biphasic modulation of TNFR-p55 expression by keratinocytes
affects the ability of these cells to respond to TNF-alpha. Human keratinocytes
lack expression of TNFR-p75. Production of sTNFR-p55 by human keratinocytes
remains unaffected by UVB irradiation [27].
As already mentioned TNF-alpha plays a crucial role in induction of
the immunomodulatory effects of UVB. UVB irradiation evokes morphological
changes of LC and impairment of CHS. These effects are mimicked by intradermal
injection of a low dose of TNF-alpha. Furthermore, UVB-induced CHS impairment
could be reversed by anti-TNF-alpha [28]. This clearly indicates that
UVB exposure impairs CHS induction by a mechanism that requires TNF-alpha,
which alters the function of LC. At present it is still not known whether
or not TNF-alpha is involved in antigen-specific immunosuppression. From
studies using TNFR-p55 knock-out mice, it was shown that TNF-alpha plays
a regulatory role in CHS, but is not required to induce UVB-induced antigen-specific
immunosuppression [29].
Interestingly, different mice strains are not equally susceptible to
UVB-induced immunosuppression. In order to obtain 50% suppression of the
CHS response, BALB/c mice require nearly six times more UVB than C57BL/6
mice [30]. The susceptibility is assumed to be a genetically determined
trait, which is governed by polymorphic alleles at the TNF-alpha and LPS loci.
Resistance to the effects of UVB is a recessive trait and can be conferred
by homozygosity at either the TNF-alpha or the LPS locus [31]. It has been
proposed that polymorphisms in the non-coding sequences at the TNF-alpha locus
between UVB-susceptible and resistant mice, results in modulation of the
transcription rate of cytokine mRNA or differences in cytokine mRNA stabilization.
Consequently, activation of the susceptibility loci in keratinocytes by
UVB results in the generation of excessive amounts of intracutaneous TNF-alpha
[32].
ANTIGEN PRESENTATION
TO T-CELLS
The viability or depletion of LC in the skin does not account for the
loss of antigen-presenting function following UVB radiation. It is believed
that the interplay between antigen-presenting cells (APC) and T lymphocytes
results in the observed antigen-specific unresponsiveness. Following acute
low dose UVB irradiation, mice demonstrate antigen-specific suppressor
T-cells in the lymph nodes and spleen, which allow adoptive transfer of
the specific tolerance to syngenic naive recipients [33]. This could explain
the observed systemic effects of UVB.
Tolerance for a specific antigen can be either based on active suppression
mediated by regulatory cells, or clonal deletion, or on complete T-cell
anergy. Continuous exposure of antigens in the skin might select regulatory
cells, like long-term specific memory Th1 cells or suppressive CD8+
cells. Clonal deletion is believed to be the result of apoptosis of antigen-specific
T-cells, whereas anergy induction is known to result from T-cell receptor
occupancy in the absence of costimulatory signals provided by APC (e.g.
B7.1 or B7.2).
In addition to the central role of LC in mediating UVB-induced tolerance,
it has been suggested that other APC play a role as well. Following UVB
irradiation, the epidermis becomes populated with infiltrating CD36+
macrophages (in humans) which are able to present antigen to CD4+
suppressor/inducer cells and to CD8+ suppressor/cytotoxic cells
[34]. This subset of macrophages is thought to play a role in UVB-induced
suppression of CHS responses. Another subset of APC worth considering
in the context of UVB induced tolerance are the Thy-1+ dendritic
epidermal T-cells (DETC) which normally reside in murine epidermis, but
following UVB radiation, can be detected in the lymph nodes. These cells
were shown to induce suppressor T-cells thereby inhibiting the CHS response
[35].
T-CELL SUBSETS
Based on their cytokine secretion patterns, the CD4+ T helper
cells can be divided into at least two effector populations: T helper
1 (Th1) and T helper 2 (Th2) cells, based on the selective production
of cytokines. The Th1 population produces interleukin (IL)-2, lymphotoxin
(LT) and interferon (IFN)-gamma, whereas the Th2 cells produce IL-4, IL-5,
IL-6 and IL-10. In addition, T helper 0 (Th0) cells have been identified
which secrete both Th1 and Th2 cytokines [36]. Cytokines are involved
in the cross-regulation of the different Th subsets. For instance, T-cells
incubated in the presence of IL-4 will result in the development of Th2
cells. On the other hand, IL-12 produced by monocytes, macrophages and
B cells, is required for the generation of Th1 cells and subsequent IFN-gamma
production. Notably, IFN-gamma has a positive feedback effect by enhancing
IL-12 production by APC [37]. The production of IL-12 can be negatively
regulated by the Th2-derived cytokines IL-4 and IL-10, resulting in decreased
stimulation of cytokine production by Th1 cells (IFN-gamma). Interestingly,
IL-12 can not inhibit priming for IL-4 production, demonstrating a dominant
effect of IL-4 on the phenotype of the induced immune response [38]. Other
cytokines, such as IFN-gamma, transforming growth factor (TGF)-ß and
IL-10 also affect the cytokine production by CD4+ T-cells,
but their effects are, in general, less pronounced then that of IL-4 and
IL-12. Hence the balance of IL-4 and IL-12 eventually determines the differentiation
of Th0 cells into either Th1 or Th2 cells. The existence of distinct positive
and negative feedback mechanisms suggest that once a Th1 or Th2 type immune
response is established, the response is irreversibly committed to a particular
cytokine profile. However, it has been shown in vitro that differentiated
Th1 cells can be converted into IL-4 producers by exposure to IL-4, while
a Th2 phenotype is generally considered to be not reversible [39].
MODULATION OF CYTOKINE
ACTIVITY BY UVB
The hypothesis that UVB alters the LC APC function and consequently
promotes the induction of T-cell tolerance was further supported by findings
of Simon et al. [40]. They demonstrated that UVB-irradiated, purified
LC had lost the ability to present keyhole limpet hemocyanin (KLH) to
Th1 cells, whereas the capacity to activate Th2 cells was not altered.
The unresponsive Th1 cells were unable to produce IL-2 and to proliferate
upon stimulation with non-irradiated APC, but they responded normally
when exogenous IL-2 was added. This suggests that UVB exposure results
in clonal anergy of Th1 cells, rather than deletion. Splenic adherent
cells incubated in vitro with supernatant of UVB-irradiated keratinocytes
could mimic the preferential presentation of LC to Th2 cells, whereas
prior treatment of the supernatant with anti-IL-10 antibodies resulted
in presentation to both Th1 and Th2 cells [41]. Furthermore, IL-10 has
been shown to induce long-term clonal anergy of Th1 cells [14, 42]. In
vivo, antibodies to IL-10 could block the UVB-induced suppression
of DTH responses [43]. In IL-10 gene-targeted mice, no suppression of
DTH was observed following UVB irradiation, whereas a normal suppression
of the CHS response was demonstrated [44]. This confirms the central role
of IL-10 in the UVB-induced inhibition of the DTH, and also shows that
the suppression of the DTH and CHS responses are mediated via different
pathways. Since IL-10 is able to negatively regulate the production of
IL-12 and inhibit the activation of Th1 cells, it may fulfill an important
role in skewing the Th population to a Th2 phenotype. Systemically, Th2
derived IL-10 may help to preserve the Th2 bias by inhibiting the activation
of Th1 cells. The local secretory source of IL-10 following UVB in the
epidermis is still open to question and, in addition, the expression of
IL-10 by human keratinocytes is still controversial. Although various
research groups have reported the expression and production of IL-10 by
these cells [23, 45], a recent report describes that in contrast to their
murine counterparts, human keratinocytes lack UVB-induced expression of
IL-10 [46]. In the latter case it is likely that not keratinocytes but
infiltrating macrophages function as the major source of IL-10 [23].
Since it has been demonstrated that both UVB and IL-10 have no effect
on MHC II expression [14], much attention has focussed on the potential
modulation of costimulatory signals. Two candidate molecules on the APC
are ICAM-1 and B7. ICAM-1 expression on LC has been reported to be reduced
following UVB exposure, thereby abrogating the possibility of the APC
providing costimulation via this pathway to the T-cell. However,
at present no studies have demonstrated that the absence of signal 2 delivered
by ICAM-1 leads to anergy of Th1 cells. In contrast, it has been reported
that signalling via B7.1 (CD80) preferentially activates Th1 cells,
whereas B7.2 (CD86) induces Th2 activation [47]. Whether or not the skewing
towards a Th2 phenotype and/or anergy of Th1 cells following UVB irradiation
can be explained in terms of B7 usage is still unclear. Freshly isolated
LC express no B7.1 and B7.2 is absent or expressed at low levels [48,
49]. Culture of LC upregulates the expression of B7 molecules, whereas
UVB irradiation prevents the upregulation of B7.1 and B7.2 [49]. Inhibition
of mixed epidermal cell leukocyte responses in this system could be overcome
by anti-CD28 antibody, indicating a role for B7 molecules in the UVB-induced
suppression of antigen-presenting functions. Whether or not these costimulatory
molecules are also responsible for the skewing towards the Th2 phenotype
remains to be determined.
IL-12 has also been recognized as a critical mediator in the cross-regulation
of Th1 and Th2 responses thereby promoting the preferential activation
of Th1 cells. Injection of IL-12 in UVB-irradiated mice restores immune
function and overcomes UVB-induced immunosuppression [50]. This observation
is in agreement with the proposed mechanism that UVB affects the Th1/Th2
bias, since IL-12 is known to induce the development of Th1 cells (in
vitro and in vivo) resulting in high levels of IFN-gamma. One possible
explanation for the restoration of the immune response by IL-12 following
UVB exposure, might be a blockade in the production of IL-10 or an increase
in the release of IFN-gamma. Recently, it has been shown that presentation
of UVB-irradiated monocytes to Th1 cells in vitro reduced IFN-gamma
and IL-12 production. Addition of IL-12 in this system restored the production
of IFN-gamma [51]. Interestingly, it has been reported that one of the effects
of IL-12 in vivo is to abrogate the activity of CD8+
suppressor cells responsible for the UVB-induced inhibition of CHS responses
in mice (T. Schwarz, oral presentation).
CONCLUSION
Current data support the hypothesis that UVB irradiation reverses the
preferential activation of LC from Th1 cells to Th2 cells. Consequently,
a number of changes are expected to occur. First of all, typical Th1-mediated
responses (such as DTH responses) are altered, whereas Th2-mediated responses
(such as specific antibody production) are not affected. The preserved
proliferative capacity of Th2 cells renders these cells potential mediators
of active suppression of Th1-mediated responses and might therefore represent
one mechanism of inducing the observed tolerance following UVB irradiation.
Notably, Th2-derived IL-10 maintains the suppression of Th1 proliferation
and cytokine production, thereby prolonging the state of tolerance.
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