Rheumatology 2006 45(Supplement 3):iii14-iii16; doi:10.1093/rheumatology/kel284
© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Pathophysiology of cutaneous lupus erythematosus — novel aspects
A. Kuhn1,2,,
P. H. Krammer2 and
V. Kolb-Bachofen3
1Department of Dermatology, University of Düsseldorf, Düsseldorf, 2Institute of Immunogenetics, Tumor Immunology Program, German Cancer Research Center, Heidelberg and 3Research Group Immunobiology, University of Düsseldorf, Düsseldorf, Germany.
Correspondence to: Annegret Kuhn, MD, Institute of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. E-mail: kuhnan{at}uni-duesseldorf.de
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Abstract
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The pathophysiology of cutaneous lupus erythematosus (CLE) has
been investigated in numerous studies demonstrating that the
combination of specific cellular and molecular events is leading
to inflammation and tissue damage in this disease. However,
a complete understanding of the diverse pathophysiological mechanisms
and interactions does not exist. Various environmental factors
influence the clinical expression of CLE and a striking relationship
has emerged between sunlight exposure and the various subtypes
of this disease. In the past years, photoprovocation tests with
different ultraviolet (UV) wavelengths have been approved to
be an optimal way to evaluate photosensitivity in patients with
CLE. Furthermore, research on the pathogenetic mechanisms of
UV-induced skin lesions has become an increasingly dynamic field
and several new aspects of this disease could be identified.
In this review, the impact of UV exposure that contributes to
the manifestations of CLE is discussed and recently reported
mechanisms in the pathophysiology of this disease are considered
including the clearance of apoptotic cells, expression of inducible
nitric oxide synthase, function of CD4
+CD25
+ regulatory T cells,
and the role of chemokines for lymphocyte recruitment. Elucidation
of the relevant factors might lead to future development of
effective strategies to prevent abnormal reactivity in patients
with CLE.
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Introduction
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Cutaneous lupus erythematosus (CLE) is a disease with a wide
spectrum of clinical manifestations with a variable evolution.
Therefore, it has been difficult to develop a unifying concept
of CLE and the similarities as well as the differences among
the various subtypes have to be considered in discussing the
pathophysiology of this disease. In 1977, a classification system
has been established dividing the cutaneous manifestations into
acute CLE (ACLE), subacute CLE (SCLE) and chronic CLE (CCLE).
Recently, the intermittent subtype of CLE (ICLE) has been added
to this classification system [
1]; however, this classification
system is not meant to rigidly define subtypes of this disease
since overlapping features can occur. Furthermore, there are
certain patterns of systemic disease activity that can also
be seen in association with these subtypes resulting in limited
patient quality of life and increased disability.
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Evidence of clinical photosensitivity
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Photosensitivity shows a strong association with manifestation
of all CLE subtypes, and abnormal reactivity to ultraviolet
(UV) light is an important factor in the pathogenesis of this
disease [
2]. Recently, the usefulness of photosensitivity as
a criterion for the classification of systemic lupus erythematosus
(SLE) by the American College of Rheumatology has been questioned
[
3]. A variety of other diseases, such as polymorphous light
eruption, also presents with a high photosensitivity as their
primary aspect of disease. In addition, only 50% of patients
with CLE are aware of an adverse effect of sunlight on their
disease and, therefore, a negative history of photosensitivity
does not necessarily exclude any effect of sun exposure on their
disease. This might be due to the fact that the development
of UV-induced skin lesions in patients with CLE is characterized
by a latency period of up to 3 weeks, which became evident on
phototesting [
4]. Standardized photoprovocation tests with artificial
UVA and UVB irradiation are an optimal way to evaluate photosensitivity
in patients with CLE demonstrating some differences with regard
to the various subtypes. However, UV exposure by artificial
light sources can trigger systemic organ manifestations [
5],
therefore, photoprovocation tests should not be performed in
patients with SLE. In the past years, phototesting has been
crucial in further characterizing the highly photosensitive
subtype ICLE and has also been shown to be very helpful for
the education of patients on photoprotection measures [
2,
4].
It has been demonstrated that broadband sunscreens are able
to suppress the induction of skin lesions on UV irradiation
in patients with CLE [
6]. Therefore, consequent protection against
UV light as well as other physical and mechanical injuries are
of significant value for the course and prognosis of this disease.
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Impaired clearance of apoptotic cells
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The capacity to reproduce skin lesions in patients with CLE
by UV irradiation is also an ideal model for several experimental
approaches, which allows the evaluation of inflammatory and
immunological events that take place prior to and during lesion
formation. In several reports, a potentially crucial role in
the initiation of the autoimmune reaction cascade has been attributed
to UV-induced keratinocyte apoptosis [
2]. Interestingly, a significantly
higher number of apoptotic nuclei in the epidermis has been
described in primary and UV-induced skin lesions of CLE patients
compared with normal healthy donors [
7]. Furthermore, in skin
sections taken 72 h after irradiation prior to lesion formation,
a significant increase of apoptotic keratinocytes was already
observed in the majority of specimens from CLE patients compared
with controls, suggesting that the clearance of apoptotic cells
in the skin of patients with this disease is either impaired
or delayed. This is in analogy with the growing evidence that
defects in the clearance of apoptotic cells may be important
in triggering the immune response in patients with autoimmune
disorders. It has been reported that apoptotic cells accumulate
in the germinal centres of lymph nodes from patients with SLE,
which might be due to impaired phagocytic activity or caused
by the absence of tingible body macrophages [
8]. Further, recent
data support the hypothesis that a defective or delayed clearance
leads to the accumulation of apoptotic cells and cellular debris
in tissue culture and circulation [
9]. Consequently, these results
indicate that apoptotic cells accumulate and subsequently enter
late stages of apoptotic cell death including secondary necrosis
in various tissues of patients with this disease.
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Aberrant expression of inducible nitric oxide synthase
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Nitric oxide (NO) is an important regulator of apoptosis and
has an implication in the course of various autoimmune diseases.
Interestingly, this molecule has also different effects on the
various cell types within the skin, and it has been shown that
NO can protect against UVA-induced apoptosis by increasing Bcl-2
expression and inhibiting UVA-induced overexpression of Bax
protein in endothelial cells [
10]. In addition, Weller
et al.
[
11] suggested an anti-apoptotic role for NO in keratinocytes
after UVB irradiation. Furthermore, UV exposure has also been
shown to modulate local NO production by the constitutively
expressed neuronal nitric oxide synthase, several further studies
reported that another isotype of this family, the inducible
nitric oxide synthase (iNOS), is expressed by epidermal keratinocytes
after endogenous and/or exogenous stimuli. In 1998, it has been
demonstrated that iNOS is also expressed in human skin after
UVA and UVB irradiation up to 48 h after exposure [
12]. In striking
contrast, an iNOS-specific signal appeared only 72 h after UV
exposure and persisted in the evolving skin lesions up to 25
days in patients with CLE. These results suggested that the
kinetics of iNOS induction and the time span of local iNOS expression
might play an important role in the pathogenesis of this disease.
According to the evidence of a delayed and prolonged expression
of iNOS in the skin of patients with CLE after UV exposure,
NO via chemical donors appear to be a promising target for therapeutic
intervention. It has further been reported that NO production
is increased in patients with SLE possibly due to up-regulated
iNOS expression in activated endothelial cells and keratinocytes
[
13]. However, polymorphism in the iNOS gene promoter does not
seem to play a relevant role in the pathogenesis of patients
with this disease [
14].
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Role of regulatory T cells and chemokines for lymphocyte recruitment
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Naturally occurring CD4
+CD25
+ regulatory T cells (T
reg) have
emerged as an important factor in our understanding of self-tolerance
and mechanisms in autoimmune diseases [
15]. Recently, a decreased
number of peripheral T
reg were found in SLE patients compared
with normal healthy donors and a significant correlation could
be detected between the number of CD4
+CD25
+ T cells and disease
activity [
16]. Lee
et al. [
17] confirmed these results by showing
a significant decrease of T
reg in paediatric patients with SLE;
however, an inverse correlation between the number of these
cells and disease activity as well as autoantibody level was
determined in this study. As suggested in a more detailed analysis
by Miyara
et al. [
18] sensitivity of T
reg to CD95L-mediated
apoptosis could explain the loss of CD4
+CD25
+ T cells in patients
with active SLE. Whether the number of T
reg is also impaired
in patients with CLE, is currently under investigation; moreover,
distribution of parenchymal T
reg in the inflamed organ itself
has not been analysed.
Although the pathophysiological role of skin-infiltrating lymphocytes is undoubted, their recruitment and activation pathways in inflammatory skin diseases are still elusive. Recently, a superfamily of small chemotactic proteins has been shown to regulate lymphocyte trafficking under inflammatory conditions, and it has been demonstrated that UV exposure induces the expression of T-cell attracting chemokines [19]. Furthermore, the CXCR3 ligands CXCL9, CXCL10 and CXCL11 have been identified as the most abundantly expressed genes in patients with CLE. Additionally, it has been reported that the CCR4 ligand TARC/CCL17 is strongly expressed in skin lesions and elevated in the serum of patients with CLE [20]. The functional relevance of lymphocytic CCR4 expression could be confirmed by TARC/CCL17-specific in vitro migration assays, suggesting that CCR4 and TARC/CCL17 play a role in the pathophysiology of this disease.
In conclusion, research on the pathogenetic mechanisms of CLE has become an increasingly dynamic field, and significant advances have been made in our understanding of the pathophysiology of this disease. The impact of UV irradiation on initial triggering and on perpetuation of the various cutaneous manifestations suggests that abnormal photoreactivity is one important factor in CLE. However, ongoing research will shed more light on the pathophysiological relevance of the different cellular and molecular factors in vivo, hopefully leading to a complete understanding of the diverse events and interactions in this complex disease.
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Acknowledgements
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This work was supported by a Heisenberg professorship from the
German Research Association (DFG) to A.K. (KU 1559/1-1).
A. K. received speaker's honorarium for participation at Actelion Winter School 2006.
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Abstract
Introduction