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PATHOGENESIS OF SUBACUTE CUTANEOUS LUPUS
ERYTHEMATOSUS
REVIEW ARTICLE
Panagiotis G. Stavropoulos, MD
Assistant Professor, First Department of Dermatology, School of Medicine,
University of Athens, “A. Syngros” Hospital, 5 Ionos Dragoumi St, 16121 Athens,
Greece.
E-mail: [email protected]
Andreas V. Goules, MD
PhD, Research Fellow, First Department of Dermatology, School of Medicine,
University of Athens, “A. Syngros” Hospital, 5 Ionos Dragoumi St, 16121 Athens,
Greece.
E-mail: [email protected]
Georgia Avgerinou, MD
Associate Professor, First Department of Dermatology, School of Medicine,
University of Athens, “A. Syngros” Hospital, 5 Ionos Dragoumi St, 16121 Athens,
Greece.
E-mail: [email protected]
Andreas D. Katsambas, MD
Professor and Chairman, First Department of Dermatology, School of Medicine,
University of Athens, “A. Syngros” Hospital, 5 Ionos Dragoumi St, 16121 Athens,
Greece.
2
E-mail: [email protected], [email protected]
Key Words: Subacute cutaneous lupus erythematosus, pathogenesis, plasmacytoid
dendritic cells, apoptosis, type I IFNs, antibody depended cell mediated cytotoxicity
Correspondence
Andreas D. Katsambas, MD
First Department of Dermatology, School of Medicine, University of Athens, “A.
Syngros” Hospital, Greece.
Ionos Dragoumi St 5
Athens 16121
Greece
Tel: 210-7210839
Fax: 210-7211122
E-mail: [email protected], [email protected],
3
ABSTRACT
Subacute Cutaneous Lupus Erythematosus (SCLE) is a photosensitive form of lupus
specific skin lesion which is strongly associated with the presence of anti-Ro/SSA
autoantibody. The pathogenesis of SCLE includes genetic, environmental and
immunologic factors. Recent studies provide strong evidences for the involvement of
innate and cell mediated immunity, underlying the important role of plasmacytoid
dendritic cells (pDC), IFNα and antibody depended cell cytotoxicity (ADCC). In
addition, a variety of cytokines, chemokines and adhesion molecules have been found
to participate in the expansion phase of the autoimmune effector mechanisms. This
article summarizes the recent immunological findings and reviews the current
mechanisms which are implied in the development of the disease.
INTRODUCTION
Subacute Cutaneous Lupus Erythematosus (SCLE) represents a distinct lupus-
specific cutaneous lesion, intermediate between the acute lesion of malar rash and the
chronic lesions such as discoid lupus or lupus profundus which usually cause scarring.
SCLE is a photosensitive, non-fixed, non-scarring, exacerbating and remitting skin
disease which commonly occurs in sun-exposed areas and may be generalized. It may
present as a papulosquamus eruption that resembles psoriasis or as an annular lesion
that resembles erythema multiforme. The most commonly affected areas are the
shoulders, the upper back, the extensor arms and the V-area of the upper chest
4
while the face and the neck are less commonly affected. SCLE presents in the third
or fourth decade of life and women are 3-4 times more likely to be affected than men
1. Half of the patients who exhibit SCLE meet the diagnostic criteria for SLE and
develop a less severe systemic disease although the skin lesions may be more
refractory.
Sometimes, SCLE needs to be differentiated from other clinical subtypes
of chronic cutaneous lupus erythematosus (LE) such as chronic discoid LE
(CDLE), LE tumidus (LET) and LE profundus (LEP). Interestingly, 20% of
patients with SCLE have concomitant CDLE 2. However, CDLE presents as one or
more erythematous papules and/or plaques which are more likely to appear on
the face, the external ears, the scalp, the extensor aspects of the forearms and the
trunk and have a tendency for scarring and atrophy 3, 4
. LET corresponds to
discoid, urticaria-like single or multiple plaques with a bright reddish or
violaceous smooth surface on sun exposed areas. The eruption is remarkable
photosensitive and persistent without a tendency for scarring 5.
Histopathologically, is characterized by dermal inflammation and the absence of
epidermal involvement 6. Finally, LEP is an inflammatory condition involving
the subcutaneous adipose tissue (lupus panniculitis) and clinically presents as
deep cutaneous nodules which are not painful and are symmetrically distributed
on the upper arms and the face 4.
The pathogenesis of SCLE is multifactorial and although the exact cause
remains unknown genetic, environmental and immunologic factors seem to contribute
to the development of the disease. Recent genetic data has elucidated potential
candidate genes for SCLE 7-9. Among the environmental factors, ultraviolet light
(UVL) and drugs appear to play the most important role in the pathogenesis of SCLE
and cutaneous lupus in general 10, 11
. Many studies have led to the postulate that innate
5
and cell mediated immunity participates in the development of the cutaneous skin
lesions 12-15
. Finally, a complex network of cutaneous cytokines, chemokines and
adhesion molecules orchestrate and promote tissue injury observed in skin lesions of
SCLE 16, 17
. In summary, the etiopathogenesis of SCLE is considered to result from
three distinct stages in genetic susceptible patients: initiation, amplification and
maintenance of autoimmune response and finally induction of tissue injury.
IMMUNOPATHOLOGY-HISTOPATHOLOGY
Histological, LE-specific lesions share many common features but SCLE can
be distinguished from the other forms 18. The major characteristics are moderate
hyperkeratosis with focal disorientation and liquefactive degeneration of the basal
layer, mild to prominent atrophy and periappendageal mononuclear cell infiltrate
confined to the superficial dermis. A dermal edema can be also observed but
basement membrane thickening and follicular plugging is minimal or absent 19. The
inflammatory infiltrate of the characteristic interface dermatitis observed in SCLE
lesions, consists mainly of activated T cells and macrophages. These inflammatory
cells appear to be in close apposition to epidermal basal keratinocytes which undergo
apoptosis and cytotoxic injury 18. The interface dermatitis is characterized by a
hybrid pattern comprising cell-poor vacuolar foci alternating with zones of
lichenoid dermatitis 20. Immunohistochemical studies including staining for the
cytotoxic molecule granzyme B, revealed a significant lower expression in
lesional lymphocytes of patients with SCLE compared to patients with CDLE 21.
Furthermore, when analyzing the expression of both granzyme B and Tia1 in
skin biopsies of patients with CDLE, LET, LEP and SCLE, it was found that
6
granzyme B and Tia1 positive cells were present in all subsets but their number
was lower in patients with SCLE 15. The above data suggest that the number of
CD8 lymphocytes is lower in SCLE lesions compared to other clinical subtypes
of cutaneous LE. Immunofluorescence studies demonstrate deposition of IgG
immunoglobulin and/or complement components in a granular pattern at the dermal-
epidermal junction, in about 60% of patients with SCLE. A dust like pattern of IgG
deposition overlying epidermal basal cells and cells below the dermal-epidermal
junction is considered by some investigators, a specific immunopathological feature
of SCLE 22.
Anti-SS-A/Ro and anti-SS-B/La autoantibodies have been strongly associated
with cutaneous lupus and SCLE 23, 24
. Approximately 90% of SCLE patients have
positive anti-Ro/SS-A antibodies 25 while a smaller percentage is being positive for
anti-La/SS-B 23. Other autoantibodies such as antinuclear antibodies (ANA), anti-
dsDNA and anti-Sm, have also been found in SCLE patients but less commonly than
anti-Ro/SS-A 2, 25
. Previous studies have focused on the close association of
antibodies against the Ro/SS-A antigen with the development of clinical symptoms 23,
26. Deposition of immunoglobulins and complement at the dermoepidermal junction
suggests a direct participation of anti-Ro/SS-A antibodies in the pathogenesis of
SCLE. Several mechanisms though have been implicated in the pathophysiology of
the disease including direct autoantibody effects, immunoglobulin deposits and cell-
mediated immunity 27.
Independently of the underlying immunological mechanisms that mediate the
tissue damage, epidermal keratinocytes and especially the basal cells seem to be the
major target of the immune system. Dermal-epidermal localization of
immunoglobulins and complement possibly results from nuclear material deriving
from apoptotic keratinocytes 28. These nuclear autoantigens can react with circulating
7
autoantibodies and form immune complexes which precipitate and initiate tissue
injury. Besides this model which is also observed in SLE and drug induced lupus, a
direct effect of autoantibody has been also proposed as a possible mechanism for the
pathogenesis of cutaneous lupus and SCLE. It has been previously shown that the
binding of anti-Ro/SS-A antibodies to the surface of epidermal cells, is an important
inducer of antibody-dependent keratinocyte damage in photosensitive cutaneous LE
29. In addition, these autoantibodies have been found to bind to UVB-irradiated human
keratinocytes both in vivo and in vitro 30-34
. It has also been shown that binding is
dependent on UVB dose and glycation 31.
Antibody-dependent cell–mediated cytotoxicity (ADCC) and CD8+
cytotoxicity may also be involved in tissue damage. Keratinocytes can be killed both
by complement-mediated cytotoxicity lysis and ADCC 13, 14
. Gershwin et al
demonstrated a destruction of DNA-coated targets by lupus antisera and lymphocyte
effectors 35. In a recent study Furukawa et al supported that keratinocytes from
patients with SLE and SCLE showed enhanced cytotoxicity to UV radiation and to
antibody-mediated cytotoxicity 36. More specifically, keratinocytes from SCLE
patients have been found to be more susceptible to ultraviolet radiation-induced
cytotoxicity and binding of anti-Ro/SS-A and showed significant ADCC after
irradiation, incubation in their own patients’ sera and exposure to mononuclear cells
from normal individuals. Furthermore, antiRo/SS-A IgG fractions induce enhanced
cytotoxicity of irradiated keratinocytes from SCLE patients. Taking into consideration
that basal keratinocytes are relative resistant to ultraviolet radiation-induced apoptosis
while suprabasal keratinocytes undergo apoptosis in vivo after irradiation 37 it seems
possible that suprabasal keratinocytes are the major targets of ADCC in SCLE lesions
38.
8
Tissue injury in SLE is mainly attributed to immune complex formation and
deposition 39. This concept is also confirmed in SCLE skin lesions, since
immunoglobulin and complement have been identified at the dermal-epidermal
junction, leading to complement activation, membrane attack complex formation and
cellular injury. Moreover, the presence of immunoglobulin at the dermal-epidermal
junction is not always accompanied by tissue damage. Besides, the presence of a
lymphocytic infiltrate implies a cell-mediated immunity. Recent findings suggest
ADCC and CD8+ cytotoxicity as underlying immunological mechanisms responsible
for the injury phase and the development of clinical symptoms. Taking together, we
can speculate that immune complexes and a direct autoantibody effect possibly
characterize the early phase of tissue damage. ADCC and direct T cell-mediated
cytotoxicity probably occur later enhancing the inflammatory response. It appears that
the injury phase of SCLE is a complex phenomenon, attributed to distinct
autoimmune effectors mechanisms which include both humoral and cell-mediated
immunity. The initial hypothesis of immune complex deposition has been enriched by
new findings which point out the role of cell mediated immunity and provide new
insights in our understanding the pathophysiology of the disease.
In another recent study, a quantitative immunohistochemical analysis of CD4+
T cells from patients with cutaneous lupus erythematosus including SCLE, revealed
that the number of Foxp3+ Treg (CD4+ CD25+) was significantly reduced compared
to that in lesions from patients with other inflammatory diseases 40. There was no
correlation between disease subtypes and the frequency of Foxp3+ Treg in the skin of
patients with cutaneous lupus erythematosus. Referring to the phenotype and number
of Treg as well as to their sensitivity of apoptosis, no differences were observed in
peripheral blood between SCLE patients and normal donors 40. The fact that Treg are
reduced in skin lesions but not in peripheral blood of patients with CLE, reflects a
9
limitation of the disease to the skin while a systemic decrease could explain an
involvement of multiple organs in patients with SLE. The relative lack of Treg could
amplify the autoimmune process and enhance the inflammatory response in skin
lesions of SCLE patients. However, a more careful interpretation is needed since this
reduction could be the result of the disease process rather than a causative factor.
GENETIC CONSIDERATIONS
Multiple genes have been involved in the development of CLE and especially
SCLE. It is well established that polymorphisms of genes encoding HLA, TNFa and
complements molecules, have the strongest genetic association with SCLE. Specific
combinations of these genes may determine individual susceptibility to SCLE. It is
currently believed that a specific genetic background is necessary for peculiar
environmental factors to act and lead the immune system to autoimmunity and SCLE
lesions.
Firstly, the HLA1, B8, DR3 haplotype has been found in 25% of a cohort of
SCLE patients 41 and since then it has been widely extended
7. Subsequently, the
HLA1, B8, DR3, DQ2, DRw52 and C4 null ancestral haplotype has been proposed as
a susceptibility haplotype for SCLE, especially for patients with positive anti-Ro
autoantibodies 42. In addition, HLA-DR3 women have been associated with SCLE,
SLE and Sjögren syndrome as well as with the presence of anti-Ro autoantibodies
suggesting a crucial immunogenetic role for the antibody production. In a past study,
the presence of HLA DQ1 and DQ2 has been found to enhance the production of
autoantibodies in patients with Sjögren syndrome 43. The mechanisms, by which the
HLA genes are involved in the pathogenesis of the disease, have not been elucidated
10
yet. It is well documented though that MHC loci influence many autoimmune
diseases and many models have been proposed. It is generally accepted that HLA
molecules are possibly involved in T cell repertoire selection and antigen presentation
leading to abnormal autoimmune responses 44.
In addition, deficiencies of C2 and C4 components of complement have been
associated with both SLE and SCLE 45, 46
. The majority of patients with C2 or C4
homozygous deficiency have anti-Ro autoantibodies implying a possible role for this
antibody in the development of SCLE 47. In a recent study a homozygous single
nucleotide polymorphism of the complement C1qA gene which encodes the A chain
of the C1q complement component, has been associated with decreased levels of C1q
and a SCLE phenotype 8. Similarly, patients with a complete deficiency of C1q, C1r
or C1s are prone to develop SLE and present with photosensitive cutaneous lesions 48.
More specifically, Pickering et al supported that C1q component of complement is
very important in the physiological clearance of apoptotic cells 49. Furthermore,
complement deficiency states may lead to impaired clearance of immune complexes
allowing subsequent deposition in tissues and injury via ligation of Fcγ receptors on
leukocytes. Thus, another physiological activity of complement is processing and
clearance of immune complexes and apoptotic cells. In this context, complement
system contributes in the resolution of immune response and prevention of
autoimmune phenomena.
Finally, a polymorphism of the TNFα gene promoter (-308A) has been found
to encode increased expression of TNFα by UV-B irradiated keratinocytes and has
been associated with SLCE lesions 8, 9
. However, the TNFα gene is located within the
HLA region and thus shares the same extended haplotype with DR3, implying a
possible linkage equilibrium. Evidence in SLE patients though, supports that each is
likely to contribute independently to disease susceptibility 50.
11
THE EFFECT OF ULTRAVIOLET LIGHT
There is a clear relationship between ultraviolet light (UV) and
photosensitivity in patients with SLE and SCLE. Photosensitivity is included in the
diagnostic criteria of SLE while SCLE is considered to be the most photosensitive
lesion of cutaneous lupus. The UV spectrum is divided into two major segments:
UVB which represents the wavelengths between 290-320nm and UVA which consists
of wavelengths between 320-400nm. Epidermis is a major absorbent of UVB and less
than 10% penetrates to dermis. On the contrary, UVA penetrates to the dermis and
contribute in altering structural and matrix proteins. Although solar light includes both
UVB and UVA, UVB is more efficient in evoking photosensitive responses and has
been markedly involved in forms of CLE 10, 51-53
. However, UVA has been also found
to induce lupus skin lesions 11, 27, 54
.
DNA damage and apoptosis
UV light is capable of DNA damage. More specifically, UVB can cause
excitation of DNA molecules leading to formation of pyrimidine dimmers acting on a
direct way 55, 56
. On the contrary UVA seems to damage DNA indirectly via a
photosensitized reaction by modifying singlet oxygen generating purine bases 55, 56
.
Altered DNA molecules with specific modifications might possess immunogenic
properties and in combination with a possible insufficiency of repairing mechanisms
could lead the immune system to autoimmunity. Consistent with this speculation is
12
the observation that SLE patients can develop immune responses to UV altered DNA
molecules 57.
Apoptosis is considered a programmed cell death which is characterized by
specific steps such as DNA cleavage and fragmentation, nuclear condensation, surface
blebbing, cytoplasmic contraction and finally packaging of cellular components
within membranes and formation of apoptotic bodies. During this process toxic agents
such as cytolytic enzymes are released and many self antigens can be redistributed
and presented to the immune system. In addition, enzymatic degradation can cause
alterations in these autoantigens and thereby increase their immunogenicity 58.
Normally, apoptotic debris is eliminated by phagocytes and overexposure of
autoantigens to immune system is prevented. Therefore, an increase rate of apoptosis
or a decreased rate of clearance of apoptotic cells predisposes to autoimmunity.
UV exposure is known to induce apoptosis in keratinocytes although basal
keratinocytes are more resistant than suprabasal cells 37, 59
. UVB is considered to be a
strong inducer of apoptosis and in that way enhances the exposure of autoantigens at
the surface of apoptotic cells. Carrichio et al supported that UVB dose plays a crucial
role in inflammation and autoantigens redistribution and determines the rate of
apoptosis 60. Low and intermediate doses induce non-inflammatory apoptotic
procedures while high doses result to proinflammatory necrosis. More specifically,
UVB can cause an upregulation of both Fas and FasL leading to apoptotic death via
the activation of this particular pathway 61. In cutaneous lupus lesions, the increased
rate of apoptosis results to translocation and display of autoantigens such as Ro/SSA
and La/SSB to keratinocytes cell surface. In a past study, it was demonstrated that
UVB irradiated keratinocytes from SLE patients, underwent apoptosis and formed
apoptotic blebs rich in lupus autoantigens including both Ro/SSA and La/SSB 62. This
finding has led to the suggestion that these autoantigens can be phagocytozed,
13
processed and presented to lymphocytes and thus contributing to the beak of immune
tolerance and generation of primary immune responses to self-antigens 63.
Furthermore, Golan et al demonstrated enhanced membrane binding of antibodies to
Ro/SSA and La/SSB to cultured keratinocytes of SLE patients after UV irradiation
implying a possible translocation of these antigens to the cell surface32.
Several studies supported a disturbed clearance of apoptotic cells in SLE.
More specifically, macrophages have been proposed to exhibit impaired clearance
capacity of apoptotic cells 64-66
. Furthermore, apoptotic neutrophils from SLE patients
have been found incapable of binding the C1q component of complement, leading to
accumulation of apoptotic debris 67. Similarly, C1q appears to bind directly to surface
blebs of apoptotic human keratinocytes 68. It has been mentioned previously that
decreased C1q levels have been also associated with the SCLE phenotype 8. The
decreased rate of clearance and the subsequent accumulation of apoptotic debris
predisposes to self antigen presentation and processing which may result to
autoimmune responses.
Apoptosis, inflammation and type I INFs
Besides, apoptosis has been also associated with the development of
inflammatory skin lesions in SLE. Macrophages that have ingested apoptotic cells
seem to release anti-inflammatory cytokines such as TGFβ 69 and thus a decreased
clearance rate enhances an inflammatory profile which can induce autoimmune
procedures. It has been supported that apoptotic cells can interact with Fcγ receptors
on phagocytes and thereby activate the latter cells and promote the inflammatory
response in SLE 70. In the skin of patients with SLE, it has been shown that DNA and
RNA particles released from apoptotic cells can induce the production of IFNα by
plasmacytoid dendritic cells 71. In a past study, Farkas et al found that pDC were
14
present at skin lesions of patients with SLE and DLE suggesting that pDC are an
important source of IFNα/β in cutaneous LE lesions 72. Activation of pDC leads to
production of INFα which induces the secretion of specific chemokines such as
CXCL9, CXCL10 and CXCL11 12. These chemokines are the major ligands of the
CXCR3 which is expressed by skin homing lymphocytes and premature pDC and
therefore contribute to the recruitment of inflammatory cells at skin lesions.
Furthermore, in a recent study it has been shown that the expression pattern of
interferon–inducible proteins including CXCL9 and CXCL10, reflects the
characteristic histological distribution of infiltrating immune cells in different CLE
subsets, including SCLE 15. More specifically, in SCLE lesions it was demonstrated
an association between these specific chemokines and the distribution of
CXCR3+CD3+ focused in epidermis and upper dermis. In another study, it has been
shown that in patients with active CLE lesions, IFN-inducible chemokines such as
IP10 and CXCL10 can lead to the recruitment of CXCR3 expressing T cells into the
skin lesions, suggesting that type I INFs can induce a Th1-bias inflammatory immune
response 73. These findings have revealed the important role of innate immunity and
IFNα and open up options for novel therapeutic approaches in CLE 74.
Cytokines and adhesion molecules
UV light is also involved in cytokine expression, vascular activation and
induction of adhesion molecules, chemokines and selectins which mediate the
migration of inflammatory cells and lymphocytes to skin lesions of CLE 16, 17
. UVB
can promote the release of proinflammatory cytokines such as TNFα and IL-1 by
keratinocytes. These cytokines can cause upregulation of ICAM on keratinocytes and
therefore account for the increased homing of leukocytes to the skin 75. Additionally,
15
TNFα is capable of inducing translocation of Ro/SSA and La/SSB autoantigens to the
surface of keratinocytes and apoptosis via the TNFR1 76. Immunohistochemical
studies in skin biopsies of SCLE patients who were receiving treatment, demonstrated
that refractory lesional skin tissue displayed a strongly positive distribution of TNFα
particularly in epidermis while no prominent staining was seen in non lesional skin
from the same group or the control group 77. These findings suggest a potential role of
TNFα in the pathogenesis of SCLE as well as a possible therapeutic target. UVA
exposure can also promote IL-12 and IFN-γ production in the skin leading to a Th1
inflammatory response 78. Blood vessels and endothelium are also involved in SCLE
lesions. Activated endothelium expresses a variety of adhesion molecules which
mediate the recruitment and transmigration of leukocytes through vascular wall, at the
sites of skin lesions. TNFα and INF-γ are potent inducers of ICAM-1 by the
endothelium after UVB exposure 79 while VCAM-1 has been found to be highly
expressed by endothelial cells in skin lesions of lupus 80, 81
. Finally, E-selectin has
also been found to be increased in lupus photosensitive lesions 81 and after UVB
exposure 82.
Although the data mentioned above are referring to SLE and cutaneous lupus,
similar alterations in vascular endothelium and cytokines are implied in SCLE. It is
obvious that the overproduction of proinflammatory cytokines affect both the
inflammatory procedures observed in skin lesions and cutaneous endothelium.
Keratinocytes are induced to express ICAM-1 which facilitates T-cell migration to the
skin. The endothelium of cutaneus lesions is activated and expresses associated
adhesion molecules such as ICAM-1, VCAM-1 and E-selectins which contribute to
recruitment of leukocytes from the circulation to the inflammatory sites. Probably,
LFA-1 is also upregulated on the surface of leukocytes and type I INFs promote the
release of specific chemokines which further attract the inflammatory cells. This
16
complex network of cytokines and chemokines plays an important role in
perpetuating and amplification of inflammation and therefore contribute to
propagation and maintenance of the autoimmune procedures.
OVERVIEW
SCLE is the most photosensitive form of cutaneous lupus erythematous and it
has been associated with the presence of anti-Ro/SSA autoantibodies. Data over the
past years support that the etiopathogenesis of SCLE share common features with
SLE and the other forms of CLE, although it is considered a distinct skin lesion. It is
well documented that specific genetic background is an important factor for the
development of SCLE and many candidate genes have been identified. The ancestral
haplotype HLA1, B8, DR3, DQ2, DRw52 and C4 null, deficiencies of C1q, C2 and
C4 components of complement and the TNFα -308 polymorphism have been found to
predispose to the SCLE phenotype. Although the exact mechanisms have not been
established yet, it seems possible that this genetic susceptibility interferes with T cell
repertoire selection and autoantigen presentation. The effect of UVL and especially
UVB appears to play an important role at the initiation and maintenance of
autoimmunity. UVL increases the rate of apoptosis of keratinocytes and causes
redistribution of autoantigens such as Ro/SSA and La/SSB. The apoptotic blebs arise
form the nuclear structures and harbor a variety of self antigens which are processed
by phagocytes and presented to lymphocytes, leading to primary autoimmune
responses. Impaired clearance of apoptotic cells results in accumulation of apoptotic
debris and further enhancement of autoantigen presentation to the immune system.
UVL also causes damage and alteration in DNA molecules which become more
17
immunogenic. These mechanisms participate in the induction phase and the loss of
immune tolerance. In addition, persistent apoptosis activates phagocytes via the Fcγ
receptors and contributes to the development of an inflammatory environment at the
skin lesions. UVL induces the overproduction of proinflammatory cytokines including
IL-1 and TNFα by the skin and the expression of adhesion molecules (ICAM-1,
VCAM-1, E-selectins) by both keratinocytes and endothelial cells. Plasmacytoid cells
produce high levels of IFNα which causes secretion of specific chemokines such as
CXCL9, 10, 11 by keratinocytes and fibroblasts. This complex network of cytokines,
adhesion molecules and chemokines participate in leukocyte recruitment at the skin
and is responsible for the expansion phase through perpetuation and maintenance of
inflammation. Finally, the injury phase is mediated by immune complexes deposition,
direct autoantibody effect, direct T cell cytotoxicity and ADDC. Recent studies
provide strong evidence for the dynamic role of the latter mechanisms and suggest
further therapeutic approaches. The current immunological concepts in the
pathogenesis of SCLE are summarized in Figure 1.
These new findings have improved our understanding of the genetic,
environmental and immunologic mechanisms which are involved in the pathogenesis
of SCLE. The variety of potent molecules and cytokines implies molecular orientated
therapeutic strategies which include cytokine inhibition, direct T cell therapies and
disruption of T cell interactions with adhesion molecules. The role of innate and cell
mediated immunity has now become apparent and directs our insights into new
researching fields.
18
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28
Genetic Susceptibility
+
UVL
Suprabasal Keratinocytes
Increased Rate of Apoptosis
Decreased Clearance of Apoptotic Debris
DNA Damage
Processing by APC/DC
Autoantigen Presentation
Initiation Phase
Primary Autoimmune Response
B autoreactive clones/anti-
Ro, anti-La
T autoreactive clones
Adhesion Molecules (ICAM-1)
Proinflammatory Cytokines (TNFα, IL-1)
Redistribution of Autoantigens (Ro, La)
Amplification Phase of Autoimmune Response
Recruitment of Leukocytes
pDC
IFNα induced Chemokines
Endothelium
Adhesion Molecules
(ICAM-1, VCAM-1, E-selectins)
Injury Phase
ICs, Direct Antibody Effect,
ADCC, CD8 cytotoxicity,
Figure 1. Current immunological concepts in the pathogenesis of SCLE.
