DOI 10.1007/s12016-007-0031-x
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
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
Epidemiology
Cutaneous LE (CLE) can occur in the presence or absence
of systemic manifestations of LE. SLE occurs in 1748/
86
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.
87
88
89
90
Table 2 Biologic effects of
ultraviolet radiation
UVB
UVA
Absorption by molecules
Direct DNA damage
Free-radical production
Depth of penetration
Epidermal effects
Melanin
Minimal
Increased
Dermal
Immediate
apoptosis
Minimal
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,
91
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].
92
93
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
94
95
96
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
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
98
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
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