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Photosensitivity in lupus erythematosus
ANNEGRET KUHN1 & STEFAN BEISSERT2
1Department of Dermatology, University of Dusseldorf, Dusseldorf, Germany, and 2Department of Dermatology,
University of Munster, Munster, Germany
AbstractLupus erythematosus (LE) is an autoimmune disease which can be triggered by environmental factors such as solarirradiation. It has long been observed that especially ultraviolet (UV) exposure can induce and exacerbate skin lesions inpatients with this disease. However, despite the frequency of photosensitivity in LE, the mechanisms by which UV irradiationactivates autoimmune responses is only now becoming increasingly unfolded by advanced molecular and cellular biologicalinvestigations. Phototesting, according to a standardized protocol with UVA and UVB irradiation has proven to be a validmodel to study photosensitivity in various subtypes of LE and to evaluate the underlying pathomechanisms of this disease.Detailed analysis of the molecular events that govern lesion formation in experimentally photoprovoced LE showed increasedaccumulation of apoptotic keratinocytes and impaired expression of the inducible nitric oxide synthase (iNOS). In the nearfuture, gene expression profiling and proteomics will further increase our knowledge on the complexity of the “UV response”in LE. This review summarizes the current understanding of the clinical and molecular mechanisms that initiatephotosensitivity in this disease.
Keywords: Autoimmunity, lupus erythematosus, photosensitivity, ultraviolet light
Introduction
Photosensitivity in lupus erythematosus (LE) shows a
strong association to disease manifestation suggesting
that abnormal reactivity to ultraviolet (UV) light is one
important factor in the pathogenesis of this disease.
However, the term “photosensitivity” (skin rash as a
result of unusual reaction to sunlight by patient history
or physician observation) is poorly defined, although it
is listed as one of the American College of
Rheumatology (ACR) criteria for the classification of
systemic LE (SLE) [1,2]. Recently, the usefulness of
photosensitivity as an ACR criterion for SLE has been
questioned since a variety of other diseases, such as
polymorphous light eruption (PLE), also show a high
photosensitivity as their primary clinical aspect [3,4].
Furthermore, dermatomyositis may present with high
photosensitivity and may also be clinically difficult to
distinguish from LE in some cases. In addition,
Albrecht et al. [3] criticized that malar rash, a further
ACR criterion for the classification of SLE, is often
indistinguishable from photosensitivity and, therefore,
both criteria are not independent. In the opinion of
these authors, a control group is needed for
developing new criteria, which should include not
only patients with connective tissue diseases but also
patients with photodermatoses, such as PLE. In
addition, a detailed clinical history is important for the
diagnosis and assessment of photosensitivity in
patients with LE. There are several key components
to a history of photosensitivity, including the
morphology of the rash, duration, distribution and
the relationship to sun exposure and specific
symptoms (such as pain, pruritus, burning, blistering
and swelling). Each of these symptoms may provide
clues to the nature of the photosensitive eruption and
thus the diagnosis. However, differentiating between
the morphology and the time course of LE and, e.g.
PLE, on the patient history alone can be difficult.
ISSN 0891-6934 print/ISSN 1607-842X online q 2005 Taylor & Francis
DOI: 10.1080/08916930500285626
Correspondence: A. Kuhn, Department of Dermatology, Heinrich-Heine-University of Dusseldorf, Moorenstrasse 5, D-40225 Dusseldorf,Germany. Tel: 49 211 811 8798/49 251 835 2210. Fax: 49 211 811 9175/49 251 835 2216. E-mail: [email protected]
Autoimmunity, November 2005; 38(7): 519–529
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Clinically, PLE consists of an acute eruption of tiny,
pruritic plaques and vesicles that lasts several days, in
contrast to subacute cutaneous LE (SCLE), which
usually involves larger, nonpruritic annular or psor-
iasiform lesions that persist for weeks to months after
UV exposure [5,6]. In contrast, LE tumidus (LET)
may, in some cases, be clinically very similar to PLE
[7,8]. Moreover, a past medical history should also
include a detailed drug history, particularly, in
temporal relation to a suspected phototoxic eruption.
Moreover, photoprovocation tests are an optimal way
to evaluate photosensitivity in patients with cutaneous
manifestations of LE and are even required for
diagnosis in some cases.
Since clinical investigations demonstrated that sun
exposure has detrimental effects on all forms and
subtypes of LE, research on the pathogenetic
mechanisms of UV-induced LE has become an
increasingly dynamic field [9–13]. Furthermore,
intensive research on the molecular mechanisms
induced by UV irradiation in the skin has been
performed; however, a full understanding of the
diverse events and interactions does not exist. Despite
the fact that UV irradiation is only a small fraction of
sunlight a multitude of biological effects are induced
by the different wavelengths (Table I). UVB
irradiation is mostly absorbed in the upper layers of
the epidermis, whereas the longer wavelength UVA is
able to reach the dermis [14]. The relatively small
amount of UV irradiation reaching deeper skin layers
should not lead to the conclusion that structures in
those areas are not affected because long-term and
repeated exposures may also have significant effects.
In addition, absorption of photons in the more
superficial structures, such as keratinocytes of the
stratum corneum or stratum granulosum, may lead to
the release of mediators that affect deeper layers. It has
further been proposed that UV exposure might cause
exacerbation of local and systemic autoimmunity by
inducing changes in the expression and binding
of keratinocyte autoantigens [15–17]. In 1994,
Casciola-Rosen et al. [18] have demonstrated the
clustering of autoantigens at the cell surface of
cultured keratinocytes with apoptotic changes due to
UV irradiation. The translocation of autoantigens to
the cell surface of apoptotic blebs may allow
circulating autoantibodies to gain access to these
autoantigens, which are usually sequestered inside the
cells [19]. Antibody binding to the exposed antigens is
proposed to result in tissue injury by complement
activation or inflammatory cells [10]. This may be
especially important if the anti-inflammatory clear-
ance of apoptotic cells is impaired or delayed and the
apoptotic cells consecutively undergo secondary
necrosis as described for LE [20–23].
Further elucidation of the various factors that
contribute to UV initiation and perpetuation of
autoimmune responses may lead to future develop-
ment of effective strategies to prevent induction and
exacerbation of LE [9,24–29]. It is conceivable that
prevention of sunburn cell formation (apoptotic
keratinocytes) by photoprotection measures and
strategies can reduce disease activity [11,12]. Accord-
ing to the evidence of a delayed and prolonged
expression of the inducible nitric oxide synthase
(iNOS) in the skin of patients with LE after UVA and
UVB irradiation, nitric oxide (NO) via chemical
donors appear to be a promising target for therapeutic
intervention [30–32]. A further concept of photo-
protection includes the addition of DNA repair
enzymes into sunscreens since DNA is the primary
target for UV-induced cellular injury [33,34]. How-
ever, these hypothetical treatment strategies have to be
strengthened and proved by clinical investigations.
Historical background of photosensitivity in
lupus erythematosus
At the end of the 19th century several physicians had
already realized that environmental factors, such as
sun exposure, play a role in the induction of LE. In
1881, Cazenave [35] described exacerbations of the
disease related to “cold, heat, fire and direct action of
the air”, and Hutchinson reported in 1888 [36] that
patients with LE did not tolerate well the sun. In 1915,
Pusey described [37] a young woman who showed
cutaneous manifestations of LE a few days after
playing golf in the summertime. The skin lesions
disappeared after avoidance of sun exposure, but
another exacerbation of the disease occurred during
the next summer, again after a golf competition. In
1929, Freund [38] demonstrated in a large series of
patients with LE (n ¼ 507), which he followed
between 1920 and 1927, that inductions and
exacerbations of this disease showed significant
clustering in spring and summer months. In agree-
ment with earlier observations, he concluded that the
increasing intensity of UV irradiation in spring and
summer was responsible for the outbreak of LE. In the
same year, Fuhs [39] described a 27-year-old woman
with a highly sun-sensitive form of LE. Since a
subacute onset of the erythematous skin lesions
subsequent to the first periods of sunny weather was
regularly observed in the patient, this photosensitive
Table I. Wavelength spectrum of solar irradiation.
Irradiation Wavelength
Ultraviolet light
UVC 200–290 nm
UVB 290–320 nm
UVA 320–400 nm
UVA1 340–400 nm
UVA2 320–340 nm
Visible light 400–760 nm
Infrared light 760 nm–10mm
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subtype was termed “LE subacutus”. The detailed
description by Gilliam in 1977 [40], with expanded
discussion in 1979 [5] and 1982 [41], confirmed that
SCLE is a very photosensitive, distinct entity of LE
with skin lesions mostly limited to sun-exposed areas.
The observation that certain photosensitizing drugs,
such as thiazide diuretics and sulfonylureas, can also
induce SCLE was a further indication that UV
irradiation plays an important role in the pathogenesis
of this disease [42].
Whereas these observations delineated natural
physical agents as triggering factors in LE, artificial
light sources were also recognized as causative
inductors of specific symptoms of this disease. In
1916, Jesionek [43] described in his “guidelines for
the modern applications of phototherapy” several skin
diseases that responded well to phototherapy. In
contrast, he advised not to irradiate patients with LE,
since he had observed exacerbation of the disease on
UV irradiation. Two patients with discoid LE (DLE)
were mentioned who developed systemic mani-
festations of the disease after having been therapeuti-
cally irradiated with artificial lamps. Several decades
later, the appearance of suntanning parlors led to
further occurrence of inductions and exacerbations of
LE by artificial irradiation units that were not medically
controlled. A number of reports on such events have
been published, e.g. by Stern and Drocken [44] and
Tronnier et al. [45], who reported the manifestation of
severe SLE after the visits to suntanning parlors.
Despite the numerous anecdotal observations and
the clinical evidence demonstrating the clear relation-
ship between sunlight exposure and the manifestations
of LE, almost no systematic studies on photobiologic
effects in patients with this disease existed until the
early 1960s. In 1929, Fuhs [39] was the first to
perform experimental light testing with different
wavelengths to characterize UV sensitivity in a patient
with a photosensitive form of LE. He could
demonstrate a high sensitivity towards unfiltered
quartz lamps but was unable to determine further
wavelength-dependent sensitivity by using different
filters in these early phototesting experiments. The
first group to phototest a larger number (n ¼ 25) of
patients with LE was Epstein et al. [46], who
introduced the repeated exposure technique using a
hot quartz lamp as a UVB source. Twenty-one
patients with SLE and 4 with DLE were studied,
and clinically abnormal reactions that lasted up to 3
months were reproduced in 5 patients. In the same
year, Everett and Olson [47] demonstrated that 1
minimal erythema dose (MED) of hot quartz UV light
exposure produced an increase in the size of skin
lesions in patients with DLE. Baer and Harber [48]
investigated 29 patients with various subtypes of LE,
applying single exposures of UVB on multiple test
sites on the lower lumbal area. Only one patient with
SCLE showed pathologic reactions with a reduced
MED and persistence of the erythema for 4 weeks.
In 1967, Lester et al. [49] tested 5 patients with SLE
and 9 patients with DLE with 5–10 times the MED
and repeated the UV exposures every second day, if
necessary, to maintain the erythema. Freeman et al.
[50] used monochromatic light to determine the
wavelength dependency of phototest reactions in 15
patients with cutaneous manifestations of LE by also
applying the repeated UV exposure technique, which
became a valuable tool later on for photoprovocation
tests in several photosensitive disorders [51]. In 1973,
Cripps and Rankin [52] used monochromatic light
between 250 and 330 nm to determine the erythema
action spectrum, and specific lesions of LE were
reproduced in the UVB range by applying 8–13 times
the MED. At 330 nm (UVA), only a persistent
erythematous response but no specific LE lesions
could be detected. Because of these studies, the action
spectrum of LE was ascribed to the UVB range despite
experimental evidence from in vitro and animal studies
indicating that UVA irradiation also has specific
detrimental effects in LE [53,54]. However, the
clinical phototesting experiments had deficiencies in
that either only a very limited number of patients had
been tested or the UVA irradiation was insufficient
[46,50,52,55].
In 1990, Lehmann et al. [56] determined that the
action spectrum of LE reaches into the long-wave-
length UVA region by standardizing the phototesting
protocol. A total of 128 patients with various forms of
LE underwent irradiation on three consecutive days
with polychromatic UVB and long-wave UVA light.
Characteristic skin lesions clinically and histologically
resembling LE were induced in 43% of patients. A
practical consequence of UVA sensitivity is that
patients with LE are not adequately protected by
glass covers or by conventional sunscreens, which
poorly absorb UVA. Moreover, high-intensity UVA
sources in suntanning parlors might also be dangerous
for these patients. Subsequent investigations by other
groups confirmed UVA reactivity in patients with LE
[57,58] and during the past 20 years, protocols for
phototesting in this disease have been further
optimized by taking into account multiple factors
[59].
Meanwhile, this testing regimen has received much
attention because reproduction of LE skin lesions by
UVA and UVB irradiation is not only an optimal
procedure to evaluate photosensitivity. Furthermore,
the capacity of UVA and UVB irradiation to reproduce
LE skin lesions is an ideal model for several
experimental approaches, which allows the study of
inflammatory and immunologic events that take place
prior to and during lesion formation [28,30,55,60–
67]. In addition, phototesting has been crucial in
further characterizing the highly photosensitive sub-
type LET [7,67]. Today, it is generally accepted that
natural and artificial UV irradiation can induce and
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exacerbate LE and, furthermore, that it may exert
specific effects on the complex pathophysiology of this
disease.
Phototesting
Physical examination of a patient with LE may reveal a
distribution suggestive of a photosensitive condition in
the absence of a history of photosensitivity. The most
common areas for skin lesions in LE include sun-
exposed areas such as the face, the V-area and
posterior aspect of the neck, the ears, the dorsa of the
hands and the forearms. However, photoprovocation
tests are an objective tool for evaluating possible
photosensitivity in patients with various forms of LE
and, in some cases, are even required for diagnosis.
Indications for phototesting include (1) the objective
demonstration of photosensitivity where there is
doubt about the history and where such demon-
stration would support a diagnosis of LE; (2) the
exclusion of other causes of photosensitivity, such as
PLE, solar urticaria and drug-induced photoallergy
and -toxicity; and (3) the use of the photoprovocation
test as a useful research tool to study the immuno-
pathology of evolving lesions in LE [9,59].
In the past years, the standardized protocol for
phototesting in patients with LE has been optimized
by taking into account multiple factors, such as light
source, test area of irradiated skin, dose of UV
exposure and frequency of irradiation [59]. Non-
lesional, non-sun-exposed areas of the upper back or
extensor aspects of the arms are used for performance
of the phototest reactions, because other parts of the
skin might not react to the same extent, probably due
to some kind of local predisposition of unknown
nature other than UV irradiation, such as thickness of
the stratum corneum, vascularization, presence of
antigens, or distribution of antigen-presenting cells
[66]. Furthermore, it is important to use defined test
areas, which should be sufficiently large to provide
positive reactions. These areas are irradiated
with single doses of 60–100 J/cm2 UVA and/or 1.5
MED UVB, respectively, daily for three consecutive
days (Table II). The evaluation follows 24, 48 and 72 h
as well as weekly up to 4 weeks after irradiation. The
initial observable response following exposure to UV
irradiation is an erythema reaction that most
commonly arises with the normal time course.
Although the duration of the erythema was not
studied in particular, a prolonged erythematous
response was not a conspicuous feature [56,59].
Criteria for positive phototest reaction require that
induced lesions clinically resemble LE, histopatho-
logic findings are compatible with LE, and that skin
lesions develop slowly and persist for several days or
weeks in contrast to other UV-induced dermatoses,
such as PLE.
In 2001, photoprovocation test reactions have been
evaluated in more than 400 patients with different
subtypes of LE [59]. In addition to previous studies,
combined UVA and UVB irradiation has been
performed and most of the patients developed
characteristic skin lesions using this regimen.
Altogether, skin lesions characteristic for LE were
observed in 54% of patients; 42% of these patients
reacted to UVB irradiation only and 34% to UVA
irradiation only. Interestingly, there were substantial
differences in the clinical subtypes of LE with regard
to response to the different UV wavelength. Patients
with LET have been found to be the most
photosensitive subtype of LE since phototesting
revealed characteristic skin lesions in 72% of these
patients. In contrast, pathologic skin reactions were
induced by UV irradiation in 63% of patients with
SCLE, in 60% of patients with ACLE and in 45% of
patients with DLE.
A history of photosensitivity in patients with LE
does not necessarily predict positive reactions on
phototesting [59]. Approximately 60% of patients
were aware of an adverse effect of sunlight on their
disease, and 62% of them showed pathologic test
reactions. However, pathologic test reactions were
also induced in 58% of patients who denied any effect
of sun exposure on their disease. This might be due
Table II. Protocol of phototesting in patients with lupus erythematosus (LE).
Test site Non-UV-exposed, unaffected areas of the upper
back or extensor aspects of the arms
Size of test field Defined test areas that should be
sufficiently large to provide reactions (4 £ 5 cm)
Dosage 60–100 J/cm2 UVA and/or 1.5 MED UVB on three consecutive days
Light sources UVA: UVASUN 3000 (330–460 nm), Waldmann, or UVA1 Sellamed 2000
(340–440 nm), Sellas
UVB: UV-800 with fluorescent bulbs,
Philipps TL 20 W/12 (285–350 nm), Waldmann
Evaluation 24, 48, 72 h up to 4 weeks after irradiation
Criteria for positive photoprovocation
† Induced skin lesions clinically resemble LE
† Skin lesions develop slowly over several days or weeks
† Skin lesions persist up to several months
† Histopathologic analysis confirms the clinical diagnosis
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to the fact that, in contrast to PLE, the development of
UV-induced skin lesions in patients with LE is
characterized by a latency period of 8.0 ^ 4.6 days
(range, 1 day to 3 weeks). For this reason, a
relationship between sun exposure and exacerbation
of LE does not seem obvious to the patient and,
therefore, it might be difficult for some patients to link
sun exposure to their disease. However, the results
of reported history of photosensitivity often differs
between various research groups [2,4,5,59,65,60,66–
84]. In addition, Walchner et al. [66] observed that
mainly patients younger than 40 years reported
photosensitivity suggesting that the age at onset of
disease also plays a role. Furthermore, some ethnic
patients, such as African blacks, have been described
to be less photosensitive than others [85–91].
Interestingly, it has been reported that the incidence
of positive phototest reactions in 15 oriental patients
with LE was similar to or a little lower than that in
Caucasian patients, but there was also no correlation
between the history of UV sensitivity and phototest
reactions in these patients [64]. Moreover, the results
of phototesting also varies between different research
groups because there are numerous technical differ-
ences [55–59,60,61,63,66,92]. Varying factors are
light source, energy dose, wavelength, time points of
provocation and evaluation, and location and size of
the test area. Classification of positive test results
might also be difficult in some patients because
persistent erythema can develop, which is even
histologically hard to interpret. It is also unclear why
skin lesions cannot always be reproduced under the
same conditions several months after the initial
phototest and why phototesting results are not positive
in all patients tested, providing indirect evidence for
variant factors in the pathophysiology of LE.
UV-induced immunosuppression
The hazardous effects of UV irradiation on cellular
immunity have especially been analyzed in great
detail. This so called “UV-induced immunosuppres-
sion” is best documented by the ability of UV
irradiation to suppress cellular responses such as
contact hypersensitivity (CHS) [93,94]. Application
of hapten onto low-dose UVB-exposed human or
murine skin leads to inhibition of the induction of
CHS (UV-induced local immunosuppression). UV-
induced changes of epidermal Langerhans cell
function as well as UV-induced release of soluble
immunosuppressive factors (IL-10, TNF-a, IL-1a,
cis-urocanic acid) influencing the local micromilieu
have been mostly proposed to contribute to this
phenomenon [95]. If larger UV doses are applied
which are able to induce visible skin pathology even
application of haptens at distant, non-irradiated skin
failed to induce CHS responses (UV-induced systemic
immunosuppression). Furthermore, in this murine high-
dose UV model also subcutaneous injection of
alloantigens at a distant, non-UV-exposed area failed
to induce delayed-type hypersentitivity (DTH)
responses upon elicitation [96]. The magnitude of
suppression by high UVB doses was found to reach its
maximum approximately four days after UV
irradiation and lasted about three weeks [97]. For
UV-induced systemic suppression of cellular immu-
nity, particularly UV-induced release of e.g. keratino-
cyte-derived cytokines (IL-10, TNF-a) have been
proposed to play an important role since treatment of
mice with the corresponding neutralizing (anti-IL-10
or anti-TNF-a) antibodies was shown to abrogate
some of the systemic immunosuppression initiated by
UVB irradiation [95].
In addition, and most likely as a separate event,
individuals sensitized through UV-exposed skin
develop hapten-specific tolerance [93]. This UV-
induced immunotolerance is characterized by the
inability to be re-sensitized and re-challenged with the
same hapten, but administration of a different hapten
after UV treatment is still able to lead to immuniz-
ation. It was proposed that UV-induced immunoto-
lerance is due to the induction of hapten-specific
regulatory (suppressor) T cells since transfer of these
cells into naıve recipients confers tolerance. To date,
little is actually known about the mechanisms
governing the generation and maintenance of these
UV-induced regulatory T cells despite the fact that
investigations on regulatory T cells are currently one
of the most competitive fields in immunology [98].
Subcellular targets, so called chromophores, have
been shown to absorb UV irradiation with significant
biological consequences. Such chromophores are
lipids, proteins, DNA and urocanic acid (UCA).
Among those DNA is the major UV-absorbing
subcellular structure. After UV irradiation, the
most frequent photoproducts formed are cyclobutyl-
dimers (“dimers”) and 6–4 photoproducts (“photo-
products”) between neighboring pyrimidine bases on
one strand of DNA [14]. After UV, the ratio between
dimers and photoproducts is about 5:2. Photochemi-
cal analysis has revealed that 1 of 500 absorbed
photons is able to induce dimer formation and
application of 1 MED produced 0.04 dimers in 1000
nucleotides. Dimers are more stable than photo-
products and have been shown to induce the release
of IL-10 from murine keratinocytes. UVB irradiation
of mice on the shaved backs stimulated the secretion of
IL-10, which mediated UV-induced immunosuppres-
sion since IL-10 inhibits antigen-presenting cells
function as well as the activation of Th1 responses.
Treatment of back skin with liposomes containing the
DNA repair enzyme T4 endonuclease V, which is able
to repair UV-induced dimer formation, abrogated IL-
10 production and protected against UV-induced
immunosupression [99]. These findings indicate that
UV-induced immunosuppression is mediated by
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DNA dimer formation and the subsequent release of
IL-10. Besides its inhibitory effects on T cells and
antigen-presenting cells, IL-10 is an important growth
factor of B cells as well as natural killer cells [100].
Perhaps the activation of especially these two subsets
of leukocytes, which have been shown to be involved
in the development of autoimmunity, contribute to
lesion formation in LE.
UV-induced DNA damage can be too severe so that
cellular DNA repair mechanisms fail. Furthermore,
these DNA repair systems such as the nucleotide
excision repair (NER) can be suppressed by UV
irradiation. Failure to repair DNA damage leads to the
development of so-called sunburn cells, apoptotic
keratinocytes within the epidermis [101]. Since LE
has been associated with decreased clearing rate of
apoptotic cell debris from tissue, such a putative
mechanism could also contribute to cutaneous LE
lesion formation.
Another interesting chromophore besides DNA is
UCA (2-propeonic acid). UCA is produced in the
metabolic pathway of the essential amino acid
histidine and accumulates in keratinocytes in the
epidermis by proteolysis of histidine-rich proteins
such as filaggrin [102]. Keratinocytes lack catabolic
enzymes to ultimately degrade UCA to CO2 and H2O
so that concentrations of 6–9mg/cm2 UCA in human
epidermis can be found. UCA exists in two isomers,
trans- and cis-UCA. Trans-UCA is primarily detect-
able in the epidermis and upon UV irradiation, trans-
UCA photoisomerizes to cis-UCA. cis-UCA acts in
many investigated models are an immunosuppressant
agent [103,104]. Injections of cis-UCA suppressed
CHS responses in mice and inhibited the function of
antigen-presenting cells. The molecular mechanisms
of immunosuppression induced by cis-UCA are not
clear. Also, the role of UCA in LE has not been
analyzed in great detail.
Besides chromophores, which directly absorb
photons, UV irradiation is also able to induce
regulatory (“suppressor”) T cells, which can mediate
some of the aspects of UV-induced immunosuppres-
sion [105]. Studies in animals have shown that UV-
induced suppressor T cells can belong to the
CD4þCD25þ or the CD8þ subset of suppressor T
cells depending on the model investigated. UV-
induced suppressor T cells can inhibit the induction
of CHS responses upon transfer into sensitized mice.
Furthermore, UV-induced suppressor T cells can
down-regulate antitumoral immunity against deve-
loping UV-induced skin tumors [106–108]. UV-
induced suppressor T cells produce IL-10, however, it
is not clear whether IL-10 mediates their suppressor
function. In humans, naturally occurring
CD4þCD25þ regulatory T cells with suppressor
function have also been isolated and these cells appear
to play an increasingly important role in inhibiting the
development of autoimmune responses [109].
Accordingly, impaired suppressor function of these
cells has been detected in patients suffering from
multiple sclerosis or psoriasis [110,111]. Perhaps,
fewer UV-induced suppressor T cells become acti-
vated in Lupus patients and such an impaired
protection mechanism could contribute to the
development of autoimmunity in Lupus-prone
individuals.
Taken together, the vast majority of experimental
data suggest that UV irradiation induces suppression
of especially cellular immune responses via several
molecular mechanisms. We are only at the beginning
of our understanding of the cutaneous UV response
and future research including high throughput
expression profiling techniques will hopefully lead to
advances in our understanding of the complexity of
UV light and induction of LE.
Pathophysiology of photosensitivity in lupus
erythematosus
In several studies and reviews, a potentially crucial role
in the initiation of the autoimmune reaction cascade
has been attributed to UV-induced keratinocyte
apoptosis [10–12]. Using in situ labeling methods
for detection of DNA strand breaks, an increased
number of apoptotic keratinocytes in skin lesions of
LE patients compared with controls has been
described [112–114]. Furthermore, a significant
increase of apoptotic nuclei was also found in UV-
induced lesions of patients with various manifestations
of LE after phototesting [115]. In addition, in tissue
sections taken 1 day after a single UV exposure, an
increased number of epidermal apoptotic nuclei was
present in controls compared with skin specimens of
patients with LE taken under the same conditions
before lesion formation. In sections taken 3 days after
irradiation from controls, a significant decrease of the
apoptotic nuclei count was observed. This was
consistent with a proper clearance of apoptotic cells
between 1 and 3 days after UV exposure. In striking
contrast, in the majority of patients with LE the
number of apoptotic nuclei increased significantly in
this period suggesting that late apoptotic cells
accumulate in the skin of a large subgroup of patients
with this disease. The hypothesis that clearance of
apoptotic cells in the skin of the majority of patients
with cutaneous manifestations of LE is either impaired
or delayed, is in analogy to the growing evidence that
defects in the clearance of apoptotic cells may be
important in triggering the immune response in
SLE [22,116,117]. Impaired clearance functions for
dying cells may explain accumulation of apoptotic,
and subsequently, of secondary necrotic cells in
various tissues of these patients. Interestingly, lymph
node biopsies from patients with SLE have been
investigated whether a defect in engulfment of
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apoptotic cell material can also be observed in
germinal centers [116]. A characteristic feature of
the lymph node germinal centers is the presence of
specialized phagocytes, usually referred to as tingible
body macrophages (TBM). Under healthy conditions,
TBM removes apoptotic cells very efficiently in the
early phase of apoptosis. However, in a subgroup of
patients with SLE, apoptotic cells accumulated in the
germinal centers of the lymph nodes. This may be due
to impaired phagocytic activity or caused by the
absence of TBM. Apoptosis might progress and the
cells enter late stages of apoptotic cell death, including
secondary necrosis [21,118].
Since NO is an important regulator of apoptosis
and has an implication in the course of various
autoimmune diseases [119,120], the role of this
molecule has also been investigated in the patho-
genesis of LE [30,121–123]. NO is a pleiotrope
molecule synthesized by a family of nitric oxide
synthases, which are constitutively expressed in
endothelial cells and inducible in a variety of cell
types, including endothelial cells and keratinocytes.
Interestingly, this molecule appears to have differen-
tial effects upon the various cell types within the skin.
Suschek et al. [124] showed that NO can protect
against UVA-induced apoptosis by increasing Bcl-2
expression and inhibiting UVA-induced overexpres-
sion of Bax protein in endothelial cells. It has
further been demonstrated by the same group that
the presence of nitrite and not nitrate, during
irradiation of endothelial cells, exerts a potent
and concentration-dependent protection against
UVA-induced apoptotic cell death [125]. Recently,
Weller et al. [126] suggested an anti-apoptotic role
for NO in keratinocytes after exposure to UVB.
However, when applied to normal, non-irradiated
skin, NO induced accumulation of CD4þ and
CD8þ T cells, unregulation of ICAM-1 and
VCAM-1, and expression of p53, followed by
keratinocyte apoptosis [127]. Altered expression of
this molecule may therefore provide a further link
between dysregulated keratinocyte apoptosis and
inflammation. Moreover, it has been reported that
there is increased production of NO during disease
development in MRL/lpr mice [123], and interest-
ingly, elevated levels of endothelial iNOS and serum
nitrite correlated with measuers of disease activity
and titers of anti-dsDNA antibodies in patients with
SLE [121]. Furthermore, our group investigated the
expression of iNOS at the messenger RNA and
protein levels in skin lesions of patients with various
subtypes of LE [30]. The results of this study
demonstrated a delayed iNOS-specific signal
after UVA and UVB irradiation in patients with
LE, suggesting that the kinetics of iNOS induction
and the time span of local iNOS expression
might play an important role in the pathogenesis of
photosensitive LE.
Concluding remarks
A very important and practically relevant feature of
photosensitivity in LE, which became evident on
phototesting, is the delayed and slow UV reactivity in
these patients. This conspicuous feature may explain
the negligence of many patients with LE as to the
negative effects of sun exposure on their disease.
Therefore, education on photoprotection measures
seems to be especially important in this disease.
Recently, it has been demonstrated that broadband
sunscreens were able to suppress the induction of skin
lesions on UV irradiation in patients with LE
[128–130]. Therefore, consequent protection against
UV light and also other physical and mechanical
injuries may be of significant value for the course and
prognosis of this disease. Further elucidation of the
various factors that contribute to the UV initiation and
perpetuation of autoimmune responses may lead to
future developments of more specific pharmaceuticals
beyond UV filters to prevent induction and exacer-
bation of LE and to counteract the detrimental effects
of UV irradiation on this disease.
Acknowledgements
This work was supported by Heisenberg professor-
ships from the German Research Association (DFG)
to A. K. (KU 1559/1-1) and to S. B. (BE 1580/6-2)
and by a grant from the DFG to S.B. (SFB 293; BE
1580-71-1) and by the IZKF, Munster, Germany.
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