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Clinic Rev Allerg Immunol (2007) 33:85106

DOI 10.1007/s12016-007-0031-x

Pathophysiology of Cutaneous Lupus Erythematosus


Julie H. Lin & Jan P. Dutz & Richard D. Sontheimer &
Victoria P. Werth

Published online: 15 August 2007


# Humana Press Inc. 2007

Abstract Cutaneous lupus erythematosus (LE; syn LEspecific skin disease) is an autoimmune disease with
well-defined skin manifestations often accentuated in a
photodistribution and frequently associated with specific
autoantibodies. These clinical observations have led to
numerous laboratory studies related to the role of ultraviolet
light, as well as studies of the cascade of immunologic
events involved in the pathogenesis of cutaneous LE. We
discuss the epidemiologic, clinical, and laboratory findings
of cutaneous LE, including the classification of disease
subsets. We review the evidence for abnormal photoreactivity in LE with an overview of the cellular, molecular,
and genetic factors that may underlie this abnormality. As

there is yet no convincing animal model of cutaneous LE,


many studies remain descriptive in nature. To arrive at an
understanding of the potential mechanisms underlying the
development of cutaneous lupus, we discuss the role of
ultraviolet light-mediated induction of apoptosis, antigen
presentation, genetic factors, and mediators of inflammation. In addition, we consider the role and importance of
humoral and cellular factors, synthesizing the current
understanding of the pathophysiology of cutaneous lupus.
Keywords Cutaneous lupus erythematosus .
Photosensitivity . Autoimmune disease . Apoptosis

Introduction
Some sections in this review have been modified with the publishers
permission from Dubois Lupus Erythematosus, chapter 28:
Pathomechanisms of Cutaneous Lupus Erythematosus, 7th ed. Daniel
J. Wallace, Bevra H Hahn, eds. Lippincott Williams & Wilkins,
Philadelphia, 2006.
J. H. Lin : V. P. Werth (*)
Department of Dermatology, University of Pennsylvania,
2 Rhoads Pavilion, 3600 Spruce Street,
Philadelphia, PA 19104, USA
e-mail: werth@mail.med.upenn.edu
J. P. Dutz
Department of Dermatology and Skin Sciences,
University of British Columbia,
Vancouver, British Columbia, Canada
R. D. Sontheimer
Department of Dermatology,
University of Oklahoma Health Sciences Center,
Oklahoma City, OK, USA
V. P. Werth
Department of Dermatology, Philadelphia V.A. Hospital,
Philadelphia, PA, USA

Three of the 11 American College of Rheumatology (ACR)


classification criteria for systemic lupus erythematosus
(SLE; malar rash, discoid LE [DLE], and photosensitivity)
relate to a photodistribution, suggesting an important role of
ultraviolet (UV) light in the pathogenesis of LE [1]. In this
review, we will discuss advances in the epidemiologic and
clinical understanding of cutaneous LE. The complex
inflammatory cascade involved with the pathogenesis of
cutaneous LE will be reviewed, including the role of UV
light, apoptosis, genetics, antigen presentation, complement, and mediators of inflammation. In addition, we will
consider the role and importance of humoral and cellular
factors.

Epidemiology
Cutaneous LE (CLE) can occur in the presence or absence
of systemic manifestations of LE. SLE occurs in 1748/

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100,000 people. Among patients with SLE, skin disease is


the second most frequent clinical manifestation. The
prevalence of CLE is dependent on the population studied.
Studies of dermatology clinic-based populations conclude
that there are two to three more times the numbers of
patients with CLE relative to SLE [2]. In a rheumatology
population, it has been reported that there is one case of
CLE for every seven cases of SLE [3]. One populationbased study suggested the incidence of definite SLE and
DLE was quite similar, with 1.8 cases/100,000 for each [4].
In this same population, there was a prevalence of 40
patients/100,000 with definite SLE relative to 27.6/100,000
with DLE. Of interest, there were equal numbers of men
and women with DLE relative to the female-predominance
seen with SLE [4]. Even with a specific subset such as
SCLE, where the genetics are quite distinct, the overall
prevalence of SCLE skin lesions in cutaneous LE ranges
from 3 up to 20%, indicating the tremendous variation in
prevalence in differing populations of patients [5, 6].
Regardless of this variability in estimated prevalence rates,
CLE is not infrequently associated with occupational
disability [2].

Diagnosis
Classification and Clinical Findings
Classification
Dr. James Gilliam originally divided LE-specific skin
lesions into three broad categories based on clinical
morphology and average lesional life span [7]. These
include chronic CLE (CCLE), subacute CLE (SCLE), and
acute CLE (ACLE; Table 1). In addition, there are a
number of distinctive forms of LE-nonspecific skin disease
that will not be addressed in this review but are included in
Table 1 for completeness. Examples include cutaneous
small vessel vasculitis presenting as dependent palpable
purpura or urticarial vasculitic lesions, livedo reticularis,
and bullous SLE. LE nonspecific skin lesions are often
seen in the context of active SLE.
The 1982 ACR classification criteria are currently being
reevaluated in the context of a trial that is also including
dermatologic control groups such as rosacea, eczema,
psoriasis, and amyopathic dermatomyositis [8, 9]. The
original criteria assign too much weight to the skin as one
expression of a multiorgan disease. Consequently, patients
having a positive antinuclear antibodies (ANA) and nothing
clinically other than the mucocutaneous manifestations of
LE can be classified as having SLE. With the need to select
more uniform populations for studies in CLE and SLE, it
will be important to carefully reevaluate these criteria.

Clinic Rev Allerg Immunol (2007) 33:85106

Chronic Cutaneous LE. CCLE is the largest subset and


includes a number of entities that can occur as isolated skin
disease or in association with SLE. DLE is the most
common subtype of CCLE. DLE can occur as a localized
process, commonly with lesions above the neck in a
photoexposed area, or as a generalized process with lesions
above and below the neck. Active lesions are typically
erythematous macules, papules, or plaques that typically
have adherent, keratotic scale, and follicular plugging.
Lesions typically resolve with atrophic scarring and
dyspigmentation (peripheral hyperpigmentation and central
hypopigmentation). A biopsy is often needed to make the
diagnosis as, clinically, there are several other diseases that
are considered in the differential diagnosis.
Subacute Cutaneous LE. SCLE was first described as a
distinct subset in 1979 [10]. Erythematous papulosquamous, psoriasiform plaques, or annular-polycyclic plaques
are the most frequent findings. Patients with SCLE are
photosensitive, with lesions commonly on the extensor
arms, shoulders, V of the neck, back, and less commonly,
the face. SCLE typically resolves without scarring,
although dyspigmentation can occur. Approximately 20%
of SCLE patients have been reported to develop otherwise
typical DLE or acute cutaneous LE skin lesions at some
point in their disease course. It has been suggested that the
appearance of localized acute cutaneous LE (i.e., malar
rash) in a patient with SCLE is a risk factor for the
development of clinically significant SLE [11].
Acute cutaneous LE. ACLE presents clinically as a
nonscarring malar erythema (butterfly rash), but other
manifestations include widespread erythema in a photodistribution and bullous or TEN-like ACLE skin lesions.
The malar erythema can be either patch or plaque-like, and
there is a tendency to spare the nasolabial folds.
Photosensitivity
The definition of photosensitivity in LE patients is
problematic. The ACR photosensitivity criterion for the
classification of SLE is defined as follows: A skin rash as
a result of unusual reaction to sunlight, by patient history or
physician observation. This is an extremely broad definition that can be fulfilled by a number of unrelated
dermatoses (e.g., polymorphous light eruption, photoallergic contact dermatitis, acne rosacea, and dermatomyositis).
In addition, the ACR definition of photosensitivity does not
address the fact that exposure to UV light can precipitate or
exacerbate the systemic manifestations of LE.
Skin lesions are common in SLE and are found in up to
90% of patients [12]. Lupus-specific cutaneous findings
such as malar rash (ACLE) and DLE (the most common
type of CCLE) were found in 64 and 31% of patients in a
large cohort of SLE patients [12], respectively. Anti Ro/

Clinic Rev Allerg Immunol (2007) 33:85106


Table 1 The classification of LE skin lesions modified from Gilliam
[237]
Classification
I. LE-specific skin disease (syn. cutaneous LE)
A. Chronic cutaneous LE (CCLE)
1. Classic discoid LE
a. Localized CLE
b. Generalized DLE
2. Hypertrophic/verrucous DLE
3. Lupus profundus/lupus panniculitis
4. Mucosal DLE
a. Oral DLE
b. Conjunctival DLE
5. LE tumidus (papulomucinous LE)
6. Chilblain LE
7. Lichenoid DLE (LE/lichen planus overlap)
B. Subacute cutaneous LE
1. Annular SCLE
2. Papulosqamous/psoriasiform
3. Less common variants (pityriasiform, erythrodermic,
exanthematous, vesiculo-pustular, toxic epidermal
necrolysis-like [TEN]-like, erythema multiformelike [Rowells syndrome overlap], pityriasis rosealike, acral annular, and poikilodermatous)
C. Acute cutaneous LE
1. Localized (malar rash; butterfly rash)
2. Generalized acute cutaneous LE ( SLE rash )
3. TEN-like
II. LE-nonspecific skin disease
A. Cutaneous vascular disease
1. Vasculitis
a. Leukocytoclastic vasculitis
i. Palpable purpura
ii. Urticarial vasculitis
2. Vasculopathy
a. Degos disease like lesions
b. Secondary atrophie blanche
3. Periungual telangiectasia
4. Livedo reticularis
5. Thrombophlebitis
6. Raynauds phenomenon
7. Erythromelalgia
B. Nonscarring alopecia
1. Lupus hair
2. Telogen effluvium
3. Alopecia areata
C. Sclerodactyly
D. Rheumatoid nodules
E. Calcinosis cutis
F. LE-nonspecific bullous lesions
1. Bullous SLE
G. Urticaria
H. Papulonodular mucinosis
I. Cutis laxa/anetoderma
J. Acanthosis nigricans
K. Erythema multiforme
L. Leg ulcers
M. Lichen planus

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SSA antibodies and exquisite photosensitivity is clearly


associated with SCLE [13]. Skin disease is the first
symptom of disease in 2328% of patients with SLE [14].
There is a clear relationship between sun exposure and the
frequent localization of cutaneous LE on photo-exposed
skin. Cazenave, in the original 1851 description of LE,
stated that outdoor workers were predisposed [15]. Isolated
case reports suggested that CLE lesions could be induced
by light [16].
In 1965, Epstein used a repeated light exposure
technique to demonstrate that UV radiation could induce
skin lesions in patients with LE [17]. This observation was
confirmed quickly by two other groups [18, 19]. Lesion
induction was often delayed by up to 2 weeks, and patients
with either systemic lupus or cutaneous lupus were shown
to develop more prolonged skin redness than normal
controls [20, 21]. Recent studies have confirmed that
clinical aberrant photosensitivity manifested as prolonged
and delayed erythema is present in almost all patients with
cutaneous or systemic disease. However, the minimal doses
of UV light required to induce erythema in standard testing
protocols appears to be within the normal range of the
general population [22].
Laboratory Findings and Pathology
Laboratory Findings
A hallmark of this autoimmune disorder is the production
of autoantibodies that have varying levels of specificity.
These are commonly detected in the serum. ANA are not
specific to cutaneous LE or SLE itself. Up to 6.5% of the
general population can have a positive ANA [23], and the
incidence of elevated ANA titers increase with age [24],
infection [25], medications [26, 27], and other autoimmune
diseases. Other autoantibodies associated with cutaneous
LE include anti-dsDNA, anti-SSA/Ro, and anti-SSB/La.
The majority of CCLE patients do not have anti-Ro/SSA
responses detected by standard immunodiffusion techniques.
However, when sensitive ELISA techniques were used, 11
out of 15 CCLE patients were found to have low-level IgG
anti-Ro/SSA antibodies [21].
Immunopathology
Autoantibodies are often detected in the skin of patients
with CLE. Immunofluorescence studies of cutaneous LE
lesions show lesional deposition of immunoglobulins in the
skin (Fig. 1). In 8090% of CCLE or ACLE and in 5060%
of SCLE, a continuous band of immunoglobulins and
complement components are deposited in a granular array
along the dermalepidermal junction [28]. These complexes
have been localized on the upper dermal collagen fibers and

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Clinic Rev Allerg Immunol (2007) 33:85106

vessels and dermal appendages. Inflammatory cells in the


infiltrate of established cutaneous LE lesions are predominantly CD3 positive cells with CD4 positive cells present
in higher numbers than CD8 cells (reviewed in [28]).
Clinical Activity of Skin Disease and Outcome Measures
Fig. 1 Immunopathology of subacute cutaneous lupus. Direct
immunofluorescence analysis for the presence of IgG reveals a
dustlike distribution of IgG deposits in the suprabasilar keratinocytes
(arrowheads mark specific IgG dust deposits). There is also IgG
deposition in the basement membrane zone

along the lamina densa of the epidermal basement


membrane zone [29]. As these deposits also are found in
clinically normal skin of patients with SLE, their role in the
local induction of cutaneous tissue injury is still unclear
[30]. Further, the specificities of these skin basement
membrane-deposited antibodies have not been defined
although colocalization of the lupus band deposits with
collagen VII has been determined using confocal laser
scanning microscopy [31]. In addition, epidermal IgG
deposits, detected with some regularity in SCLE, are found
rarely in CCLE, and immunoglobulin deposition is limited
to the dermalepidermal junction (DEJ) [32].
The pathology of cutaneous lupus is one of a lichenoid
tissue reaction in which the basal keratinocytes are the
primary focus of injury [33] (Fig. 2). This injury is
associated with keratinocyte hyperproliferation, with normal early differentiation and premature terminal differentiation [34]. The inflammatory-cell infiltrate is characterized
by mononuclear cells at the DEJ, as well as around blood

Fig. 2 Photomicrograph of a biopsy of subacute cutaneous lupus.


There is disarray in the maturation pattern of the keratinocytes. There
is evidence of hyperkeratosis (increase the thickness of the horny-cell
layer). The basement membrane zone is disorganized with a
mononuclear cell infiltrate and thickening of the basement membrane
zone. There is a dermal mononuclear cell infiltrate that is predominantly perivascular. The mononuclear cells are predominantly CD4 T
cells, many showing an activation phenotype and macrophages

An outcome measure to evaluate cutaneous lupus activity


and damage has recently been validated [35, 36]. The
cutaneous lupus activity skin index (CLASI) is a useful
clinical instrument to separately follow activity and damage
during therapy of cutaneous LE [36]. This tool is currently
being used in a number of clinical trials and should allow
evaluation and comparison of new therapies that may
improve cutaneous LE.

Etiology and Pathogenesis


UV Light and Lupus
UV light is commonly divided into germicidal UV light
(UVC), midrange UV light or sunburn UV light (UVB),
and long-wave UV light (UVA), also termed near UV or
black light (Fig. 3). This distinction is important, as the
differing wavelengths have varying biologic effects. Although UVC has been used in many in vitro studies of the
cellular response to UV irradiation, this spectrum of UV
light is completely blocked by the earths atmosphere and is
of dubious pathophysiological relevance to humans on the
earths surface. Early investigators defined an action
spectrum in the UVB range (290320 nm) for the cutaneous
forms of LE [1719, 37, 38]. More recent studies have
demonstrated that UVA (320400 nm) also can contribute
to the induction of skin lesions. The UVA spectrum has
been subdivided into UVAII (320340 nm) and UVAI
(340400 nm), as these two different wavelength spectra
are associated with different biological effects.
Repeated single patient observations indicate that sunlight may precipitate disease de novo or aggravate existing
disease. Phototherapy for incorrectly presumed psoriasis
(using UVB) has led to aggravation of the lupus lesions [39].
Tanning-bed use (a predominantly UVA source) also has
been reported to either induce or exacerbate SLE [40, 41].
Lehmann et al. [42] performed extensive photoprovocation studies. They were able to induce lesions with UV light
in 63% of patients with SCLE, in 72% of tumid LE, in 60%
of SLE cases, and 45% of CCLE cases [43]. Of those with
UV induced lesions, 53% were induced by a combination
of UVB and UVA, 34% by UVA alone, and 42% by UVB
alone. Abnormally prolonged erythema was also noted in
SLE patients after exposure to UVA [44]. Although UVAinduced erythema in normal skin requires 1,000 times more

Clinic Rev Allerg Immunol (2007) 33:85106

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Fig. 3 The spectrum of ultraviolet (UV) light irradiation by


wavelength. Ultraviolet light is
commonly divided into germicidal UV light (UVC), midrange
UV light or sunburn light
(UVB), and long-wave UV light
(UVA) also termed near UV or
black light. Both UVB and UVA
can induce skin lesions in photosensitive lupus erythematosus.
UVA-1 is light limited to the
longer wavelength spectrum of
UVA and has been used therapeutically in systemic lupus
erythematosus

energy than UVB, daily exposure to UVA energy is much


greater than UVB energy, and at the level of the dermal
capillaries, the UVA effect, as a result of greater skin
penetrance, is much stronger that UVB [38] (Fig. 4). Thus,
UV light of varying wavelengths can induce abnormal skin
responses in lupus patients and can induce cutaneous

lesions. The clinical observations suggestive of UV light


as a role in the pathogenesis of SLE and CLE have been
supported by mechanistic studies detailed below.
It often is stated that sunlight cannot only aggravate
cutaneous LE but can potentiate systemic features of
disease. Up to 73% of patients with SLE report photosensitivity [45]. However, phototesting with standardized
protocols correlates poorly with patient-reported photosensitivity [46]. This may be because of the delayed nature of
the phenomena observed on phototesting [43]. Patients
report that several disease symptoms (including weakness,
fatigue, and joint pain) are increased by sun exposure [45].
Two recent studies showed that although cutaneous
manifestations are more common in the summer months,
systemic disease activity is increased in the 36 months
after maximal potential sun exposure. This has led these
authors to suggest that summer UV light exposure may lead
to systemic flares several months later [47, 48]. Interestingly, a pale, sun-reactive skin type was independently
associated with increased risk (OR=2.3) of developing SLE
in a Swedish case-control study [49].
Role of UV in CLE

Fig. 4 Photomicrograph of normal skin depicting the depth of


penetration of the various forms of ultraviolet radiation (UVR). The
skin is formed by an epidermal compartment that includes the stratum
corneum (horny layer), the epidermis proper, and a basement
membrane zone. Keratinocytes (skin cells), melanocytes (pigment
cells), and Langerhans cells (dendritic cells) are found in this
compartment. The dermal compartment includes the vasculature of
the skin and connective tissue. Penetration of UVR is directly
proportional to the wavelength of the radiation. UVB is absorbed
primarily in the epidermis. UVA penetrates the dermis and can affect
the skin vasculature. UVA1 has the potential to penetrate the skin
more deeply that UVA of shorter wavelength

Biologic Response To UV Light


UV light has multiple effects on living tissue. Potential
molecular targets of UV light include not only DNA but
RNA, proteins, and lipids. The biologic effects of UV light
on the skin are summarized (Table 2). In addition to
alteration of DNA, cytoskeletal reorganization was noted in
keratinocytes after UV irradiation [50]. An early study by
LeFeber [51] revealed that UV light can induce the binding

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Table 2 Biologic effects of
ultraviolet radiation

UVA Ultraviolet A, UVB ultraviolet B

Clinic Rev Allerg Immunol (2007) 33:85106


Characteristic

UVB

UVA

Absorption by molecules
Direct DNA damage
Free-radical production
Depth of penetration
Epidermal effects

DNA, amino acids, melanin, urocanoic acid


Increased
Minimal
Epidermal
Stratum corneum thickening, intermediate and delayed
apoptosis, keratinocyte cytokine transcription, and release
Inactivation, emigration

Melanin
Minimal
Increased
Dermal
Immediate
apoptosis
Minimal

Langerhans cell effects

of antibodies to selected nuclear antigens on cultured


human keratinocytes. The specificity of these antibodies
was not defined, but it is now known that they are
commonly directed against Ro/SSA, La/SSB, ribonucleoprotein, and Smith (Sm) antigens and are the antibodies
associated with LE and photosensitivity. Norris later noted
increased antibody binding to keratinocytes (KCs) after in
vivo UV irradiation of human skin [50]. This was
confirmed independently by Golan [52], who observed
binding of anti-Ro/SSA positive sera to cultured KCs.
These results could be explained by UV-induced translocation of antigens to the cell surface with or without the death
of the cell or by other alterations in the antigens allowing
the binding of autoantibodies taken up by the living cell
[52]. In 1994, Casciola-Rosen et al. [53] demonstrated that
when KCs grown in cell culture are irradiated with UVB,
they actively cleave their DNA and die by a process termed
apoptosis. During this process, the antigens recognized by
autoantibodies such as Ro/SSA, and calreticulin are
concentrated in structures termed blebs or apoptotic bodies
found at the cell surface. Larger blebs arise from the
nucleus and harbor Ro/SSA, La/SSB, and other nuclear
material. These investigators and others have proposed that
these bleb-associated antigens may then be phagocytosed,
packaged, and presented to lymphocytes thereby stimulating autoimmune responses [54, 55].
UV Light Causes KC Apoptosis
Apoptosis and necrosis are the two major mechanisms of
cell death. Apoptosis is an ordered means of noninflammatory cell removal in which a central biochemical program
initiates the dismantling of cells by nuclear fragmentation,
formation of an apoptotic envelope, and shrinking of the
cell into fragments, leading to phagocytosis by parenchymal cells as well as phagocytes [5658].
KC Apoptosis And UV Light
KCs die by programmed cell death as part of their normal
program of differentiation [5961]. This occurs normally in
the granular cell layer of the epidermis at the interface with
the stratum corneum. The molecular machinery controlling

this programmed cell death in KCs is complex and still


poorly understood [62]. Basilar KCs have been found to be
relatively resistant to apoptosis induced by a variety of
stimuli [63], whereas it has long been known that suprabasilar KCs are more vunerable to UV-induced apoptotic
death; such cells were called sunburn cells by morphologists [64]. UV light now is known to induce apoptosis by
multiple mechanisms. Long-wave UV light (UVA1; 340 to
400 nm) can induce immediate apoptotic death through
singlet-oxygen damage to mitochondrial membranes [65].
UVB can induce direct, ligand-independent activation of
membrane death receptors such as Fas as well as FasL (Fas
ligand) upregulation and subsequent FasFasL binding [66,
67]. UVB also sensitizes KCs to TRAIL (TNF related
apoptosis-inducing ligand-CD253)-induced apoptosis by
downregulating the level of TRAIL decoy receptors [68].
Tumor necrosis factor- (TNF-) release and consequent
ligation of the TNF receptor p55 (TNFR1) also has been
shown to be an important mediator of UVB-induced KC
apoptosis [69, 70]. UVB can also induce KC apoptosis
secondary to DNA damage [71] or the mitochondrial
pathway [65]. Once the signal for apoptosis is triggered,
specific enzymes within the cell begin the dismantling
process. These enzymes are collectively called caspases, an
acronym for cysteine asparate proteinases [72]. These
enzymes are known to be important in UV-induced cell
death because specific inhibitors of these enzymes prevent
the UV-induced death of KCs [73].
Apoptosis In CLE
The potential importance of apoptosis in the pathogenesis
of cutaneous lupus is underscored by a number of
observations. Using terminal deoxynucleotidyl transferasemediated UTP nick-end labeling (TUNEL) staining to
detect nuclei with DNA damage, Norris et al. [63]
demonstrated the presence of an increased number of
apoptotic KCs in the basal zone of CCLE lesions and in
the suprabasal zone of SCLE lesions. Kuhn et al. [74]
confirmed ex vivo not only that apoptotic cells accumulate
in the epidermis of patients with cutaneous LE after UV
irradiation, but that the number of apoptotic cells were
higher than in normal healthy controls and patients with

Clinic Rev Allerg Immunol (2007) 33:85106

polymorphous light eruption, implying that the accumulation of apoptotic cells were a result of impaired or delayed
clearance. An increase in the number of apoptotic cells in
lesional skin from patients with cutaneous LE has been
confirmed and associates with increased p53 protein
expression, as determined by immunohistochemistry [75,
76]. The nuclear phosphoprotein p53 is a tumor suppressor
that is upregulated in response to UV-induced DNA
damage [77] and in response to the cytokines TNF- [64]
and interferon- (IFN-) [78]. Upregulation of p53 in
suprabasilar KCs can initiate cell death by apoptosis [79].
The increased number of apoptotic cells therefore could be
a result of an increased rate of apoptosis induction mediated
directly by UV light or as a consequence of UV-induced
cytokine release. Apoptosis also can be induced by cellular
cytotoxic mechanisms. Cytotoxic T lymphocytes (CTL)
and natural killer (NK) cells can induce apoptosis through
multiple mechanisms (reviewed in [80]), including the
release of perforin and granzymes [78], cytokine release
[IFN-, tumor necrosis factor (TNF)-, interleukin (IL)-1]
[81], and triggering of Fas by FasL [82]. The presence of
leukocytes in proximity to the apoptotic cells [63] and the
presence of FasL positive macrophages in proximity to
apoptotic cells in lesional hair follicles [83] suggest a role
for such cellular apoptotic mechanisms in established
lesions.
There is evidence that the biochemical processes of
apoptosis generate novel antigens that are uniquely targeted
by autoantibodies. Casciola-Rosen et al. [84] have shown
that the caspases activated during apoptosis cleave intracellular proteins into fragments that are bound by autoantibodies from some patients with LE. Further, proteins
specifically phosphorylated by stress-induced apoptosis
are targeted by antibodies from LE patient sera [85, 86].
From these observations, it has been inferred that the
process of apoptosis is important in the initiation of
autoimmune responses. Recently, it has been shown that
patients with LE skin disease have autoantibodies that
preferentially recognize apoptotic-modified U1-70-kd RNP
antigen when compared to patients without skin disease
[87]. This provides further in vivo evidence that immune
recognition of modified forms of self-antigen occurs in
cutaneous LE and suggests that this immune recognition
and the processing of apoptotic-derived antigens may
participate in the pathogenesis of the disease.
Granzyme B, a serine protease found principally in the
cytotoxic granules of CTL and NK cells, also can induce
cell death by apoptosis in susceptible target cells. Granzyme B can cleave cellular proteins into unique fragments
not detected in other forms of apoptosis. Such cleavage
products, specific for cytotoxic-granule induced death, also
are bound by antibodies present in LE sera [88]. Interestingly, expression of granzyme B has been detected in KCs,

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suggesting that these molecules may participate in cutaneous defense mechanisms and perhaps in KC death [89]. In
this case, specific correlation of autoantibodies to granzyme
B-generated epitopes with cutaneous LE has not yet been
made. Novel autoantigens can be generated by apoptosis
that are either stress-induced (UV light, viral infection, or
other trigger) or secondary to cellular immune mechanisms.
The generation and concentration of such neoantigens
could pose a challenge to self-tolerance [90]. Whether the
increased KC apoptosis noted in cutaneous LE leads
directly to the formation of autoantibodies specific to
apoptosis-derived byproducts is still speculation.
Predisposing Factors in CLE
Abnormalities of UV-Induced KC Apoptosis
as a Predisposing Factor in CLE and Possible Defects
in Clearance of Apoptotic Cells
Although detection of an increased number of apoptotic
cells in LE epidermis may reflect an increase in apoptosis, a
decrease in the rate of clearance of apoptotic debris could
also lead to the observed increase in apoptotic KC number
[74, 76]. Phagocytosis by macrophages or parenchymal
cells is the final event in the clearing of cells undergoing
apoptosis [58, 91]. A number of observations suggest that
clearance of apoptotic debris may be impaired in LE.
Systemic autoimmunity has been noted in mice deficient
for molecules potentially involved in the clearance of
apoptotic cells including serum amyloid P (SAP), c-Mer,
C4, IgM, or C1q (reviewed in [92]). SAP is a member of a
family of proteins termed pentraxins that bind to apoptotic
cells and then interact directly with phagocyte receptors or
with C1q. C1q and a related protein, mannose binding
lectin (MBL), function as collectins, which are proteins
with globular lectin like heads and collagen-like tails that
bind to and flag late-apoptotic cells for disposal by
phagocytosis. Interestingly, the surface blebs of apoptotic
KCs bind C1q, an early component of the complement
cascade [93]. The C1q-binding protein that was initially
identified to be present in apoptotic plasma membrane
blebs is calreticulin [53], and autoantibodies to calreticulin
can interfere with this binding [94]. The binding of C1q to
apoptotic cells has been postulated to facilitate the
clearance of these cells by macrophages that express a
C1q cell surface receptor [95].
A potential role for C1q in the clearance of apoptotic
debris and in the genesis of cutaneous LE is suggested by
two observations. First, patients with complete congenital
C1q deficiency frequently develop LE-like photosensitive
eruptions at an early stage [96]. Second, mice with C1q
deficiency develop an SLE-like disease associated with an
accumulation of apoptotic cells in the kidney [97].

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However, the clearance of UV-induced sunburn cells


(apoptotic KCs) was not observed to be altered in C1qdeficient mice [98].
Moreover, a recent study in humans has demonstrated
that the clearance of apoptotic lymphocytes by macrophages is indeed impaired in some patients with SLE [99],
and impaired uptake of apoptotic cells by macrophages has
been noted in germinal centers of patients [100]. Whereas a
number of cellular signals and receptors for the phagocytosis
of apoptotic debris have been identified, the magnitude of
a clearance defect in patients with cutaneous LE remains
unclear. Further, it is unknown if impaired clearance is
secondary to a defect in the recognition and the binding of
apoptotic particles or in macrophage phagocytosis.
It is also unknown if this defect extends to the phagocytosis of other cell types such as KCs. Sunburn cells
normally are cleared rapidly and disappear within 2448 h
in murine skin [101, 102]. Whether this is the result of
shedding or of phagocytosis by either neighboring KCs or
macrophages has not yet been clarified.
Macrophages are the organisms primary remover of
cellular debris. Macrophages that have ingested apoptotic
cells in vitro secrete factors such as transforming growth
factor- (TGF-) and prostaglandin E2 (PGE2). These
factors can inhibit the release of proinflammatory cytokines
such as TNF- by neighboring cells. In addition to removal
of cellular debris, macrophages may therefore actively
promote tolerance and inhibit proinflammatory cytokine
production [103].
Acquisition of apoptotic cell material by immature
dendritic cells (DCs), similar to macrophages, is enhanced
by C1q and MBL and promotes the production of
immunomodulatory cytokines such as IL-10 [104]. Mature
DCs, in contrast, are professional antigen-presenting cells
present in the skin that have been shown both to acquire
antigen from apoptotic cells and then to prime naive T cells
in an antigen-specific fashion [105]. Thus, depending on
the nature of the phagocytic cell (macrophage and immature
DCs versus mature DCs), with which the apoptotic cell
interacts, autoimmunity or tolerance may ensue. High
numbers of apoptotic cells have been shown to act as a
trigger for local DC maturation and to promote antigen
presentation to class I and class II MHC-restricted T cells in
a murine system [106]. Necrosis is a cell death process
characterized by the rapid depletion of ATP stores and
subsequent loss of cell membrane integrity that can also
result from UV light injury. For example, high doses on
UVB preferentially induce KC necrosis [107]. Necrotic
cells release potent proinflammatory mediators such as high
mobility group 1 protein and uric acid [108, 109]. The
incidence of necrotic cells after UV insult has not been
accurately determined. An abundance of apoptotic cells and
possibly necrotic cells, either from excessive amount of

Clinic Rev Allerg Immunol (2007) 33:85106

death induction by UV or other mechanisms or from a


defect in clearance, could permit tolerance to self-antigens
to be broken. The potential role of apoptotic mechanisms in
the initiation and perpetuation of photosensitive LE is
summarized in Fig. 5.
Immunogenetics
Clearance of necrotic or apoptotic cells may be defective in
CLE, leading to the generation of autoantigens. Individuals
with CLE may also have a genetic predisposition toward
specific autoantibody production. There is a strong association between SCLE, anti-Ro/SSA antibodies, and the
HLA-B8, DR-3, DRw52 phenotypes [110]. Associations
between Ro antibody responses and DQA1 alleles, DQ2
alleles, and HLA-DR3 in different populations suggest that
specific MHC class II molecules participate in the anti-Ro
response [111113].
There is also diversification of the Ro/SSA and La/SSB
antibody response linked to specific HLA class II phenotypes [114]. This would imply the participation of Ro/SSA
antigen-specific T cells in the generation of the Ro/SSA
antibody response. Although 52 kd of Ro/SSA-specific T
cells have been described in the salivary glands of Sjgrens
patients [115], no antigen-specific T cells have been
described in cutaneous LE. Murine T-cell epitopes have
been defined in a number of lupus autoantigen systems
including the La/SSB autoantigen [116] and the Ro/SSA
antigen [117]. The specificity and role of similar autoantigen-specific T cells in humans is an area of ongoing
investigation.
The polymorphic variant in the TNF- promoter in
humans (TNF--308A) is associated with increased production of TNF- [118]. The presence of this promoter is
associated with an increased risk of SLE in African
Americans [118]. It is an independent susceptibility factor
for systemic lupus in Dutch Caucasians [119]. TNF-
production in KCs shows interindividual variability, and it
has been proposed that this variability may underlie a
predisposition to cutaneous lupus [120, 121]. Recently,this
concept has found support in that the TNF--308A promoter
polymorphismassociatedwithincreasedTNF-productionhas
been shown to be highly associated with photosensitive SCLE
[122] and confirmed in a separate population [123] as well
as the related cutaneous neonatal LE [124].
Deficiency in C1q, as mentioned above, is thought to be
a contributing factor to the pathogenesis. C1q deficiency
confers high risk for development of SLE [96, 125128,
129]. There is also an unconfirmed association between
SCLE and a single nucleotide polymorphism (SNP) in the
C1QA gene (C1qA276[G> A]). This SNP association was
found to correlate with lower levels of serum C1q. Studies
have suggested that this SNP appears to be associated with

Clinic Rev Allerg Immunol (2007) 33:85106

93

Fig. 5 Potential role of keratinocyte apoptosis in the pathogenesis of


photosensitive lupus erythematosus. Apoptosis is an ordered means of
cell death. Apoptosis can be initiated in keratinocytes by ultraviolet
(UV) radiation (UVB as well as UVA), viruses, cytokines (TNF),
growth-factor withdrawal, differentiation, and cytotoxic cellular
assault. Apoptosis leads to small bleb formation in which Ro antigen
and calreticulin are concentrated. Larger apoptotic bodies contain

other potential autoantigens including Ro antigen (60 kd), La,


nucleosomes, and 70-kd RNP antigen. Apoptosis leads to the exposure
of phosphtidylserine on the cell surface and to the binding of C1q. The
presence of apoptotic cells in a proinflammatory environment may
lead to uptake and processing by antigen-presenting cells leading to
the priming and boosting of T cells and B cells to self-antigen

a functional abnormality of C1q expression, as its presence


correlates inversely with serum levels of C1q antigenic
protein in both SCLE patients and normal controls. The
mechanism by which this phenotypic change is associated
with the translationally silent (synonymous; C1qA276[G> A])
genetic variation is currently unknown [130].
Complement activation is also felt to contribute to
disease pathogenesis. The in vivo function of DAF
(decay-accelerating factor, CD55), a glycosylphosphatidylinositol-anchored membrane protein that restricts complement activation on autologous cells, has been studied in a
knockout mouse model. Miwa et al. [131] found that the
deletion of DAF exacerbates autoimmune disease development in MRL/lpr mice, one model for human SLE.
Histology and immunostaining demonstrated an inflammatory infiltrate and focal C3 deposition in early skin lesions,
mostly along the dermalepidermal junction. These results
reveal a protective function of DAF in the development of a
systemic autoimmune syndrome and suggest that complement activation may contribute to autoimmune disease
pathogenesis.

neuropeptides, and cytokines released from KCs, mast


cells, endothelial cells, and fibroblasts [132, 133]. The wide
range of mediators released by UV light in the skin is listed
(Table 3). As discussed, UV light can induce prolonged
erythema and cutaneous lesions in patients with LE. UV
light is not only an executioner, killing KCs by apoptosis, it
also is a generator of neoantigens (such as UV-DNA).

UV Light is an Inflammatory Stimulus


Erythema (redness) is a normal response to UV light and is
mediated by multiple eicosanoids, vasoactive mediators,

Table 3 Mediator release by ultraviolet radiation


Source of mediator

UVB

Keratinocyte

IL-1, TNF-
GM-CSF, IL-6, IL-8
IL-10
TGF-
PGE2, PGF2
TNF-
LTC4, LTD4, PGD
Histamine
TNF-, PCI2

Mast cell

Endothelial cell
Langerhans cell

UVA

IL-8
IL-10, IL-12
PGE2, PGF2

PCI2
IL-12

Ultraviolet radiation results in the release of interleukins (IL),


prostaglandins (PG), prostacyclin (PC), leukotrienes (LT), and other
mediators.
UVA Ultraviolet A, UVB ultraviolet B

94

Cytokines, Chemokines, and Cutaneous Vasculature


UV light can induce cutaneous inflammation by promoting
the release of inflammatory mediators and cytokines by
inducing adhesion molecule display and by releasing
chemokines to attract inflammatory cells into the skin
[reviewed by Bennion and Norris [134]). Both UVB and
UVA can participate in lesion induction and act by differing
mechanisms. UVB induces the release of the primary
cytokines, IL-1 and TNF-, from the epidermis, initiating
a cascade of inflammatory events. UVB induces IL-1
gene transcription in KCs [135] and elevates circulating
levels of IL-1 bioactivity [136]. Likewise, UVB induces
the release of TNF- from KCs [137]. TNF- appears to
increase very quickly after UVB exposure [138]. This likely
relates to the ability of UVB to stabilize TNF- messenger
RNA molecules via direct interaction with AU-rich controlling elements in the 3 untranslated region, similar to
that which has been described for IL-6 [139].
IL-1 and TNF- are primary cytokines, which
induce the release of a number of other proinflammatory
cytokines from the epidermis (reviewed in [140]). For
example, IL-1 and TNF- induce the secondary release of
IL-6, PGE2, IL-8, and granulocytemonocyte colonystimulating factor (GM-CSF) by KCs [141, 142]. These
molecules are costimulatory factors for lymphocyte activation by antigens or superantigens, stimulate Langerhans cell
function (the Langerhans cell is the resident DC of the
skin), stimulate collagenase production, and act as pyrogens
and stimulators of acute-phase reactants. In addition, IL8 and GM-CSF are chemotactic and induce inflammatory
cell migration into the skin [143]. Both IL-1 and TNF-
also induce adhesion molecule expression such as ICAM-1.
Importantly, TNF- can induce activation of Langerhans
cells, the professional antigen-presenting cells of the
epidermis, via binding of the TNF p75 receptor (TNFR2)
on these cells [144]. This results in migration of these cells
to the regional lymph nodes, where they can participate in
immune responses [145]. Strong expression of myxovirus
resistance protein A (MxA), a protein specifically induced
by type I interferons, has also been found in lesional skin.
Large numbers of infiltrating CXCR3+lymphocytes correlated closely with lesion MxA expression [146].
Chemokines are chemo-attractive proteins that are
associated with inflammatory cell recruitment. UVB irradiation of primary human KCs, in the presence of proinflammatory cytokines such as IL-1 and TNF- or IFN-,
significantly enhances the expression of the inflammatory
chemokines CCL5, CCL20, CCL22, and CXCL8 [147].
This is of relevance in cutaneous lupus as CCL5 and
CXCL8 have been reported to be highly upregulated in LE
skin lesions [147]. Other groups have found that CXCR3,
CXCL10, and CXCL11 as being the most abundantly

Clinic Rev Allerg Immunol (2007) 33:85106

expressed chemokine family members in CLE [147]. After


phototesting, elevated levels of CCL27, a novel skinspecific chemokine known to recruit memory T cells into
the skin, was also found in the dermis of LE patients [147].
In contrast to UVB, UVA upregulates ICAM-1 in KCs
directly by producing oxygen free radicals that affect gene
transcription [148]. UVA also upregulates IL-8 and IL-10
production in KCs and FasL expression in dermal mononuclear cells [149, 150]. The longer wavelength of UVA
allows it to penetrate into the dermis and to upregulate
vascular endothelial ICAM-1 and E-selectin, thereby
increasing leukocyte-vascular adhesion [151].
Overall, exposure to UVB radiation correlates with a
predominance in cytokines that promote T helper 2 (Th2)
immune responses at the expense of T helper 1 (Th1)
immune responses, and that may result in photoimmunosuppression [152]. Whereas potentially suppressing cellular
immune responses, Th2 responses generally promote
antibody production [153].
Dermal blood vessels are involved in all forms of
cutaneous lupus as targets for cytokines and other mediators released. These vessels are also affected directly by UV
light. Immunohistochemical studies have confirmed that the
endothelium underlying cutaneous lupus lesions is activated: Vascular cell adhesion molecule (VCAM-1) is expressed
both in lesional and nonlesional cutaneous endothelium in
active systemic lupus [154]. VCAM-1 is necessary for
leukocyte emigration from the microvasculature and is the
ligand for very late antigen 4 (VLA-4) on leukocytes.
Taken together, UV-induced injury induces apoptosis,
necrosis, and chemokine production. These factors mediate
the recruitment and activation of autoimmune T cells and
IFN- producing plasmacytoid DCs (pDCs), which subsequently release more effector cytokines, thus amplifying
chemokine production and leukocyte recruitment, leading
to the development of the cutaneous LE phenotype [147].
Possible Benefits of Ultraviolet in Cutaneous LE
Although the above discussion has focused on the potential
inflammatory effects of UV light, recent work has
suggested that selective UV radiation may have beneficial
effects in LE. UVA irradiation of NZB/NZW mice has
resulted in increased survival and decreased levels of
circulating anti-DNA antibodies [155]. Subsequently, a
randomized, double-blind cross-over study of low dose
UVA1 light (light limited to the longer wavelength
spectrum of UVA, 340400 nm) compared to visible light
showed significant clinical and serologic improvements in
SLE patients treated with UVA1 light [156]. Recently,
UVA1 treatment of patients with moderately active SLE
was shown to significantly decrease disease activity scores
[157] and to improve skin disease. This correlated with a

Clinic Rev Allerg Immunol (2007) 33:85106

decrease in the proportion of circulating IFN- producing T


cells, particularly of the CD8+ T cell subset [158]. Whereas
selective UVA therapy has been thought to be of potential
benefit, others have also recently advocated repeated
exposure to low doses of UVB, UV hardening therapy,
as a novel way for improved tolerance to environmental
UV radiation to prevent downstream effects [159]. However, the enthusiasm for UVA1 therapy for cutaneous and
systemic LE is somewhat dampened by evidence suggesting that UVA1 can induce some aspects of the lupus
photosensitivity [44]. It is possible that the therapeutic
index of UVA1 phototherapy in cutaneous LE/systemic LE
could be quite narrow. This concept at first may seem
controversial, as many advocate photoprotection for this
population of patients, but it is well known that UV (either
UVA or UVB), in the absence of causing cell death, is
immunosuppressive. Therefore, each individuals susceptibility to cell death by UV may dictate the dose at which
immunosuppression versus immunostimulatory apoptosis/
necrosis occurs.
Humoral Responses
Autoantibody production is a sine-qua non of SLE, and the
autoantibodies can be pathogenic. Several specific autoantibodies have a special relationship to cutaneous LE. SCLE
was recognized as a distinct and uniquely photosensitive
subset of cutaneous LE by Sontheimer et al. [10]. This form
of cutaneous disease is strongly associated with a particular
autoantibody specificity, anti-Ro/SSA [13]; Ro/SSA antibodies have been observed in frequencies ranging from 40
to 100% of SCLE patients by immunodiffusion techniques
[32]. Neonatal LE also is strongly associated with an antiRo response [160]. Other studies have shown that mice
lacking the Ro protein develop an autoimmune syndrome
characterized by antiribosome antibodies, antichromatin
antibodies, and glomerulonephritis. Moreover, in one strain
background, Ro-/- mice display increased sensitivity to
irradiation with UV light. One function of this major human
autoantigen may be to protect against autoantibody development, possibly by sequestering defective ribonucleoproteins from immune surveillance. Furthermore, the finding
that mice lacking the Ro protein are photosensitive suggests
that loss of Ro function could contribute to the photosensitivity associated with anti-Ro antibodies in humans [161].
The originally described Ro antigen is a protein of 60 kd
that may be bound in vivo to four small RNA molecules
called Y RNA or hY RNA[162]. Subsequent studies
have indicated that the hY RNA molecules also can be
targets of autoantibody production in SLE patients [163].
The term Ro derives from the first two letters of the last
name of the index patient from whom the antibody was
characterized. It is identical to an antigen characterized

95

from patients with Sjgrens syndrome and given the name


SSA or SS-A [164]. It is now known that Ro/SSA
autoantibodies can variably bind to at least four antigenically distinct polypeptide components of the Ro/SSA
ribonucleoprotein [165] in addition to the hY RNA
molecules themselves. The function of the 60-kd antigen
still is unknown, but it has been proposed that it may be
involved in ribosome synthesis, assembly, or transport
[166], or that it may be part of a salvage pathway for
mutant rRNA precursors [167].
Reactivity against a 52-kd polypeptide is another
antibody specificity commonly found in anti-Ro/SSA
positive sera [168]. The expression of the 52-kd Ro/SSA
is upregulated in KCs by TNF [169]. The function of
the 52-kd Ro/SSA antigen is likewise still unknown, but the
protein recently has been shown to interact with the
deubiquinating enzyme UNP, suggesting an involvement
in the ubiquitin pathway [170]. A physical association
between the 52- and 60-kd proteins has been demonstrated
by immunoprecipitation assays [171]. A proteinprotein
interaction between these two polypeptides recently has
been confirmed [172].
Calreticulin is a 46-kd calcium-binding protein that has
an apparent molecular weight of 60 kd in SDS page
analysis because of its negative charge. This protein also
has been reported to bind both hY RNA and 52-kd Ro
[173] and may play a role in facilitating the binding of the
60-kd Ro/SSA to hY RNA. Calreticulin binds calcium in
the endoplasmic reticulum and has been found to have
multiple functions including the inhibition of C1q-mediated
immune functions [174, 175]. Calreticulin also has been
shown to have in vivo peptide-binding activity and to
facilitate the priming of CTL against such bound peptides
[176]. Calreticulin also functions as a receptor for the
collagenous domain of C1q.
The La/SSB antigen is a 48-kd protein that participates
in the control of RNA polymerase III transcription
termination [177]. Recently, La/SSB has been shown to
control the synthesis of the x-linked inhibitor of apoptosis
protein (XIAP), a key inhibitor of apoptosis upregulated in
cells under physical stress [178]. La/SSB also is associated
with the 60-kd Ro, likely through mutual binding to hY
RNA [179]. The functions and cellular redistribution of
calreticulin [180], the 52- and 60-kd Ro/SSA polypeptides
[181183], and the La antigen [182] all have been
associated with the heat-shock response. The heat-shock
response is characterized by the production and activation
of ubiquitous cellular proteins that detect and bind proteins
damaged by heat or other physiologically stressful stimuli
[184]. The potential involvement of the variable cutaneous
LE-associated autoantibody antigens with the heat-shock
response may relate to the general importance of this
response to cellular stresses or may be a function of a

96

potentially unique relationship of this response to the


abrogation of self-tolerance. Heat shock proteins (HSP),
which are induced in heat-shock responses, have been
shown to promote cellular immune responses by both
chaperoning peptides into cellular antigen processing
compartments and by directly activating antigen-presenting
cells [185, 186]. HSP induction by UV light has been
correlated to the increased binding of Ro/SSA and La/SSB
antibodies in KCs in vitro [201]. Finally, increased HSP70
expression is increased in both sun-exposed and sunprotected skin of SLE patients [187].
Epitope Spreading
Epitope spreading is the process by which specific immune
responses that arise to particular determinants on a macromolecule diversify over time [188]. B cells, by virtue of
their immunoglobulin receptors, can process and concentrate antigen before T-cell presentation and are central to
this process. This spread of immune responses can occur to
epitopes within the primary macromolecule (intramolecular
epitope spreading) or to physically associated molecules
(intermolecular epitope spreading). Both inter- and intramolecular epitope spreading have been reported in cases of
murine immunization with peptides of the 60-kd Ro/SSA,
52-kd Ro/SSA, and La [208210]. This is consistent with a
physical linking of these antigens [189]. Spreading of the
immune response for the 52-kd Ro/SSA and 60-kd Ro/SSA
(but not La/SSB) to calreticulin is consistent with the notion
that calreticulin may associate with a subpopulation of Ro/
SSA particles from which La/SSB already has dissociated
[190, 191]. The observation that human anti-Ro/SSA
immune responses segregate with either anticalreticulin
responses or anti-La/SSB responses [192] also is consistent
with a differential compartmentalization of Ro/SSA and La/
SSB antigens at the time of initiation of the immune
response. The secondary recruitment of antibodies to the
inducible heat shock proteins, Grp78 and HSP70, after
immunization of mice with either 52-kd Ro/SSA, 60-kd Ro/
SSA but not La/SSB, suggests physical association and colocalization of these proteins with the Ro/SSA polypeptides
under conditions such as apoptosis that may promote
autoimmunization [181]. In addition to providing evidence
for the physical association of autoantigens, the phenomenon of epitope spreading to specific antigens associated
with cutaneous LE in these animal models suggests that
such epitope spreading may occur in human disease. These
autoantibodies thereby may enhance and perpetuate cellmediated autoimmune inflammation.
There is compelling evidence that antibodies to Ro/SSA
and La /SSB bind to human epidermis in vivo [193]. The
binding of these antibodies to KCs in vitro can be enhanced
by UV radiation in the presence [53] or absence [194] of

Clinic Rev Allerg Immunol (2007) 33:85106

apoptosis. Estrogens [195], heat shock [182], and viralinduced apoptosis [196] also can enhance binding, and
uptake of apoptotic debris bound to antibodies may
facilitate uptake of the binding to DCs through the Fc
receptor [197].
The predominant IgG subclass that is deposited in SCLE
and neonatal LE skin lesions is IgG1, a form that is known
to activate complement and initiate antibody-dependent
cellular cytotoxicity (ADCC) [198]. The presence of
complement membrane attack complex at the dermal
epidermal junction (DEJ) of cutaneous LE lesions further
suggests an antibody-mediated pathogenesis for the cell
damage seen in cutaneous LE [199]. The presence of the
complement membrane attack complex (C5b-9) in only the
lesional skin of patients with SLE, SCLE, or CCLE [200,
201] suggests that this complex may then play a role in the
pathogenesis of the lesions.
Furukawa et al. [202, 203] have shown that KCs from
patients with lupus are more susceptible to binding of antiRo/SSA antibodies after UV exposure than controls, and
that these KCs can be lysed by ADCC when sera and
peripheral blood leukocytes from patients are added to the
KCs. This increased binding may be from an increased
susceptibility to UV-induced apoptosis or from other causes
of increased Ro/SSA antigen availability [52]. Considerable
interindividual variation in levels of KC Ro/SSA and
La/SSB epitope expression has been suggested [204], and
expression is higher in lupus patients with documented
photosensitivity [205]. Despite this evidence, anti-Ro/SSA,
La/SSB, and other autoantibodies may not have an
initiating role in the clinical lesions of cutaneous lupus
because the deposition of immunoglobulin and complement
components as detected by fluorescence microscopy generally follows the appearance of perivascular inflammation
in photo-provoked lesions [19, 42] and are typically
observed in nonlesional skin.
Cellular Responses
Autoantibodies were the first immune effector mechanisms
associated with cutaneous LE, and therefore, the early
research was targeted toward the humoral arm of the
immune response. More recently, a global understanding
of the immune system has led to additional studies in cell
mediated immunity. It is now known that the immune
system is a complex orchestration of all arms that mediate
and perpetuate the autoimmune response in concert.
T Cells and Antigen Presenting Cells
The specificity and role of similar autoantigen-specific T
cells in humans is an obvious area of ongoing investigation.
There is growing evidence that the highly specific humoral

Clinic Rev Allerg Immunol (2007) 33:85106

immune response to autoantigens in SLE is T-cell dependent [206]. Although there is no murine model that
accurately recapitulates the cutaneous pathology seen in
human disease, murine models have nevertheless been
useful in the dissection of the potential cellular mechanisms
of autoimmune inflammation. These murine models include
spontaneously occurring and UV-accelerated forms of
disease in MRL/lpr mice, graft-versus-host disease, and
NZB/NZW mice (reviewed in [207]).
MRL-Fas/lpr strain mice also made deficient in B7-1
(CD80) and B7-2 (CD86; costimulatory molecules) are
found to have diminished skin lesions and do not develop
renal pathology, indicating a critical role for these molecules. B7-1 and B7-2 provide essential signals for T-cell
activation and immunoglobulin class switching, establishing a crucial role for B and T cells in this disease [208].
Another costimulatory molecule that may have a primordial
role is CD40 expressed on DCs. Transgenic expression of
CD40 ligand in the skin using a keratin promoter resulted in
constitutive activation of cutaneous DCs and a CD8+ T cellmediated autoimmune disease characterized by dermatitis,
myositis, pneumonitis, nephritis, and autoantibody formation [209]. This model recapitulates a number of features of
SLE and places the skin DC at the center of disease
initiation.
In 1979, Notkins et al. [210] reported the first observation from a small study that 71% of patients with active
SLE had raised serum IFN levels. Other autoimmune
diseases, including arthritis and scleroderma, were also
noted to have increased IFN activity. Twenty-five years
later, the type I interferon signature has been found
mainly in SLE by others in lesional skin and blood [211
215, 146]. To explain the significance of elevated type I
interferons in SLE and CLE, the suggestion is that pDCs
are the main source for these type I interferons and the
production of IFN is in response to autoimmune complexes
containing nuclear antigens. The pDCs are thought to
recognize the self-immune complexes via TLR-9 (Toll-like
receptor-9) [216] or TLR7/8 [225]. Whereas type-I interferons are normally generated in response to a viral
infection, in autoimmunity, endogenous self-ligands such
as RNA protein particles (snRNP) are thought to drive and
perpetuate the response in the absence of infection.
Mammalian DNA and RNA are potent self-antigens for
TLR 9 and TLR 7, respectively, and induce IFN
production by pDCs [217].
The study of photo-induced cutaneous LE lesions has
allowed an analysis of early histological changes and their
evolution. In early lesions, this analysis has demonstrated
CD4+ T cells predominantly at the DEJ associated with rare
HLA class II expression by KCs. In spontaneous lesions
and late photo-induced lesions, an increased number of
CD8+ T cells was observed, epidermal class II MHC

97

expression was increased, and the number of Langerhans


cells was reduced [218221]. The decrease in Langerhans
cell number may reflect DC activation and migration into
the regional lymph nodes.
The predominant type of T cell in established inflammatory infiltrates remains controversial. Volc-Platzer et al.
[222] have suggested that T cells of a specific T-cell
receptor phenotype are preferentially expanded within the
infiltrates. They proposed that these cells may recognize
heat shock proteins induced or translocated in KCs by UV
or stress. Fivenson et al. [223] however, reported that T
cells are virtually absent in the infiltrates. Robak [224] has
observed significantly decreased number of T cells in
SLE patients compared to healthy volunteers and a positive
correlation between the percentage of T lymphocytes in
skin and the activity of SLE. The accumulation of T
lymphocytes can be seen in clinically normal skin of SLE
patients, and the percentage of these cells correlates with
the activity of the disease.
It has been proposed that apoptotic cells are a source of
lupus autoantigens and targets for autoantibodies. Apoptotic blebs and bodies have been suggested to be a preferred
target of antigen presenting cells (dendritic cells) for
phagocytosis. Uptake of the apoptotic cells is a novel
pathway for the presentation of nuclear Ags that could
induce an autoimmune response and T cell response [197].
Toll-Like Receptors
Toll-like receptors (TLRs) bridge innate and adaptive
immune responses. There is emerging evidence that TLRs
play a key role in the development of the autoimmune
response. Thus, they may play a role in the pathogenesis of
SLE and cutaneous lupus.
The TLR family recognizes specific pattern associated
ligands common to pathogenic various organisms. TLR
signaling downstream ultimately results in the activation of
innate antimicrobial immunity and modulation of the
adaptive immune responses. TLRs represent the earliest
warning signal of danger in the integrated inflammatory
and immunological process that rids the host of the
invading pathogens. More controversial is the concept that
TLRs on inflammatory cells and DCs not only recognize
foreign structures but also endogenous ligands that could
consequently lead to the development of autoimmune
disease [225, 217].
TLR-9 typically recognizes CpG motifs in microbial
DNA, whereas TLR-7 recognizes single-stranded viral
RNA. It has been suggested that TLRs can recognize
mammalian self-RNA and DNA as well as viral RNA and
DNA [226]. It is also possible that TLRs can recognize
mammalian RNA and DNA molecules that have been made
to appear foreign as a result of alteration by environmental

98

Clinic Rev Allerg Immunol (2007) 33:85106

stimuli (e.g., thymidine dimers resulting from UV damage


to DNA). However, there is no direct experimental support
for this hypothesis at this time. However, synthetic
thymidine dinucleotides have been shown to activate
cutaneous TNF- expression, and TNF- gene expression
is a key component of the TLR signaling pathway [227]. In
the appropriate milieu, recognition of endogenous selfRNA/DNA or environmentally altered RNA/DNA may
result in the development of autoimmunity.
In a novel murine model for SLE, based on hyperreactive B cell activation mediated by mutant phospholipase
Cg2, the genetic deficiency of TLR9 does not protect from
spontaneous anti-DNA autoantibody formation and glomerulonephritis. Furthermore, in TLR9-deficient mice, disease
induction is aggravated, and additional nucleolar antibody
specificity develops [228]. These findings suggest that,

whereas TLR9 can aggravate autoimmunity, there are TLR9


independent pathways that can also promote autoimmunity.
Additional work has also shown that TLR-9-deficient animals
of both the MRL/+ and MRL/lpr backgrounds developed
more severe lupus, suggesting here that TLR-9 signaling
might also play a protective role perhaps by modulating the
activity of regulatory T cells [229].
Defects in the TLR signaling could explain how the autoimmune response is perpetuated. Autoantibodies, Sm/RNP,
and Ro 60 kd drive the response in an attempt to clear the
foreign virus, when in fact, the source of the endogenous
signal was initiated by self. In actuality, it is a self-induced
cyclical response. It has been proposed that the RNA
component of these antigens act as endogenous adjuvants
by stimulating DC maturation and IFN- production probably via TLR-7 [230].

Fig. 6 A model of the pathogenesis of photosensitive cutaneous lupus


erythematosus. Recent studies of photosensitive lupus patients have
demonstrated an increased number of apoptotic keratinocytes in both
established lesions and following photoprovocation. Either increased
apoptosis/necrosis or a delay in the clearance of apoptotic cells could
result in an increase in autoantigen packaging and processing in a
form accessible to the immune system (a). Ultraviolet radiation can
induce keratinocyte apoptosis and/or necrosis and can also stimulate
local cytokine release. This cytokine release can then lead to the
observed increase in local mediators of inflammation including
selectins, adhesion molecules, chemokines, and prostanoids. These

molecules serve to recruit and activate DCs and T cells. Plasmacytoid


DCs release IFN locally resulting in further chemokine release (b).
The end result is a stimulation of the immune system to produce
antibodies and to activate DCs to prime T cells directed against stressinduced or stress-altered molecules (Ro antigen, La antigen, calreticulin). These agents of the immune system then act to promote further
inflammation and tissue damage by processes such as epitope
spreading mediated by antibodies and B cells and cellular cytotoxic
mechanisms mediated by T cells, natural-killer cells, and monocytemacrophages (c)

Clinic Rev Allerg Immunol (2007) 33:85106

This emerging area of interest argues for the development of inhibitors of TLR signaling as potential novel
therapeutic agents for the treatment of lupus.

Concluding Remarks
Norris [231] originally proposed a four-step model for the
pathogenesis of cutaneous lupus: (1) exposure to UV light
induces the release of proinflammatory epidermal and
dermal mediators such as IL-1 and TNF-; (2) these
mediators induce changes in the dermal and epidermal
cells including the induction of adhesion molecules and the
promotion of translocation of normally intracellular autoantigens such as Ro/SSA to the surface of epidermal cells;
(3) autoantibodies then bind to the translocated autoantigens; and (4) KC cytotoxicity ensues as the result of
lymphoid cells that are recruited from the circulation via an
antibody-dependent cellular cytotoxicity mechanism.
According to this model, several factors are required
concurrently for the development of cutaneous LE: (1)
abnormal susceptibility to UV light, resulting in altered
cytokine expression and possibly increased KC apoptosis
induction; (2) the presence of antibodies with appropriate
specificities targeting KC components upregulated by
stress; and (3) the presence of activated lymphocytes
specific for autodeterminants.
Since this model was first proposed, a great deal of new
data has accumulated (reviewed here and in [232236]).
Clinical and experimental data now suggest that apoptosis
may be an important mechanism leading to autoantigen
display in cutaneous LE and that UV light might be an
important initiator of apoptosis and possibly necrosis.
Genetically determined abnormalities may exist in either
apoptosis induction or in apoptotic cell clearance that result
in an increased load of apoptotic and necrotic cells. In
addition to promoting cell death and neoantigen generation
(such as UV-DNA), UV light induces and modulates
inflammatory mediator release. Genetic abnormalities in
TNF-, IL1 receptor antagonist, C1q, and IL-10 have been
linked tentatively to cutaneous lupus. The dysregulation of
such cytokines may allow the upregulation of adhesion
molecules, chemokines, and costimulatory molecules to
allow self-antigen recognition and the initiation of an
immune response in genetically predisposed individuals.
The autoantibodies linked with cutaneous LE are directed at
antigens involved in cellular-stress responses and in the
heat-shock response. Autoantibody production and directed
T-cell responses may perpetuate and amplify autoantigen
recognition as well as KC toxicity leading to the clinical
hallmarks of cutaneous LE disease. A central role for skin
resident DCs such as plasmacytoid DCs and for dysregulated IFN- production in the initiation and perpetuation of

99

skin disease is emerging, as well as the role of TLRs in


bridging innate and adaptive immunity. The salient points
of this revised model are shown (Fig. 6). Ongoing research
will no doubt shed light on the in vivo role of cellular
apoptosis in disease induction and perpetuation, the primary
or secondary pathophysiologic role of specific autoantibodies, and the nature of the underlying genetic makeup
that predisposes to disease.

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