03 - pathophysiology of cutaneous lupus erythematosus

8/10/2019 03 - Pathophysiology of Cutaneous Lupus Erythematosus

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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 LE-

specific 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 photo-

reactivity 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 inflamma-

tion. 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

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, comple-

ment, 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/

Clinic Rev Allerg Immunol (2007) 33:85106

DOI 10.1007/s12016-007-0031-x

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: [email protected]

J. P. DutzDepartment 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


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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 population-based 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.

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 typicallyhave 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 papulosqua-

mous, 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 photo-

distribution 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 defini-

tion that can be fulfilled by a number of unrelated

dermatoses (e.g., polymorphous light eruption, photoaller-

gic 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/

86 Clinic Rev Allerg Immunol (2007) 33:85106


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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 inducedby 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

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 epidermalnecrolysis-like [TEN]-like, erythema multiforme-

like [Rowells syndrome overlap], pityriasis rosea-

like, 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 nodulesE. 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

Clinic Rev Allerg Immunol (2007) 33:85106 8787


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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 nor-

mal early differentiation and premature terminal differenti-

ation [34]. The inflammatory-cell infiltrate is characterized

by mononuclear cells at the DEJ, as well as around blood

vessels and dermal appendages. Inflammatory cells in the

infiltrate of established cutaneous LE lesions are predom-

inantly 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

An outcome measure to evaluate cutaneous lupus activityand 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. Al-

though 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 sun-

light 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 photoprovoca-

tion 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 UVA-

induced erythema in normal skin requires 1,000 times more

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

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 predomi-

nantly perivascular. The mononuclear cells are predominantly CD4 T

cells, many showing an activation phenotype and macrophages



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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 photosen-

sitivity [45]. However, phototesting with standardized

protocols correlates poorly with patient-reported photosen-

sitivity [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]. Interest-

ingly, 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

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

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

Fig. 3 The spectrum of ultravi-

olet (UV) light irradiation by

wavelength. Ultraviolet light is

commonly divided into germi-

cidal 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 pho-tosensitive lupus erythematosus.

UVA-1 is light limited to the

longer wavelength spectrum of

UVA and has been used thera-

peutically in systemic lupus

erythematosus



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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, ribonucleo-

protein, 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 transloca-

tion 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 stimulat-

ing 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 noninflamma-

tory 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 parenchy-

mal 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 supra-

basilar KCs are more vunerable to UV-induced apoptotic

death; such cells were called sunburn cells by morphol-

ogists [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 transferase-

mediated 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

Table 2 Biologic effects of

ultraviolet radiation

UVAUltraviolet A, UVB ultra-violet B

Characteristic UVB UVA

Absorption by molecules DNA, amino acids, melanin, urocanoic acid Melanin

Direct DNA damage Increased Minimal

Free-radical production Minimal Increased

Depth of penetration Epidermal Dermal

Epidermal effects Stratum corneum thickening, intermediate and delayed

apoptosis, keratinocyte cytokine transcription, and release

Immediate

apoptosis

Langerhans cell effects Inactivation, emigration Minimal



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polymorphous light eruption, implying that the accumula-

tion 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 DNAdamage [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 intra-

cellular proteins into fragments that are bound by autoanti-

bodies 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. Gran-

zyme 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]. Interest-

ingly, expression of granzyme B has been detected in KCs,

suggesting that these molecules may participate in cutane-

ous 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 neoantigenscould 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 C1q-

deficient mice [98].

Moreover, a recent study in humans has demonstrated

that the clearance of apoptotic lymphocytes by macro-

phages 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 anumber 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 phago-

cytosis 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 andimmature

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

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 associ-

ation 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 pheno-

types [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 autoan-

tigen-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 produc-

tion 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

polymorphismassociatedwith increasedTNF-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



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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 glycosylphosphatidy-

linositol-anchored membrane protein that restricts comple-

ment 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 develop-

ment in MRL/lpr mice, one model for human SLE.

Histology and immunostaining demonstrated an inflamma-

tory 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 comple-

ment activation may contribute to autoimmune disease

pathogenesis.

UV Light is an Inflammatory Stimulus

Erythema (redness) is a normal response to UV light and is

mediated by multiple eicosanoids, vasoactive mediators,

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).

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

Table 3 Mediator release by ultraviolet radiation

Source of mediator UVB UVA

Keratinocyte IL-1, TNF-

GM-CSF, IL-6, IL-8 IL-8

IL-10 IL-10, IL-12

TGF-

PGE2, PGF2 PGE2, PGF2Mast cell TNF-

LTC4, LTD4, PGD

Histamine

Endothelial cell TNF-, PCI2 PCI2Langerhans cell IL-12

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

prostaglandins (PG), prostacyclin (PC), leukotrienes (LT), and other

mediators.

UVAUltraviolet A, UVB ultraviolet B



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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 differingmechanisms. UVB induces the release of the primary

cytokines, IL-1and 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 con-

trolling 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-1and TNF-induce the secondary release of

IL-6, PGE2, IL-8, and granulocytemonocyte colony-

stimulating factor (GM-CSF) by KCs [141, 142]. These

molecules are costimulatory factors for lymphocyte activa-

tion 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, IL-

8 and GM-CSF are chemotactic and induce inflammatory

cell migration into the skin [143]. Both IL-1and 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 corre-

lated closely with lesion MxA expression [146].

Chemokines are chemo-attractive proteins that are

associated with inflammatory cell recruitment. UVB irradi-

ation of primary human KCs, in the presence of proin-

flammatory 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

expressed chemokine family members in CLE [147]. After

phototesting, elevated levels of CCL27, a novel skin-

specific 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 mono-nuclear 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 photoimmuno-

suppression [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 media-

tors released. These vessels are also affected directly by UV

light. Immunohistochemical studies have confirmed that the

endothelium underlying cutaneous lupus lesions is activat-

ed: 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 subse-

quently 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



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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]. Howev-

er, the enthusiasm for UVA1 therapy for cutaneous andsystemic LE is somewhat dampened by evidence suggest-

ing 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 suscepti-

bility to cell death by UV may dictate the dose at which

immunosuppression versus immunostimulatory apoptosis/

necrosis occurs.

Humoral Responses

Autoantibody production is asine-qua nonof SLE, and the

autoantibodies can be pathogenic. Several specific autoanti-

bodies 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 anti-

bodies 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 anti-

Ro 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 devel-

opment, possibly by sequestering defective ribonucleopro-

teins from immune surveillance. Furthermore, the finding

that mice lacking the Ro protein are photosensitive suggests

that loss of Ro function could contribute to the photosensi-

tivity 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

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 antigeni-

cally 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], an d 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



12/22

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/SSBantibodies in KCs in vitro [201]. Finally, increased HSP70

expression is increased in both sun-exposed and sun-

protected skin of SLE patients [187].

Epitope Spreading

Epitope spreading is the process by which specific immune

responses that arise to particular determinants on a macro-

molecule diversify over time [188]. B cells, by virtue of

their immunoglobulin receptors, can process and concen-

trate 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 intra-

molecular 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 co-

localization 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 phenome-

non 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 cell-

mediated 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

apoptosis. Estrogens [195], heat shock [182], and viral-

induced 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-dependentcellular 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 anti-

Ro/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 gen-

erally 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



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immune response to autoantigens in SLE is T-cell depen-

dent [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, andNZB/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 mole-

cules. B7-1 and B7-2 provide essential signals for T-cell

activation and immunoglobulin class switching, establish-

ing 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 cell-

mediated autoimmune disease characterized by dermatitis,

myositis, pneumonitis, nephritis, and autoantibody forma-

tion [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 observa-

tion 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 inter-

ferons 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

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 inflamma-

tory infiltrates remains controversial. Volc-Platzer et al.

[222] have suggested that T cells of a specific T-cell

receptor phenotype are preferentially expanded within theinfiltrates. 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. Apopto-

tic 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



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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 self-

RNA/DNA or environmentally altered RNA/DNA mayresult in the development of autoimmunity.

In a novel murine model for SLE, based on hyperreac-

tive B cell activation mediated by mutant phospholipase

Cg2, the genetic deficiency of TLR9 does not protect from

spontaneous anti-DNA autoantibody formation and glomer-

ulonephritis. 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 auto-immune 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 proba-

bly 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 stress-

induced or stress-altered molecules (Ro antigen, La antigen, calreti-

culin). 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 monocyte-

macrophages (c)



15/22

This emerging area of interest argues for the develop-

ment 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 thepathogenesis 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 auto-

antigens such as Ro/SSA to the surface of epidermal cells;

(3) autoantibodies then bind to the translocated autoan-

tigens; 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 dysregu-

lated IFN-production in the initiation and perpetuation of

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 autoanti-

bodies, and the nature of the underlying genetic makeup

that predisposes to disease.

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03 - pathophysiology of cutaneous lupus erythematosus

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