Get the Wolf by the Genes
Thursday, September 10, 2009
The first description of lupus erythematosus, made by Cazenave
in 1851, arose from a case presentation of a patient who had skin
lesions which resembled discoid lupus.1 This
initial discovery spurred on further investigation into the
disease, and it was found that the presence of discoid lupus
affected multiple organs.2 This instance
exemplifies the importance of skin disease in lupus, as it could
often be the key finding that unveils the correct diagnosis.
Dr. James N. Gilliam classified cutaneous lupus erythematosus
(CLE) into three forms: acute (ACLE), sub-acute (SCLE) and chronic
(CCLE).3 The acute form, which is always associated
with systemic lupus erythematosus (SLE), is characterized by the
transient malar rash and erythema in photosensitive areas. SCLE can
present as polycyclic erythematous plaques with peripheral scaling
or psoriasiform papules and plaques in photosensitive areas. CCLE
contains various subtypes, with discoid lupus erythematosus (DLE)
as the most common subtype. DLE lesions begin as erythematous
macules and papules with follicular plugging that evolve into
atrophic dyspigmented scarring patches and plaques. The factors
that dictate the subtype of cutaneous lupus in an individual remain
The multiple manifestations of CLE provide an indication of the
complex etiology of this disease. It has a multi-factorial
pathogenesis that includes genetic, environmental, and
immunological causes. Although each factor alone is not sufficient
for disease induction, the interplay between these three factors is
essential to the formation of CLE. The genetic makeup distinguishes
individuals who are more susceptible to this disease. Environmental
factors such as ultraviolet light (UV) and viruses can initiate a
cascade of events that leads to a heightened immune system activity
that involves autoantibody formation.
Genetics can predispose individuals towards developing CLE by
highlighting genes that drive one's immune response toward
hyperactivity or losing the ability to distinguish from self and
non-self. Numerous genes linked to CLE have been found within the
major histocompatibility complex (MHC), which encodes proteins such
as human leukocyte antigen (HLA), complement components, and tumor
necrosis factor (TNF) -α and -β. Specifically, patients with
various HLA subtypes have been associated with different types of
CLE, which suggests that abnormal antigen presentation could lead
to a dysregulated immune system in CLE. Furthermore, SCLE has been
linked to several HLA subtypes, such as HLA-B8, especially those
with polycyclic plaques,4 -A1 and
-DRw3.5 Moreover, both class I and II HLA alleles
have been associated with DLE, such as
HLA-DQA1,6 -Cw7, -DR2 and
-DR3.7 Genetic deficiencies in complement
components have also contributed to the formation of CLE.
Racila et al. reported a single nucleotide
polymorphism in the C1QA gene in SCLE patients, which correlated
with decreased levels of serum C1q, and which binds to apoptotic
keratinocytes and aids in their clearance.8
Furthermore, C1q,9 C210 and C5
deficiencies11 have been reported in patients with
DLE. Finally, the frequency of the genetic polymorphism in the
TNF-α promoter -308A, which increases TNF-α
production,12 was determined to be augmented in
SCLE patients and responsive to ultraviolet B (UVB)
Whereas genetics might set up the foundation for a hyperactive
immune system, the formation of CLE depends on environmental
factors, such as UV light and viruses. Inflammatory responses can
be activated by UV light by prompting keratinocyte release of the
primary cytokines, IL-1α14 and
TNF-α,15 which enhance the presence of adhesion
molecules on dermal venules16,
cytokine17 and chemokine
production.18 Keratinocyte apoptosis can also be
induced by UV light. When cultured keratinocytes irradiated with
UVB underwent apoptosis, nuclear antigens such as Ro/SSA were
transported to the cellular surface and formed apoptotic blebs,
which resulted in their exposure to the immune
system.19 Human keratinocytes from SLE and SCLE
patients who were irradiated with UVB showed heightened antibody
binding to nuclear antigens, which led to increased
antibody-mediated cytotoxicity.20 These in
vitro findings have been confirmed by the amplified
presence of apoptotic keratinocytes in CLE skin by
immunohistochemistry.21 Viruses might also
instigate formation of CLE lesions by inducing keratinocyte
apoptosis.22 Molecular mimicry, in which foreign
antigens such as viruses cross-react with lupus autoantigens, and
epitope spreading, in which the immune response against an epitope
of a specific antigen extends to other epitopes on the same antigen
or similarly structured antigens, can be responsible for this
phenomenon. Specifically, animals immunized with the Epstein-Barr
virus antigen-1 developed anti-Ro antibodies.23
As mentioned earlier, autoantibodies, which appear downstream in
the events initiated by environmental influences, recognize nuclear
antigens on the surface of apoptotic keratinocytes and induce
antibody-mediated cytotoxicity and complement activation. Anti-Ro
antibodies, which have been linked to SCLE
patients,4 have demonstrated this pathogenic
potential. Keratinocytes cultured from SCLE patients demonstrated
increased cytotoxicity when exposed to sera containing anti-Ro
antibodies compared with anti-ssDNA sera and normal human
sera.20 Bennion and colleagues noted that the
principal subclass of anti-Ro antibodies in SCLE skin was IgG1,
which is capable of activating the complement
pathway.24 Anti-La antibodies are often
concomitantly present with anti-Ro antibodies, which is probably
due to intermolecular epitope spreading and which has been observed
in mice immunized with Ro and La.25 However,
although autoantibodies have been involved in renal damage in lupus
nephritis through the formation of immune complexes bound to the
glomerular basement membrane,26 the ability of
autoantibodies to induce skin damage has yet to be explained .
The evolution of CLE depends on several steps, which include
having a genetic makeup that renders individuals susceptible to CLE
by having hyperactive immune systems, being exposed to
environmental triggers including sunlight and viruses, and by
igniting a dysregulated chain of events that enhance the presence
and activity of autoantibodies through epitope spreading and
molecular mimicry. The importance of this multi-step model is
reflected in the treatment regimens, such as sun-protective
measures and immunomodulatory therapies, because they target the
latter two steps to inhibit disease progression. The reversal of
genetic abnormalities that predispose individuals to CLE through
gene therapy could be even more beneficial because it would inhibit
the cascade of events early on. In fact, genetically engineered
anti-cytokine inhibitors27 and anti-inflammatory
cytokines such as TGF-β28 have been explored as
treatments for SLE in murine models and could have therapeutic
value in SLE and CLE patients. The exciting potential of these
therapies and other investigational drugs might revolutionize
future treatment in CLE.
- Cazenave PLA, Chausit, M. Du lupus. Ann Malad Peau
- Fatovic-Ferencic S, Holubar K. Early history and iconography of
lupus erythematosus. Clin Dermatol.
- Gilliam JN, Sontheimer RD. Distinctive cutaneous subsets in the
spectrum of lupus erythematosus. J Am Acad Dermatol.
- Sontheimer RD, Maddison PJ, Reichlin M, et al.
Serologic and HLA associations in subacute cutaneous lupus
erythematosus, a clinical subset of lupus
erythematosus. Ann Intern Med. 1982;97:664-671.
- Stastny P, Gilliam JN. HLA-A1, B8, DRw3 in patients with a
distinct form of lupus erythematosus. Transplant
- Fischer GF, Pickl WF, Fae I, et al. Association
between chronic cutaneous lupus erythematosus and HLA class II
alleles. Hum Immunol. 1994;41:280-284.
- Knop J, Bonsmann G, Kind P, et al. Antigens of
the major histocompatibility complex in patients with chronic
discoid lupus erythematosus. Br J Dermatol.
- Racila DM, Sontheimer CJ, Sheffield A, et al.
Homozygous single nucleotide polymorphism of the complement C1QA
gene is associated with decreased levels of C1q in patients with
subacute cutaneous lupus
erythematosus. Lupus. 2003;12:124-132.
- Uenaka A, Akimoto T, Aoki T, Tsuyuguchi I, Nagaki K. A complete
selective C1q deficiency in a patient with discoid lupus
erythematosus (DLE). Clin Exp Immunol.
- Stern R, Fu SM, Fotino M, Agnello V, Kunkel HG. Hereditary C2
deficiency: association with skin lesions resembling the discoid
lesion of systemic lupus erythematosus. Arthritis
- Asghar SS, Venneker GT, van Meegen M, et al.
Hereditary deficiency of C5 in association with discoid lupus
erythematosus. J Am Acad Dermatol.
- Abraham LJ, Kroeger KM. Impact of the -308 TNF promoter
polymorphism on the transcriptional regulation of the TNF gene:
relevance to disease. J Leukoc Biol.
- Werth VP, Zhang W, Dortzbach K, Sullivan K. Association of a
promoter polymorphism of tumor necrosis factor-alpha with subacute
cutaneous lupus erythematosus and distinct photoregulation of
transcription. J Invest Dermatol.
- Chung JH, Youn SH, Koh WS, et al. Ultraviolet B
irradiation-enhanced interleukin (IL)-6 production and mRNA
expression are mediated by IL-1 alpha in cultured human
keratinocytes. J Invest Dermatol.
- Köck A, Schwarz T, Kirnbauer R, et al. Human
keratinocytes are a source for tumor necrosis factor alpha:
evidence for synthesis and release upon stimulation with endotoxin
or ultraviolet light. J Exp Med.
- Chung KY, Chang NS, Park YK, Lee KH. Effect of ultraviolet
light on the expression of adhesion molecules and T lymphocyte
adhesion to human dermal microvascular endothelial
cells. Yonsei Med J. 2002;43:165-174.
- Ansel J, Perry P, Brown J, et al. Cytokine
modulation of keratinocyte cytokines. J Invest
- Meller S, Winterberg F, Gilliet M, et al.
Ultraviolet radiation-induced injury, chemokines, and leukocyte
recruitment: An amplification cycle triggering cutaneous lupus
- Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens targeted in
systemic lupus erythematosus are clustered in two populations of
surface structures on apoptotic keratinocytes. J Exp
- Furukawa F, Itoh T, Wakita H, et al.
Keratinocytes from patients with lupus erythematosus show enhanced
cytotoxicity to ultraviolet radiation and to antibody-mediated
cytotoxicity.Clin Exp Immunol. 1999;118:164-170.
- Baima B, Sticherling M. Apoptosis in different cutaneous
manifestations of lupus erythematosus. Br J Dermatol.
- Lin JH, Dutz JP, Sontheimer RD, Werth VP. Pathophysiology of
cutaneous lupus erythematosus. Clin Rev Allergy
- McClain MT, Heinlen LD, Dennis GJ, et al. Early
events in lupus humoral autoimmunity suggest initiation through
molecular mimicry. Nat Med. 2005;11:85-89.
- Bennion SD, Ferris C, Lieu TS, Reimer CB, Lee LA. IgG
subclasses in the serum and skin in subacute cutaneous lupus
erythematosus and neonatal lupus erythematosus. J Invest
- Topfer F, Gordon T, McCluskey J. Intra- and intermolecular
spreading of autoimmunity involving the nuclear self-antigens La
(SS-B) and Ro (SS-A). Proc Natl Acad Sci U S
- Trouw LA, Groeneveld TW, Seelen MA, et al.
Anti-C1q autoantibodies deposit in glomeruli but are only
pathogenic in combination with glomerular C1q-containing immune
complexes.J Clin Invest. 2004;114:679-688.
- Lawson BR, Prud'homme GJ, Chang Y, et al.
Treatment of murine lupus with cDNA encoding
IFN-gammaR/Fc. J Clin Invest. 2000;106:207-215.
- Raz E, Dudler J, Lotz M, et al. Modulation of
disease activity in murine systemic lupus erythematosus by cytokine
gene delivery. Lupus. 1995;4:286-292.