11
Photosensitivity in lupus erythematosus ANNEGRET KUHN 1 & STEFAN BEISSERT 2 1 Department of Dermatology, University of Du ¨sseldorf, Du ¨sseldorf, Germany, and 2 Department of Dermatology, University of Mu ¨nster, Mu ¨nster, Germany Abstract Lupus erythematosus (LE) is an autoimmune disease which can be triggered by environmental factors such as solar irradiation. It has long been observed that especially ultraviolet (UV) exposure can induce and exacerbate skin lesions in patients with this disease. However, despite the frequency of photosensitivity in LE, the mechanisms by which UV irradiation activates autoimmune responses is only now becoming increasingly unfolded by advanced molecular and cellular biological investigations. Phototesting, according to a standardized protocol with UVA and UVB irradiation has proven to be a valid model 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 increased accumulation of apoptotic keratinocytes and impaired expression of the inducible nitric oxide synthase (iNOS). In the near future, 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 initiate photosensitivity 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 Du ¨ sseldorf, Moorenstrasse 5, D-40225 Du ¨ sseldorf, 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 Autoimmunity Downloaded from informahealthcare.com by McMaster University on 11/06/14 For personal use only.

Photosensitivity in lupus erythematosus

  • Upload
    stefan

  • View
    212

  • Download
    0

Embed Size (px)

Citation preview

Page 1: Photosensitivity in lupus erythematosus

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

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/06/

14Fo

r pe

rson

al u

se o

nly.

Page 2: Photosensitivity in lupus erythematosus

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

A. Kuhn & S. Beissert520

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/06/

14Fo

r pe

rson

al u

se o

nly.

Page 3: Photosensitivity in lupus erythematosus

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

Photosensitivity in lupus erythematosus 521

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/06/

14Fo

r pe

rson

al u

se o

nly.

Page 4: Photosensitivity in lupus erythematosus

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

A. Kuhn & S. Beissert522

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/06/

14Fo

r pe

rson

al u

se o

nly.

Page 5: Photosensitivity in lupus erythematosus

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

Photosensitivity in lupus erythematosus 523

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/06/

14Fo

r pe

rson

al u

se o

nly.

Page 6: Photosensitivity in lupus erythematosus

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

A. Kuhn & S. Beissert524

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/06/

14Fo

r pe

rson

al u

se o

nly.

Page 7: Photosensitivity in lupus erythematosus

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.

References

[1] Hochberg MC. Updating the American College of Rheumato-

logy revised criteria for the classification of systemic lupus

erythematosus. Arthritis Rheum 1997;40:1725.

[2] Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ,

Rothfield NF, Schaller JC, Talal N, Winchester RJ. The 1982

revised criteria for the classification of systemic lupus

erythematosus. Arthritis Rheum 1982;25:1271–1277.

[3] Albrecht J, Berlin JA, Bravermann IM, Callen JP, Costner

MI, Dutz J, Fivenson D, Franks AG, Jorizzo JL, Lee LA,

McCauliffe DP, Sontheimer RD, Werth VP. Dermatology

position paper on the revision of the 1982 ACR criteria for

systemic lupus erythematosus. Lupus 2004;13:839–849.

[4] Doria A, Biasinutto C, Ghirardello A, Sartori E, Rondinone

R, Piccvoli A, Veller Fornasa C, Gambari PE. Photosensi-

tivity in systemic lupus erythematosus: Laboratory testing of

ARA/ACR definition. Lupus 1996;5:263–268.

[5] Sontheimer RD, Thomas JR, Gilliam JN. Subacute

cutaneous lupus erythematosus: A cutaneous marker for a

distinct lupus erythematosus subset. Arch Dermatol

1979;115:1409–1415.

[6] Stratigos AJ, Antoniou C, Katsambas AD. Polymorphous

light eruption. J Eur Acad Dermatol Venereol

2002;16:193–206.

[7] Kuhn A, Richter-Hintz D, Oslislo C, Ruzicka T, Megahed M,

Lehmann P. Lupus erythematosus tumidus: A neglected

subset of cutaneous lupus erythematosus. Report of 40 cases.

Arch Dermatol 2000;136:1033–1041.

Photosensitivity in lupus erythematosus 525

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/06/

14Fo

r pe

rson

al u

se o

nly.

Page 8: Photosensitivity in lupus erythematosus

[8] Kuhn A, Hanneken S, Megahed M, Ruzicka T, Neumann NJ.

Extreme Photosensitivitat seit der Kindheit. Hautarzt 2005;

in press.

[9] Kuhn A, Lehmann P. Photosensitivity in lupus erythemato-

sus. In: Kuhn A, Lehmann P, Ruzicka T, editors. Cutaneous

lupus erythematosus. 1st ed. Heidelberg: Springer; 2004.

p 161–175.

[10] Norris DA. Pathomechanisms of photosensitive lupus

erythematosus. J Invest Dermatol 1993;100:58S–68S.

[11] Orteu CH, Sontheimer RD, Dutz JP. The pathophysiology of

photosensitivity in lupus erythematosus. Photodermatol

Photoimmunol Photomed 2001;17:95–113.

[12] Sontheimer RD. Photoimmunology of lupus erythematosus

and dermatomyositis: A speculative review. Photochem

Photobiol 1996;63:583–594.

[13] Werth V, Bashir M, Zhang. Photosensitivity in rheumatic

diseases. J Invest Dermatol Symp Proc 2004;9:57–63.

[14] Beissert S, Granstein RD. UV-induced cutaneous photobio-

logy. Crit Rev Biochem Mol Biol 1996;31:381–404.

[15] Furukawa F, Kashihara-Sawami M, Lyons MB, Norris DA.

Binding of antigens SS-A/Ro and SS-B/La is induced of

human keratinocytes by ultraviolet light (UVL): Implications

for the pathogenesis of photosensitive cutaneous lupus. J

Invest Dermatol 1990;94:77–85.

[16] Golan TD, Elkon KB, Gharavi AE, Krueger JG. Enhanced

membrane binding of autoantibodies to cultured keratino-

cytes of systemic lupus erythematosus patients after

ultraviolet B/ultraviolet A irradiation. J Clin Investig

1992;90:1067–1076.

[17] LeFeber WP, Norris DA, Ran SR, Lee LA, Huff JC, Kubo M,

Boyce ST, Kotzin BL, Weston WL. Ultraviolet light induces

binding of antibodies to selected nuclear antigens on cultured

human keratinocytes. J Clin Investig 1984;74:1545–1551.

[18] Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens

targeted in systemic lupus erythematosus are clustered in

two populations of surface structures on apoptotic keratino-

cytes. J Exp Med 1994;179:1317–1330.

[19] Casciola-Rosen LA, Rosen A. Ultraviolet light-induced

keratinocyte apoptosis: A potential mechanism for the

induction of skin lesions and autoantibody production in

LE. Lupus 1997;6:175–180.

[20] Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY,

Henson PM. Macrophages that have ingested apoptotic cells

in vitro inhibit proinflammatory cytokine production through

PGE2, and PAF. J Clin Investig 1998;101:890–898.

[21] Gaipl US, Voll RE, Sheriff A, Franz S, Kalden JR, Herrmann.

Impaired clearance of dying cells in lupus erythematosus.

Autoimmun Rev 2005;4:189–194.

[22] Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner

BB, Kalden JR. Impaired phagocytosis of apoptotic cell

material by monocyte-derived macrophages from patients

with systemic lupus erythematosus. Arthritis Rheum

1998;41:1241–1250.

[23] Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR,

Girkontaite I. Immunosuppressive effects of apoptotic cells.

Nature 1997;390:350–351.

[24] Beissert S, Schwarz T. Role of immunomodulation in

diseases responsive to phototherapy. Methods 2002;

28:138–144.

[25] Furukawa F. Photosensitivity in cutaneous lupus erythe-

matosus: Lessons from mouse and men. J Dermatol Sci

2003;33:81–89.

[26] Gil EM, Kim TH. UV-induced immune suppression and

sunscreen. Photodermatol Photoimmunol Photomed

2000;16:101–110.

[27] Lehmann P, Ruzicka T. Sunscreens and photoprotection in

lupus erythematosus. Dermatol Therapy 2001;14:167–173.

[28] Nyberg F, Skoglund C, Stephansson E. Early detection of

epidermal dust-like particles in experimentally UV-induced

lesions in patients with photosensitivity and lupus erythe-

matosus. Acta Derm Venereol 1998;78:177–179.

[29] Ting WW, Sontheimer RD. Local therapy for cutaneous and

systemic lupus erythematosus: Practical and theoretical

considerations. Lupus 2001;10:171–184.

[30] Kuhn A, Fehsel K, Lehmann P, Krutmann J, Ruzicka T,

Kolb-Bachofen V. Aberrant timing in epidermal expression of

inducible nitric oxide synthase after UV irradiation in

cutaneous lupus erythematosusu. J Invest Dermatol

1998;111:149–153.

[31] Seabra AB, Fitzpatrick A, Paul J, De Oliveira MG, Weller R.

Topically applied S-nitrosothiol-containing hydrogels as

experimental and pharmacological nitric oxide donors in

human skin. Br J Dermatol 2004;151:977–983.

[32] Weller R. Nitric oxide donors and the skin: Useful therapeutic

agents? Clin Sci 2003;105:533–535.

[33] Stege H, Roza L, Viink AA, Grewe M, Ruzicka T, Grether-

Beck S, Krutmann J. Enzyme plus light therapy to repair

DNA damage in ultraviole-B-irradiated human skin. Proc

Natl Acad Sci USA 2000;97:1790–1795.

[34] Yarosh DB, O’Connor A, Alas L, Potten C, Wolf P.

Photoprotection by topical DNA repair enzymes: Molecular

correlates of clinical studies. Photochem Photobiol

2000;69:136–140.

[35] Cazenave PLA. Lupus erythemateux (erytheme centrifuge).

Ann Mal Peau Syph 1881;3:297–299.

[36] Hutchinson J. Harveian lectures on lupus. Lecture III. On the

various form of lupus vulgaris and erythematosus. Br Med J

1888;1:113–118.

[37] Pusey WA. Attacks of lupus erythematosus following

exposure to sunlight or other weather factors. Arch Derm

Syph 1915;34:388.

[38] Freund H. Inwieweit ist der Lupus erythematosus von

allgemeinen Faktoren abhangig? Dermatol Wochenschr

1929;89:1939–1946.

[39] Fuhs E. Lupus erythematosus subacutus mit ausgesproch-

ener Uberempfindlichkeit gegen Quarzlicht. Z Hautkr

1929;30:308–309.

[40] Gilliam JN. The cutaneous signs of lupus erythematosus.

Cont Educ Fam Phys 1977;6:34–70.

[41] Gilliam JN, Sontheimer RD. Subacute cutaneous lupus

erythematosus. Clin Rheum Dis 1982;8:343–352.

[42] Reed BR, Huff JC, Jones SK, Orton PW, Lee LA, Norris DA.

Subacute cutaneous lupus erythematosus associated with

hydrochlorothiazide therapy. Ann Intern Med 1985;103:

49–51.

[43] Jesionek A. Richtlinien der modernen Lichttherapie. Strah-

lentherapie 1919;7:41–45.

[44] Stern RS, Drocken W. An exacerbation of SLE after visiting a

tanning salon. JAMA 1986;155:3120.

[45] Tronnier H, Petri H, Pierchalla P. UV-provozierte bullose

Hautveranderungen bei systemischem Lupus erythematodes.

Z Hautkr 1988;154:617A.

[46] Epstein JH, Tuffanelli DL, Dubois EL. Light sensitivity and

lupus erythematosus. Arch Dermatol 1965;91:483–485.

[47] Everett MA, Olson RL. Response of cutaneous lupus

erythematosus to ultraviolet light. J Invest Dermatol

1965;44:133–134.

[48] Baer RL, Harber LC. Photobiology of lupus erythematosus.

Arch Dermatol 1965;92:124–128.

[49] Lester RS, Burnham TK, Fine G, Murray K. Immunologic

concepts of light reactions in lupus erythematosus and

polymorphous light eruptions. I. The mechanism of action of

hydroxychloroquine. Arch Dermatol 1967;96:1–10.

[50] Freeman RG, Knox JM, Owens DW. Cutaenous lesions of

lupus erythematosus induced by monochromatic light. Arch

Dermatol 1969;100:677–682.

A. Kuhn & S. Beissert526

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/06/

14Fo

r pe

rson

al u

se o

nly.

Page 9: Photosensitivity in lupus erythematosus

[51] Lehmann P, Holzle E, Kries RV, Plewig G. Lichtdiagnos-

tische Verfahren bei Patienten mit Verdacht auf Photo-

dermatosen. Zbl Haut- und Geschl-Kr 1986;152:667–682.

[52] Cripps DJ, Rankin J. Action spectra of lupus erythematosus

and experimental immunoflourescence. Arch Dermatol

1973;107:563–567.

[53] Friou GJ. Clinical application of lupus serum: Nucleoprotein

reaction using fluorescent antibody technique. J Clin Invest

1957;36:890–896.

[54] Zamansky GB, Kleinmann LF, Kaplan JC. Effect of UV light

irradiation on the survival of NZB mouse cells. Arthritis

Rheum 1980;23:866–867.

[55] Van Weelden H, Velthuis PJ, Baart de la Faille H. Light-

induced skin lesions in lupus erythematosus: Photobiological

studies. Arch Dermatol Res 1989;281:470–474.

[56] Lehmann P, Holzle E, Kind P, Goerz G, Plewig G.

Experimental reproduction of skin lesions in lupus erythe-

matosus by UVA and UVB radiation. J Am Acad Dermatol

1990;22:181–187.

[57] Nived O, Johansen PB, Sturfelt G. Standardized ultraviolet-A

exposure provokes skin reaction in systemic lupus erythe-

matosus. Lupus 1993;2:247–250.

[58] Wolska H, Blazczyk M, Jablonska S. Phototests in patients

with various forms of lupus erythematosus. Int J Dermatol

1989;28:98–103.

[59] Kuhn A, Sonntag M, Richter-Hintz D, Oslislo C, Megahed

M, Ruzicka T, Lehmann P. Phototesting in lupus erythe-

matosus: A 15-year experience. J Am Acad Dermatol

2001;45:86–95.

[60] Beutner EH, Blaszczyk M, Jablonska S, Chorzelski TP,

Kumar V, Wolska H. Studies on criteria of the European

Academy of Dermatology and Venerology for the classifi-

cation of cutaneous lupus erythematosus. I. Selection of

clinical groups and study factors. Int J Dermatol

1991;30:411–417.

[61] Hasan T, Nyberg F, Stephansson E, Puska P, Hakkinen M,

Sarna S, Ros AM, Ranki A. Photosensitivity in lupus

erythematosus, UV photoprovocation results compared with

history of photosensitivity and clinical findings. Br J Dermatol

1997;136:699–705.

[62] Janssens AS, Lashley EE, Out-Luiting CJ, Willemze R, Pavel

S, de Gruijl FR. UVB-induced leucocyte trafficking in the

epidermis of photosensitive lupus erythematosus patients:

Normal depletion of Langerhans cells. Exp Dermatol

2005;14:138–142.

[63] Kind P, Lehmann P, Plewig G. Phototesting in lupus

erythematosus. J Invest Dermatol 1993;100:53S–57S.

[64] Leenutaphong V, Boonchai W. Phototesting in oriental

patients with lupus erythematosus. Photodermatol Photo-

immunol Photomed 1999;15:7–12.

[65] Millard TP, Hawk JL, McGregor JM. Photosensitivity in

lupus. Lupus 2000;3–10.

[66] Walchner M, Messer G, Kind P. Phototesting and photo-

protection in L.E. Lupus 1997;6:167–174.

[67] Kuhn A, Sonntag M, Richter-Hintz D, Oslislo C, Megahed

M, Ruzicka T, Lehmann P. Phototesting in lupus erythe-

matosus tumidus: Review of 60 patients. Photochem

Photobiol 2001;73:532–536.

[68] Callen JP. Discoid lupus erythematosus—variants and clinical

associations. Clin Dermatol 1985;3:49–57.

[69] Callen JP, Klein J. Subacute cutaneous lupus erythematosus.

Clinical, serologic, immunogenetic, and therapeutic con-

siderations in seventy-two patients. Arthritis Rheum

1988;31:1007–1013.

[70] Drosos AA, Dimou GS, Siamopoulou-Mavridou A, Hatzis J,

Moutsopoulos HM. Subacute cutaneous lupus erythemato-

sus in Greece. A clinical, serological and genetic study.

Ann Med Intern 1990;141:421–424.

[71] Grigor R, Edmonds J, Lewkonia R, Bresnihan B, Hughes

GRV. Systemic lupus erythematosus—a prospective analysis.

Ann Rheum Dis 1978;37:121–128.

[72] Harvey AM, Shulman LE, Tumulty PA, Conley CL,

Schoenrich EH. Systemic lupus erythematosus: Review of

the literature and clinical analysis of 138 cases. Medicine

1954;33:291–437.

[73] Herrero C, Bielsa I, Font J, Lozano F, Ercilla G, Lecha M,

Ingelmo M, Mascaro JM. Subacute cutaneous lupus

erythematosus: Clinicopathologic findings in thirteen cases.

J Am Acad Dermatol 1988;19:1057–1062.

[74] Hymes SR, Russell TJ, Jordon RE. The anti-Ro antibody

system. Int J Dermatol 1986;25:1–7.

[75] Lee PL, Urowitz MB, Bookman AM, Koehler BE, Smythe

HA, Gordon DA, Ogryzlo MA. Systemic lupus erythe-

matosus. A review of 110 cases with reference to nephritis, the

nervous system, infections, aseptic necrosis and prognosis.

Q J Med 1977;46:1–32.

[76] Mond CB, Peterson MG, Rothfield NF. Correlation of anti-

Ro antibody with photosensitivity rash in systemic lupus

erythematosus patients. Arthritis Rheum 1989;32:202–204.

[77] O’Loughlin S, Schroeter AL, Jordon RE. A study of lupus

erythematosus with particular reference to generalized

discoid lupus. Br J Dermatol 1978;99:1–11.

[78] Pande I, Sekharan NG, Kailash S, Uppal SS, Singh RR,

Kumar A, Malavivya AN. Analysis of clinical and laboratory

profile in Indian childhood systemic lupus erythematosus and

its comparison with SLE in adults. Lupus 1993;2:83–87.

[79] Pistiner M, Wallace DJ, Nessim S, Metzger AL, Klinenberg

JR. Lupus erythematosus in the 1980s: A survey of 570

patients. Semin Arthritis Rheum 1991;21:55–64.

[80] Scheinfeld N, Deleo VA. Photosensitivity in lupus erythe-

matosus. Photodermatol Photoimmunol Photomed 2004;

20:272–279.

[81] Sontheimer RD. Subacute cutaneous lupus erythematosus: A

decade’s perspective. Med Clin North Am 1989;73:

1073–1090.

[82] Tuffanelli DL, Dubois EL. Cutaneous manifestations of

systemic lupus erythematosus. Arch Dermatol 1964;90:

377–386.

[83] Vila LM, Mayor AM, Valentin AH, Rodriguez SI, Reyes ML,

Acosta E, Vila S. Association of sunlight exposure and

photoprotection measures with clinical outcome in systemic

lupus erythematosus. P R Health Sci J 1999;18:89–94.

[84] Wysenbeek AJ, Block DA, Fries JF. Prevalence and

expression of photosensitivity in systemic lupus erythemato-

sus. Ann Rheum Dis 1989;48:461–463.

[85] Choonhakarn C, Poonsriaram A, Chaivoramukul J. Lupus

erythematosus tumidus. Int J Dermatol 2004;43:815–818.

[86] Mody GM, Parag KB, Nathoo BC, Pudifin DJ, Duursma J,

Seedat YK. High mortality with systemic lupus erythemato-

sus in hospitalized African blacks. Br J Rheumatol

1994;33:1151–1153.

[87] Petri M, Perez-Gutthann S, Craig Longenecker J, Hochberg

M. Morbidity of systemic lupus erythematosus: Role of race

and socioeconomic status. Am J Med 1992;91:345–353.

[88] Shi SY, Feng SF, Liao KH, Fang L, Kang KF. Clinical study

of 30 cases of subacute cutaneous lupus erythematosus.

Chin Med J 1987;100:45–48.

[89] Sutej PG, Gear AJ, Morrison RC, Tikly M, de Beer M, Dos

Santos L, Sher R. Photosensitivity and anti-Ro (SS-A)

antibodies in black patients with systemic lupus erythemato-

sus (SLE). Br J Rheumatol 1989;28:321–324.

[90] Taylor HG, Stein CM. Systemic lupus erythematosus in

Zimbabwe. Ann Rheum Dis 1986;45:645–648.

[91] Ward MM, Studenski S. Clinical manifestations of systemic

lupus erythematosus. Identification of racial and socio-

economic influences. Arch Intern Med 1990;150:849–853.

Photosensitivity in lupus erythematosus 527

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/06/

14Fo

r pe

rson

al u

se o

nly.

Page 10: Photosensitivity in lupus erythematosus

[92] Sanders CJ, Van Weelden H, Kazzaz GA, Sigurdsson V,

Toonstra J, Bruijnzeel-Koomen CA. Photosensitivity in

patients with lupus erythematosus: A clinical and photo-

biological study of 100 patients using a prolonged phototest

protocol. Br J Dermatol 2003;49:131–137.

[93] Elmets CA, Bergstresser PR, Tigelaar RE, Wood PJ, Streilein

JW. Analysis of the mechanism of unresponsiveness produced

by haptens painted on skin exposed to low dose ultraviolet

radiation. J Exp Med 1983;158:781–794.

[94] Toews GB, Bergstresser PR, Streilein JW. Epidermal

Langerhans cell density determines whether contact hyper-

sensitivity or unresponsiveness follows skin painting with

DNFB. J Immunol 1980;124:445–453.

[95] Ullrich SE. The role of epidermal cytokines in the generation

of cutaneous reactions and ultraviolet radiation-induced

immune suppression. Photochem Photobiol 1995;62:

389–401.

[96] Beissert S, Schwarz T. Mechanisms involved in ultraviolet

light-induced immunosuppression. J Invest Dermatol Symp

Proc 1999;4:61–64.

[97] Beissert S, Hosoi J, Kuhn R, Rajewsky K, Muller W,

Granstein RD. Impaired immunosuppressive response to

ultraviolet radiation in interleukin-10-deficient mice. J Invest

Dermatol 1996;107:553–557.

[98] Shevach EM. Regulatory/suppressor T cells in health and

disease. Arthritis Rheum 2004;50:2721–2724.

[99] Nishigori C, Yarosh DB, Ullrich SE, Vink AA, Bucana CD,

Roza L, Kripke ML. Evidence that DNA damage triggers

interleukin 10 cytokine production in UV-irradiated murine

keratinocytes. Proc Natl Acad Sci USA 1996;93:

10354–10359.

[100] Ding W, Beissert S, Deng L, Miranda E, Cassetty C, Seiffert

K, Campton KL, Yan Z, Murphy GF, Bluestone JA,

Granstein RD. Altered cutaneous immune parameters in

transgenic mice overexpressing viral IL-10 in the epidermis.

J Clin Invest 2003;111:1923–1931.

[101] Murphy G, Young AR, Wulf HC, Kulms D, Schwarz T.

The molecular determinants of sunburn cell formation. Exp

Dermatol 2001;10:155–160.

[102] Mohammad T, Morrison H, HogenEsch H. Urocanic acid

photochemistry and photobiology. Photochem Photobiol

1999;69:115–135.

[103] Beissert S, Mohammad T, Torri H, Lonati A, Yan Z,

Morrison H, Granstein RD. Regulation of tumor antigen

presentation by urocanic acid. J Immunol 1997;159:92–96.

[104] Beissert S, Ruhlemann D, Mohammad T, Grabbe S, El-

Ghorr A, Norval M, Morrison H, Granstein RD, Schwarz T.

IL-12 prevents the inhibitory effects of cis-urocanic acid on

tumor antigen presentation by Langerhans cells: Implications

for photocarcinogenesis. J Immunol 2001;167:6232–6238.

[105] Beissert S, Schwarz A, Schwarz T. New perspective series:

Regulatory T cells. J Invest Dermatol 2005; in press.

[106] Fisher MS, Kripke ML. Suppressor T lymphocytes control

the development of primary skin cancers in ultraviolet-

irradiated mice. Science 1982;216:1133–1134.

[107] Loser K, Scherer A, Krummen MB, Varga G, Higuchi T,

Schwarz T, Sharpe AH, Grabbe S, Bluestone JA, Beissert S.

An important role of CD80/CD86-CTLA-4 signaling during

photocarcinogenesis in mice. J Immunol 2005;174:

5298–5305.

[108] Schwarz A, Maeda A, Wild MK, Kernebeck K, Gross N,

Aragane Y, Beissert S, Vestweber D, Schwarz T. Ultraviolet

radiation-induced regulatory T cells not only inhibit the

induction but can suppress the effector phase of contact

hypersensitivity. J Immunol 2004;172:1036–1043.

[109] Sakaguchi S. Naturally arising Foxp3-expressing

CD25+CD4+ regulatory T cells in immunological tolerance

to self and non-self. Nat Immunol 2005;6:345–352.

[110] Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of

functional suppression by CD4+CD25+ regulatory T cells in

patients with multiple sclerosis. J Exp Med 2004;199:

971–979.

[111] Sugiyama H, Gyulai R, Toichi E, Garaczi E, Shimada S,

Stevens SR, McCormick TS, Cooper KD. Dysfunctional

blood and target tissue CD4+CD25 high regulatory T cells in

psoriasis: Mechanism underlying unrestrained pathogenic

effector T cell proliferation. J Immunol 2005;174:164–173.

[112] Baima B, Sticherling M. Apoptosis in different cutaneous

manifestations of lupus erythematosus. Br J Dermatol

2001;144:958–966.

[113] Chung JH, Kwon OS, Eun HC, Youn JI, Song YW, Kim JG,

Cho KH. Apoptosis in the pathogenesis of cutaneous lupus

erythematosus. Am J Dermatopathol 1998;20:233–241.

[114] Pablos JL, Santiago B, Galindo M, Carreira PE, Ballestin C,

Gomez-Reino JJ. Keratinocyte apoptosis and p53 expression

in cutaneous lupus and dermatomyositis. J Pathol

1999;188:63–68.

[115] Kuhn A, Herrmann M, Kleber S, Beckmann-Welle M,

Fehsel K, Martin-Villalba A, Lehmann P, Ruzicka T,

Krammer PM, Kolb-Bachofen V. Accumulation of apoptotic

cells in the epidermis of patients with cutaneous forms of

lupus erythematosus. 2005; (Manuscript submitted for

publication).

[116] Baumann I, Kolowos W, Voll RE, Manger B, Gaipl U,

Neuhuber WL, Kirchner T, Kalden JR, Herrmann M.

Impaired uptake of apoptotic cells into tingible body

macrophages in germinal centers of patients with systemic

lupus erythematosus. Arthritis Rheum 2002;46:191–201.

[117] Herrmann M, Voll RE, Kalden JR. Etiopathogenesis of

systemic lupus erythematosus. Immunol Today

2000;21:424–426.

[118] Munoz LE, Gaipl US, Franz S, Sheriff A, Voll RE, Kalden

JR, Herrmann M. SLE—a disease of clearance deficiency?

Rheumatology 2005;44: 1101–1107.

[119] Kolb H, Kolb-Bachofen V. NO in autoimmune disease:

Cytotoxic or regulatory mediator? Immunol Today

1998;1912:556–561.

[120] Razavi HM, Hamilton JA, Feng Q. Modulation of apoptosis

by nitric oxide: Implications in myocardial ischemia and heart

failure. Pharmacol Ther 2005;106:147–162.

[121] Belmont HM, Levartovsky D, Goel A, Amin A, Giorno R,

Rediske J, Skovron ML, Abramson SB. Increased nitric oxide

production accompanied by the upregulation of inducible

nitric oxide synthase in vascular endothelium from patients

with systemic lupus erythematosus. Arthritis Rheum

1997;40:1810–1816.

[122] Serrano NC, Paez C, Correa PA, Anaya JM. Endothelial

nitric oxide synthase gene polymorphism is associated with

systemic lupus erythematosus. J Rheumatol 2004;31:

2163–2168.

[123] Weinberg JB, Ganger DL, Pisetzky DS, Seldin MF,

Misukonis MA, Mason SN, Pippen Am, Ruiz P, Wood ER,

Gilkeson GS. The role of nitric oxide in the pathogenesis of

spontaneous murine autoimmune disease: Increased nitric

oxide production and nitric oxide synthase in MRL/lpr mice,

and reduction of spontaneous glomerulonephritis and

arthritis by orally administered NG-monomethyl-L-arginine.

J Exp Med 1994;179:651–660.

[124] Suschek CV, Krischel V, Bruch-Gerharz D, Berendji D,

Krutmann J, Kroncke KD, Kolb-Bachofen. Nitric oxide fully

protects against UVA-induced apoptosis in tight correlation

with Bcl-2 up-regulation. J Biol Chem 1999;274:6130–6137.

[125] Suschek CV, Schroeder P, Aust O, Sies H, Mahotka C,

Horstjann M, Ganser H, Murtz M, Hering P, Schnorr O,

Kroncke KD, Kolb-Bachofen V. The presence of nitrite

during UVA irradiation protects from apoptosis. FASEB J

2003;17:2342–2344.

A. Kuhn & S. Beissert528

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/06/

14Fo

r pe

rson

al u

se o

nly.

Page 11: Photosensitivity in lupus erythematosus

[126] Weller R, Schwentker A, Billiar TR, Vodovotz Y. Autologous

nitric oxide protects mouse and human keratinocytes from

ultraviolet B radiation-induced apoptosis. Am J Physiol Cell

Physiol 2003;284:C1140–C1148.

[127] Ormerod AD, Copeland P, Hay I, Husian A, Ewen SW. The

inflammatory and cytotoxic effects of a nitric oxide releasing

cream in normal skin. J Invest Dermatol 1999;113:392–397.

[128] Herzinger T, Plewig G, Rocken M. Use of sunscreen to

protect against ultraviolet lupus erythematosus. Arthritis

Rheum 2004;50:3045–3046.

[129] Kuhn A, Sonntag M, Boyer F, Lehmann P, Dupuy P.

Evaluation of photoprotective effects of a broadspectrum

highly protective sunscreen in photoinduced cutaneous lupus

erythematosus. Ann Dermatol Venereol 2002;129:

1S726–1S727.

[130] Stege H, Budde MA, Grether-Beck, Kruttman J.

Evaluation of the capacity of sunscreens to photoprotect

lupus erythematosus patients by employing the photoprovo-

cation test. Photodermatol Photoimmunol Photomed

2000;16:256–259.

Photosensitivity in lupus erythematosus 529

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

cMas

ter

Uni

vers

ity o

n 11

/06/

14Fo

r pe

rson

al u

se o

nly.