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Lowes MA, Bowcock AM, Krueger JGPathogenesis and therapy of psoriasis. Nature 445:866-873

Authors:

Abstract

Psoriasis is one of the most common human skin diseases and is considered to have key genetic underpinnings. It is characterized by excessive growth and aberrant differentiation of keratinocytes, but is fully reversible with appropriate therapy. The trigger of the keratinocyte response is thought to be activation of the cellular immune system, with T cells, dendritic cells and various immune-related cytokines and chemokines implicated in pathogenesis. The newest therapies for psoriasis target its immune components and may predict potential treatments for other inflammatory human diseases.
Psoriasis is a common skin disease that has been recognized since
ancient times, when it was erroneously thought to be a variant of lep-
rosy. Psoriasis affects about 25 million people in North America and
Europe, and is probably the most prevalent immune-mediated skin
disease in adults. It is an organ-specific autoimmune disease that is
triggered by an activated cellular immune system
1–6
and is similar to
other immune-mediated diseases such as Crohns disease, rheumatoid
arthritis, multiple sclerosis and juvenile-onset diabetes. All of these fit
the definition of an autoimmune disease as “a clinical syndrome caused
by the activation of T cells and B cells, or both, in the absence of an
ongoing infection or other discernable cause
7
.
Because psoriasis occurs in an accessible organ it has been possible to
study its cellular and genomic features in tremendous detail compared
with those of other human autoimmune diseases. In turn, evolving
pathogenic concepts are increasingly being tested directly in patients
with psoriasis by administration of new therapies targeted to specific
immune molecules. In this review we consider how interactions between
resident skin cells and elements of the immune system — a complex
network of cells and molecules that mediate innate and adaptive immu-
nity — conspire to produce a disease that can last for decades in focal
regions of the skin. We also briefly consider potential contributions of
transmitted genes that increase susceptibility to psoriasis. More detailed
discussion of the genetic defects and genomic pathways involved in pso-
riasis, and comparisons with other autoimmune diseases, are available
elsewhere
4,8
.
Clinical and histological appearance
Psoriasis vulgaris, the common form of psoriasis, is characterized by red,
scaly, raised plaques. Although psoriasis vulgaris can occur in children, it
often begins in late adolescence or early adulthood and then usually per-
sists for life. Classic psoriasis vulgaris has a predilection for certain areas
such as elbows, knees and the scalp. It may remain localized or become
generalized over time. There are clinical variants of psoriasis, defined
as subsets, with identical histopathological changes in the skin. Guttate
psoriasis is characterized by small, scattered papules and is potentially
linked to preceding streptococcal infections
1
. Other recently described
variants of psoriasis vulgaris include thick versus thin plaque disease
9
,
and small versus large plaque disease
10
. A notable subset of patients with
psoriasis develops psoriatic arthritis, a potentially debilitating illness
2
.
Histologically, psoriasis has a defining appearance
1
(Fig. 1). There
is marked thickening of the epidermis, due to increased proliferation
of keratinocytes in the interfollicular epidermis, and epidermal rete
— downward undulations of the epidermis — become very elongated
and form long, thin downward projections into the dermis (Fig. 1).
The differentiation of keratinocytes is extensively altered in psoriasis
4
,
paralleling ‘regenerative maturation, an alternative cell differentiation
programme that is transiently expressed during wound repair. Psoriatic
plaques have surface scale, which is caused by aberrant terminal dif-
ferentiation of keratinocytes. The granular layer of the epidermis, in
which terminal differentiation begins, is greatly reduced or absent in
psoriatic lesions. Consequently, a stratum corneum forms from incom-
pletely differentiated keratinocytes that aberrantly retain a cell nucleus
(this is known as parakeratosis, and the affected cells as parakeratotic
keratinocytes). Scaling, and the consequential break in the protective
barrier, are caused by failure of psoriatic corneocytes (terminally dif-
ferentiated keratinocytes) to stack normally, secrete extracellular lipids
and adhere to one another.
Other defining histological features of psoriasis include the presence
of neutrophils within small foci in the stratum corneum and significant
mononuclear infiltrates in the epidermis, which are detectable with
immunostaining. In addition, there is marked infiltration of mono-
nuclear leukocytes (T cells and dendritic cells, DCs) into the dermis
and elongated/hyperplastic blood vessels in the papillary dermal region
(between epidermal rete). Marked dilation of these vessels causes the
visible redness of psoriatic skin lesions. Many lymphocytes, monocytes
and neutrophils are clearly adherent to endothelial cells that acquire
characteristics of high endothelial venules, which are usually found in
lymph nodes. Endothelial cells are activated in psoriatic lesions, as is
indicated by staining for intracellular adhesion molecule-1 (ICAM-1,
also known as CD54), vascular cell adhesion molecule-1 (VCAM-1, or
CD106) and E-selectin (CD62E)
1
. Leukocytes can gain entry to skin
parenchyma by transmigration through reactive vessels, but resident
skin leukocytes might also expand to create the dense infiltrates seen
in psoriatic lesions.
It is increasingly being recognized that even normal skin contains
abundant stores of T lymphocytes
11
as well as resident populations of
DCs
12
, suggesting that skin might be a potential site for the direct trig-
gering of recall immune responses. Experiments in which non-lesional
skin from patients with psoriasis has been grafted to immunodeficient
AGR mice have established the important principle that resident popula-
tions of T cells and DCs might be sufficient, when expanded, to induce
psoriasis
13
. As illustrated in Fig. 1, psoriasis vulgaris lesions contain
prominent aggregates of mononuclear leukocytes in the dermis that
consist of hundreds to thousands of intermixed T cells and DCs, and
these regions might function as organized lymphoid tissue that perpetu-
ates immune infiltrates in psoriatic plaques
14
.
Pathogenesis and therapy of psoriasis
Michelle A. Lowes
1
, Anne M. Bowcock
2
& James G. Krueger
1
Psoriasis is one of the most common human skin diseases and is considered to have key genetic
underpinnings. It is characterized by excessive growth and aberrant differentiation of keratinocytes, but is
fully reversible with appropriate therapy. The trigger of the keratinocyte response is thought to be activation
of the cellular immune system, with T cells, dendritic cells and various immune-related cytokines and
chemokines implicated in pathogenesis. The newest therapies for psoriasis target its immune components
and may predict potential treatments for other inflammatory human diseases.
1
Laboratory for Investigative Dermatology, The Rockefeller University, 1230 York Avenue, Box 178, New York, New York 10021, USA.
2
Department of Genetics, Washington University, School of
Medicine, 4566 Scott Avenue, Saint Louis, Missouri 63110, USA.
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The yin and yang of cellular interactions in psoriasis
Two fundamentally different cell types interact in the formation of a
psoriatic lesion: epidermal keratinocytes and mononuclear leukocytes.
Gene-expression programmes in these diverse cell types are likely to be
influenced by distinct psoriasis susceptibility genes
4
. Whereas keratino-
cytes might be viewed only as bystander cells in terms of immune activa-
tion, it is more likely that they are active participants in the recruitment
and activation of leukocytes in psoriatic lesions. Thus, there are two sets
of interactive cellular responses in the psoriatic lesion that potentially
create a yin/yang relationship — the balance between the activation of
innate and acquired immune cell types, and the factors produced by
epidermal keratinocytes that directly affect T cells and DCs, and vice
versa (Fig. 2).
Effector cells of innate immunity in psoriatic lesions include neu-
trophils, plasmacytoid DCs and CD11c
+
DCs. Because neutrophils are
short-lived, they must be constantly recruited into lesions from blood
stores. The chemokines interleukin-8 (IL-8) and growth-regulated onco-
gene-α (GRO-α, also known as CXCL1) — and possibly also S100A7/
A8/A9 proteins — from keratinocytes produce a chemotactic gradient
for the migration of neutrophils into the epidermis
1
. BDCA-2
+
CD123
+
plasmacytoid DCs, which produce high levels of interferon-α (IFN-α)
upon activation, have been proposed to have an important role in the
triggering of lesions
15
. CD11c
+
DCs are increased in psoriatic lesions and
constitute a cell group roughly equal to T cells in overall abundance
16
.
Although Langerhans cells and dermal DCs have long been recognized
as the main types of DC in skin
17
, it is now clear that psoriatic lesions
contain additional types of DC. CD11c
+
(myeloid) DCs correspond to
interstitial DCs in other tissues and are the most abundant DC type in
the dermis
16
. In addition, plasmacytoid DCs and several populations of
activated DCs are present in psoriatic lesions (Fig. 2).
In psoriatic lesions, CD11c
+
DCs express high levels of tumour necro-
sis factor (TNF) and the enzyme inducible nitric oxide synthase (iNOS),
and have been proposed to be the human equivalent of TIP-DCs (TNF-
and iNOS-producing DCs), cells that have effector functions in clearing
some bacterial infections in mice
16,18
. In addition, CD11c
+
DCs prob-
ably produce the cytokines IL-23 and IL-20, which have the potential to
activate T cells and keratinocytes, respectively
19,20
. A fraction of CD11c
+
DCs also bear ‘maturation’ markers, such as DC-LAMP or CD83 (ref.
16), and so could function as conventional DCs in terms of presenting
antigens to T cells for the triggering of acquired immune responses. In
fact, the juxtaposition of T cells and mature DCs in dermal aggregates
(Fig. 1), as well as the expression of lymphoid-organizing chemokines
such as CCL19, CCL21, CXCL12 and CCL18 (ref. 21; Fig. 2), may well
promote T-cell activation in situ
14,22,23
.
Collagen
Resident leukocytes
Abnormal stratum
corneum
Epidermal scale
Epidermis
Rete
Elongated rete
(psoriaform
hyperplasia)
Papillary dermis
Reticular dermis
Reticular dermis
Normal stratum
corneum
Papillary dermis
Organized lymphoid
infiltrate
Small blood vessels
Enlarged blood vessels
(angiogenesis)
Langerhans cell
Inflammatory DC
(TIP-DC)
Plasmacytoid DC
Neutrophil
Skin-homing T cell
Immature CD11c
+
DC
Mature DC
(DC-LAMP
+
or CD83
+
)
Expanded leukocytes
Adjacent skin (normal appearance)
Psoriatic plaque
Epidermis
Figure 1 | Histological components of a mature psoriatic plaque
compared with normal skin. Skin histology in normal skin and psoriatic
lesions, with corresponding diagrams. The skin has three main layers.
First there is the epidermis, which consists mainly of epithelial cells
(keratinocytes). Second is the dermis, the bulk of which is made up of
an extracellular matrix composed predominantly of collagens. This
contains fibroblasts and a rich neurovascular network as well as many
epidermal appendages that extend into the dermis, such as hair follicles,
sebaceous glands and sweat glands. Third is the hypodermis, or layer of
subcutaneous adipose tissue with supporting stromal cells (not shown in
figure). In psoriatic, cells of the stratum corneum (the outermost layer
of the epidermis) stack abnormally, leading to the formation of scales,
and the granular layer of the epidermis is much reduced. Epidermal
rete are considerably elongated and blood vessels in the dermis are
enlarged. Although normal skin contains notable numbers of resident
and trafficking immune cells (and is an immune-competent organ), in
psoriatic lesions the leukocyte number is significantly increased and many
immune-related pathways are activated.
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T cells in psoriatic lesions are polarized as T helper 1 (T
H
1; CD4
+
)
and T cytotoxic (T
C
1; CD8
+
) subsets
1
, but probably also include a sepa-
rate population of T
H
17 cells (induced by IL-23 in model systems)
24
.
Some CD8
+
T cells are specialized for homing into the epidermis
through expression of α
E
β
7
integrin, which binds to E-cadherin on
keratinocytes
1
. In addition, many T cells express CD161 and other
killer receptors, which might indicate a role for natural killer T cells
in pathogenesis
25
.
Keratinocyte products influence immune activation, and products
of activated immunocytes alter keratinocyte responses, including the
induction of new adhesion molecules for T cells (Fig. 2). Triggers for
innate DCs might include heat-shock proteins or S100A12 produced
by keratinocytes, or various environmental Toll-like receptor (TLR)
agonists. Peptide antigens might also trigger conventional or acquired
immune activation of T cells, as implied by the presence of clonal popu-
lations of T cells in lesions
26
. Although antigen persistence could explain
chronic immune activation, defective function of regulatory T (T
reg
) cells
has been suggested as another factor that might contribute to unbridled
T-cell activation
27
.
The sum of cellular interactions creates a tissue profile and a clinical
phenotype, which we recognize as psoriasis vulgaris. Effective treatment
with various immune antagonists breaks pathogenic immune activation
and restores normal keratinocyte growth. In fact, the most important
evidence that psoriasis is an immune-mediated disease comes from the
finding that disease can be reversed with selective immune-targeted bio-
logical agents such as DAB389IL-2 (ref. 28) and CTLA4Ig (refs 29, 30).
Molecular pathways of inflammation
The ability to develop effective therapeutics by rational design is cru-
cially dependent on elucidation of the molecular circuitry of inflamma-
tion in human autoimmune diseases. Cytokine interactions in psoriasis
have previously been illustrated as a ‘type-1 pathway’, which assumes a
linear relationship between proximal inducers (IL-23 or IL-12), produc-
tion of IFN-γ and TNF by type-1 T cells, and downstream activation of
numerous IFN-responsive genes through signal transducer and activa-
tor of transcription 1 (STAT1)
14
. Although this model is conceptually
useful, it accounts for only a small fraction of the more than 1,300 genes
that become upregulated in psoriatic lesions
21
. Figure 3 presents an
alternative view of the inflammatory circuitry in psoriasis, which is
more of a network or interactive model
8
. Clearly, STAT1, STAT3 and
nuclear factor-κB (NF-κB) transcription factors are activated in psoria-
sis. Upstream activators may well be IFNs for STAT1, and TNF or IL-1
for NF-κB, but more recently discovered cytokines such as IL-20 and
IL-22 also have the ability to activate STAT and NF-κB pathways
20,31
,
thus supporting the network concept.
Keratinocyte-derived cytokines such as platelet-derived growth factor
(PDGF) and vascular endothelial growth factor (VEGF) influence the
growth of supporting stromal cells. Activated stromal cells overproduce
factors such as keratinocyte growth factor (KGF) that can induce prolif-
eration of keratinocytes
32
. Many immune-derived cytokines, including
IL-1, IL-6, IL-17, IL-19, IL-20, IL-22, TNF and IFNs, can also regulate
keratinocyte proliferation, with some immune-derived cytokines clearly
serving as alternative mitogens for this cell type. Antagonism of TNF
Innate immunity Acquired immunity (T cells)
CCL20
CXCL8
GROα
S100A7/A8/A9
S100A12
Heat-shock proteins
Defensin
MIG
CXCL10
CD4
Neutrophil
Plasmacytoid DC
(Epithelial homing)
Interferon-γ
TNF
Lymphotoxin
IL-17
TNF
Nitric oxide
IL-20
IL-23
Interferon-α
IL-8
S100 proteins
Proteases
CD3
Organized
lymphoid infiltrate
NK-T
CCL19 CCL21
CXCL12 CCL18
IL-23
Interferon-γ
TNF
TLR agonists
Microbial products
Environment
Genetic factors
Keratinocyte
Bacterial antigens
Aberrant terminal
differentiation
T
reg
Mature
DC
Angiogenic factors
Connective tissue growth factors
TIP-DC
CD8
Figure 2 | A dynamic picture of the bidirectional flow of ‘information’ and
cells in a mature psoriasis lesion: the yin and yang of psoriasis. There is
close interdependence of the epidermis and dermal inflammatory infiltrate,
as well as a balance between the innate and acquired immune systems.
Chemokines produced by keratinocytes in the epidermis act on both
the innate and acquired immune systems, stimulating DCs, neutrophils
and other innate mediators as well as T cells. Keratinocytes also release
cytokines and growth factors, leading to altered gene expression and
regenerative hyperplasia, and also to the induction of adhesion molecules
for T cells on keratinocytes. Immune-system-derived cytokines, in turn,
act on keratinocytes to either induce inflammatory genes or increase
proliferation. Meanwhile, in the lymphoid-like tissue of the psoriatic
dermis, molecules of the innate and acquired immune systems also interact.
The genetic underpinnings of psoriasis are known to be complex, with
ten or more susceptibility loci, and these probably interact with various
environmental factors that act on the skin and/or immune system.
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and IL-12, and/or IL-23 (p40) cytokines with antibodies or fusion pro-
teins, can break the activated pathways shown in Fig. 3, so the concept
of proximal versus distal inflammatory regulators probably still holds
even with more complex network circuitry.
Role of genetic factors in psoriasis
Psoriasis is essentially a disease of Caucasians, in whom its frequency
is 1–2%. It is less common in Asians (about 0.1%) and is rarely seen
in Africans
33
. That psoriasis has a genetic basis has been accepted for
many years
4
, and it is commonly thought of as a complex trait. So far,
between 10 and 20 chromosome regions have been proposed to harbour
psoriasis genes but less than a handful of genes have been identified
4,8
.
This is due, in part, to their low-risk effects and the limitations in the
number of patients and families that have been studied.
One locus consistently identified in studies of psoriasis is the class I
region of the major histocompatibility locus antigen cluster (MHC)
4
.
However, its low penetrance — about 10% — indicates that other
genetic and environmental factors are also involved
34
. The identity of
psoriasis susceptibility 1 (PSORS1) remains controversial. Although its
association with human leukocyte antigen (HLA) Cw6 and psoriasis
was reported more than 25 years ago
35
, the extensive linkage disequilib-
rium across the class I region and its complex evolutionary history has
made identification of the susceptibility variant(s) very difficult. Genes
within this region lying about 160 kilobases telomeric to HLA-C, such
as corneodesmosin (CDSN) and the α-helical coiled-coil rod (HCR),
have been proposed as contenders
4
. A consensus is now beginning to
emerge that supports the location of PSORS1 as being closer to the region
harbouring HLA-C/HLA-B and excluding CDSN and HCR
36–38
. How-
ever, whether PSORS1 is a classical MHC allele, or a regulatory variant
within this region, has not yet been agreed upon.
Other predisposing polygenes might affect the immune system or
be involved in keratinocyte differentiation. Common variants in the
SLC9A3R1/NAT9 region and loss of a potential RUNX binding site have
been described that could potentially affect regulation of the immune
synapse
4,39
. There has also been a report of an association of psoriasis
with variant alleles of the lymphoid phosphatase PTPN22 (ref. 40). This
is also involved in regulation of the immune synapse and an R620W poly-
morphism is associated with at least four other autoimmune diseases
33
.
Associations with alleles encoding other components of the immune
system such as IL-12 (ref. 41), IL-19/20 (ref. 42) and IRF2 (ref. 43) have
also been described.
Some genetic variants such as those from the epidermal differentia-
tion complex (EDC) might directly affect keratinocyte proliferation or
differentiation
4
. How subtle alterations in keratinocyte differentiation
interact with alterations in the immune system to lead to the devel-
opment of an inflammatory skin disease will be an important area of
research as genetics progresses to global association scans, attempting
to identify most of the common alleles.
The locus responsible for rare instances in which many members of
a family are affected by psoriasis — which occurs when the disease seg-
regates as a Mendelian trait — has been mapped to chromosome 17q25
(refs 44-46). These families are from the United States, Taiwan and Israel.
Affected members of the Israeli family have autosomal-dominant sebor-
rhoea-like dermatitis with psoriasiform elements that segregates with
TLR agonist
Cytokines
Infection
KGF
PDGF
ECGF
VEGF
TGF-β
IL-1
IL-6
IL-20
HSPs
ENVIRONMENT
Vascular
response
Fibroplasia
STAT3-P
IL-12
IL-23
IFN-α
IL-20
TNF-α
STAT1
NF-κB
IFN-response
genes
Genes with composite
IFN and NF-κB
response elements
NF-κB- regulated
genes
CD11c
+
DC
(TIP-DC)
PDC
IFN-γ
LT
IFN-γ
IL-22
IL-17
T
H
1/T
C
1
T
H
17
TNF
STAT1-P
NF-κB
LT
TNF
Initiating events Amplification of inflammation End response
Tissue-resident
T cell
Keratinocyte
Skin
Figure 3 | Potential cytokine networks in psoriatic lesions. This figure
shows some of the known interactions and products of cytokines and
growth factors that are upregulated in psoriatic lesions. A notable fraction
of the 1,300+ genes that are differentially expressed in psoriatic lesions
are known to be regulated by STAT family or NF-κB transcription factors,
as well as by growth factors that are upregulated in psoriatic lesions. Key
cytokines that can activate STAT or NF-κB transcription factors (which are
involved in amplifying inflammation) include TNFs, lymphotoxin (LT),
IL-1, IL-17, IL-20, IL-22 and IFNs. Activated DCs may contribute IFN-α,
IL-20, IL-12 and IL-23. T-cell activation through IL-12 or IL-23 (blue arrow)
leads to the synthesis of T-cell-derived inflammatory cytokines. Immune
activation could be initiated by DC activation through pattern-recognition
receptors, cytokines, or heat-shock proteins (HSPs), as well as by direct
interaction with counter-receptors on T cells. Other cytokines synthesized
by keratinocytes or stromal cells probably cross-regulate the epithelial–
stromal (vascular) hyperplasia and fibroplasia that takes place in psoriatic
lesions. TGF-β, IL-1, IL-6 and IL-20 may act as keratinocyte autocrine and/
or paracrine growth factors. Certainly an equally complex set of chemokine
interactions exists, as at least 15 chemokines have increased expression in
psoriatic lesions
21
and many other interactive pathways probably coexist.
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a frameshift mutation of zinc finger protein 750 (ZNF750). This is nor-
mally expressed in keratinocytes but not in fibroblasts and is barely
detectable in CD4 lymphocytes. Thus, in this case, the primary defect
is in the keratinocyte rather than the immune system.
Theraputic engineering and model systems
It is important to understand that human skin is a complex organ com-
prising many distinct tissues, and that its structure is significantly dif-
ferent from the skin of most lower species. Compared with fur-bearing
animals, human skin has broad areas of epidermis situated between hair
follicles, known as interfollicular epidermis (Fig. 1; Box 1). There are
many different skin diseases that involve altered growth of epidermal
keratinocytes and inflammation in the interfollicular epidermis, and
psoriasis and atopic eczema are common examples. These disorders
do not appreciably alter the growth of keratinocytes in the follicular
epithelium or the growth of hair. Other diseases can alter the growth of
follicular epithelium, sebaceous glands or hair (the pilosebaceous unit),
and many such conditions are associated with immune infiltrates in or
around follicular structures. Psoriasis does not exist as a spontaneous
disease in the skin of lower animals
47
, but some features of psoriasis
have been induced in murine skin by genetic or immune manipulations.
Even so, the structure of murine skin imposes serious limitations on
resultant cellular alterations and, so far, psoriasis has not been faith-
fully reproduced by manipulation of native skin in any lower species
(Box 1).
In the future, we need better model systems that will help us dissect
the interactions of many complex molecular pathways or networks in the
skin. We also need better systems with which to test possible therapeutic
targets for psoriasis and other inflammatory diseases. Mice engineered
with various transgenes to produce both epithelial hyperplasia and cuta-
neous inflammation might help with the first problem, but such models
usually do not have ‘regulated’ or reversible phenotypes, as is the case
with psoriatic lesions. From the therapeutic engineering perspective, it
is important to model the extent to which pathological cell activation
in psoriasis can be reversed by effective therapeutics (Table 1). Unlike
many other autoimmune diseases, skin tissue is not irreversibly dam-
aged by inflammation, so a complete reversal to normal skin structure is
possible (Fig. 4). In this regard, models in which psoriatic skin has been
xenotransplanted to immunodeficient mouse strains have produced
clear examples of the prevention of disease induction by targeted thera-
peutics and of suppression of active psoriasis by antagonists of immune
cells or inflammatory cytokines
15,48
. More work might establish these
models as predictive of clinical responses of psoriasis to various thera-
peutic agents, but at present the only reliable test of a new therapeutic is
its ability to suppress psoriasis in a proof-of-concept clinical trial.
Therapeutics in psoriasis
Choice of treatment for psoriasis depends on many factors, includ-
ing the extent of disease, its effect on a patients life, and the patient’s
perception of their illness. For severe psoriasis, we now have biologi-
cal therapies, which have been approved only during the past 3 years.
Unlike earlier treatments for psoriasis, biological agents are proteins
or antibodies that target specific molecules thought to be essential in
psoriasis pathogenesis (Fig. 3). So far, these fall into two main groups,
aimed either at specific inflammatory mediators such as TNF or more
generally at T cells. The main concern about these and other biological
agents is the effects of long-term chronic immunosuppression, which
has the potential to increase infection and the risk of cancer. In clini-
cal practice these drugs have been remarkably well tolerated, but we
have only short-term safety data and need to continue to monitor these
patients for long-term safety.
Table 1 lists selected systemic therapeutics used in psoriasis. Agents
have been classified into four groups: first, agents used in early studies to
establish the immunological basis of psoriasis (all of which are approved
for other indications); second, common systemic immunosuppressives;
third, new therapies that have recently been approved by regulatory
agents in the United States or Europe; and, fourth, promising new thera-
pies that are still under development. The main biological agents that
are currently widely approved or in late-phase trials are discussed with
respect to the relationship between therapeutics and pathogenesis. Such
drugs include alefacept (LFA3-TIP, Amevive; Biogen), efalizumab (anti-
CD11a, Raptiva; Genentec, Xoma, Serono), etanercept (Enbrel; Amgen,
Wyeth), infliximab (Remicade; Centocor) and adalimumab (Humira;
Abbott). See refs 49–51 for recent comprehensive reviews.
The images show representative micrographs of
adult human and mouse skin photographed at
the same magnification. Human skin contains
sparse hair follicles that separate wide regions
of interfollicular epidermis (no hair follicles are
present in this image). By contrast, mouse skin
has closely spaced hair follicles throughout
(black arrows). Human skin has much thicker
dermis (d) and epidermis (e), with many
more cell layers in the epidermis. Note that
the epidermal rete (downward projections
of the epidermis, blue arrows), common in
human epidermis, is absent in mouse skin. In
addition, interfollicular epidermis in human
skin has a distinct differentiation programme
from keratinocytes in the follicular epithelium,
whereas this distinction is less clear in mouse
epidermis.
A wide variety of transgenic and knockout
mouse strains have been engineered in
which growth factors, keratinocyte adhesion
molecules, inflammatory mediators or
leukocytes in the skin are altered
47,62
. Often,
perturbation of one of these pathways creates
a phenotype with reactive keratinocyte
hyperplasia, vascular proliferation and
increased leukcocyte infiltration of the skin.
However, the dominant feature of almost
all such models is hyperplasia of follicular
keratinocytes. Tangential sections of this
hyperplastic follicular epithelium can resemble
elongated rete seen in psoriatic lesions (Fig. 1),
and be confused with the papillary elongation
seen in psoriasis. In addition, many of these
models have hair loss (alopecia) or even
neonatal lethality
63
, which are not normally
associated with human psoriasis. Frequently,
the ‘psoriasis-like’ phenotypes share features
with other inflammatory skin disorders, such as
atopic eczema, or inflammatory diseases of hair
follicles. Thus, the pathology of models is often
a unique phenotype that does not represent any
human skin disease.
Occasionally, psoriasis-like phenotypes
are created by molecular alterations that
are uncommon in psoriatic plaques
64,65
, and
this leads to unnecessary confusion about
the human condition and its underlying
pathogenesis. In general, it is important to
explore pathways consistently detected in
psoriatic lesions. In addition, inflammatory skin
models should be evaluated for reversal with
common drugs used to treat psoriasis vulgaris;
so far not many have been. Perhaps of most
interest and therapeutic relevance are models
in which human skin or psoriatic lesions are
transplanted to immunodeficient mouse strains.
In these cases, it has been possible to reproduce
almost the full spectrum of cellular and
histological changes that define psoriasis
13,15
.
Box 1 | Key differences in the structure of human versus mouse skin
Normal human skin Normal mouse skin
Rete
Hair follicles
Hypodermis
Muscle
0.5 mm 0.5 mm
E
E
D
D
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In a subset of patients with severe psoriasis, alefacept is a highly effec-
tive therapy and gives relatively long remissions in patients. Alefacept is
a fusion protein that contains the extracellular domain of CD58 (LFA3)
and binds to the surface co-stimulatory molecule CD2. The main cell
types expressing CD2 are T cells and natural killer (NK) cells, but a
small population of circulating CD14
+
DCs are also CD2
+
. The main
early hypotheses of alefacepts mechanism of action involved the bridg-
ing of T cells and NK cells by binding CD2 and the Fc receptor (FcR),
respectively, leading to T-cell apoptosis
52
. This might explain the T-cell
reductions associated with alefacept therapy, although we have not been
able to demonstrate apoptosis in circulating cells (M.A.L. and J.G.K,
unpublished observations). We have shown that in responding patients,
alefacept induces a parallel reduction in CD11c
+
and CD83
+
DCs as
well as T cells. A range of inflammatory genes such as IFN-γ, STAT1,
MIG (CXCL9), iNOS, IL-8, and IL-23 subunits, as well as IL-20, are also
reduced
20,53
. It seems that T cells are the primary target for therapy, but
that DCs and a spectrum of type-1 inflammatory genes are coordinately
suppressed.
Efalizumab is an example of an agent that was also designed to inter-
fere with T-cell adhesion and co-stimulation. It is effective in a subset
of patients with severe psoriasis, although, like other therapies, it often
requires long-term treatment to maintain disease control. Efalizumab
is a humanized murine monoclonal antibody that targets CD11a, which
forms a heterodimer with the β
2
integrin CD18 to form LFA-1. The
CD11a/CD18 molecule is selectively expressed by T cells, and binds to
ICAM-1 and 2. This interaction permits T-cell adhesion to ICAM
+
DCs
during the initial generation of immune responses in lymph nodes and is
important in the skin during T-cell migration from the blood into der-
mis, local DC-activation of T cells, and T-cell entry into the epidermis.
Administration of efalizumab induces a peripheral leukocytosis (pre-
dominantly of CD8
+
memory cells
54
), which is probably due to blockade
of the LFA-1/ICAM-1 interaction between T cells and endothelial cells.
In addition, efalizumab therapy in patients with psoriasis causes a sig-
nificant reduction in CD11c
+
TIP-DCs
16
, and the ‘switching off ’ of the
mediators produced by this important cell type might also explain the
clinical response.
The TNF inhibitors have greatly increased the treatment choices for
patients with severe psoriasis. At present there are two FDA-approved
agents for psoriasis (infliximab and etanercept) and one agent in late-
phase trials (adalimumab). These TNF inhibitors have impressive dis-
ease control rates depending on the agent, formulation, dose and length
of treatment. Etanercept is a human TNF receptor and immunoglobulin
fusion protein that binds TNF and lymphotoxin-α and prevents their
biological activity. Infliximab is a chimaeric human–murine mono-
clonal antibody against TNF that can bind both soluble and recep-
tor-bound TNF. Adalimumab is the first fully human recombinant
anti-TNF antibody, and, theoretically, has similar actions and effects
to infliximab.
The use of targeted immune antagonists has tremendous potential not
only for the treatment of psoriasis but also for the study of pathogenic
contributions of specific immune molecules or pathways in autoimmune
diseases such as psoriasis. The response of psoriasis to three distinct
TNF inhibitors, which probably block the interaction of soluble TNF
with TNF receptors on target cells, certainly suggests that this cytokine
has a key role in disease pathogenesis. When coupled with cellular and
genomic analyses of how inflammatory pathways collapse in response
to targeted agents, we can learn more about how individual molecules
influence the complex inflammatory networks that are apparent in pso-
riasis. For example, the progressive changes in inflammatory cytokines
and chemokines induced by etanercept in psoriatic lesions suggests that
TNF strongly regulates some proximal cytokines — for example, IL-1
and IL-8 — but has more complex long-range interactions to support
inflammation driven by IFN-γ and STAT pathways, as well as chemo-
kines that are thought to regulate T cells and DC interactions in the
skin
55
. In addition, several products that are inhibited by etanercept,
such as iNOS and IL-23, are products of DCs that strongly express TNF
(TIP-DCs)
16
and are likely to be regulated by this cytokine.
However, the therapeutic actions of TNF inhibitors might not be as
simple as blockade of the soluble cytokine. The antibody-based inhibi-
tors (infliximab and adalimumab) have the potential to bind pro-TNF
Table 1 | Examples of systemic therapeutics for psoriasis vulgaris
Generic name (trade name) Target Status
Agents used in early studies to establish immunological basis of psoriasis
Denileukin diftitox*/DAB389IL-2
(Ontak)
CD25 (toxic)
Abatacept/CTLA4Ig (Orencia) CD80 and CD86
Tacrolimus/FK506 (Prograf) Calcineurin
Daclizumab*† (Zenepax) CD25 (antagonist)
Basiliximab*† (Simulect) CD25 (antagonist)
Widely used systemic agents approved for use (immunosuppressives)
Cyclosporine* (Neoral, Gengraf) Calcineurin Widely used
Methotrexate (Rheumatrex,
Trexall)
Leukocytes Widely used
Fumarates* T cells Widely used in
Germany
Approved biological agents
Alefacept* (Amevive) CD2 FDA approved
Efalizumab*† (Raptiva) CD11a (LFA-1) FDA and EMEA
approved
Infliximab†‡ (Remicade) TNF FDA and EMEA
approved
Etanercept‡ (Enbrel) TNF, lymphotoxin FDA and EMEA
approved
Drugs/biological agents under investigation (human or murine trials)
Adalimumab†‡ (Humira) TNF In clinical trials
59
(FDA
approved for psoriatic
arthritis)
Pimecrolimus Calcineurin In clinical trials
60
Cent-1275†‡ IL-12/23p40 In clinical trials
61
ABT-874†‡ IL-12/23p40 In clinical trials
146B7†‡ IL-15 In clinical trials
48
*T-cell targeted.
†Monoclonal antibodies.
‡Cytokine inhibitors.
a
cd
b
Figure 4 | Effective treatments are available for psoriasis and reverse the
disease phenotype. a, b, Psoriatic lesions before treatment. c, d, Psoriatic
lesions after 12 weeks of treatment with the T-cell-targeted monoclonal
antibody efalizumab (anti-CD11a), showing reversibility and normalization
of cutaneous histology. Panels a and c are stained with haematoxylin and
eosin. Haematoxylin (purple) stains the chromatin of nuclei and eosin (pink)
stains cytoplasmic material, connective tissue and collagen. Panels b and d
are stained for keratin 16, a marker of epidermal regenerative maturation.
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on the cell surface and TNF in its receptor-bound forms, and might
therefore modify the biology of TNF
+
cells through ligation of surface
complexes or even induction of apoptosis
56
. All of the TNF inhibitors
have immunoglobulin domains that bind FcRs, which are expressed by
several cell types but especially by DCs in psoriatic lesions. Some FcRs,
particularly CD32b, have the potential to suppress immune responses
when activated by antibody binding
57
. Thus, suppression of immune
circuits at the ‘whole cell’ level or through the elimination of TNF
+
leu-
kocytes could have the ability to suppress immune reactions that are not
strictly TNF-dependent. The same arguments hold for antibody-like
therapeutics to other targeted pathways. Therefore, we must couple the
testing of targeted therapeutics with good cellular and molecular stud-
ies of skin lesions and circulating leukocytes to understand fully how
inflammatory circuits are being affected by these agents. At the same
time we need to gain a better understanding of how normal, protective
immune responses might be affected during a lifetime of treatment with
immune-regulating agents. Ideally, we might be able to find therapeu-
tic agents that affect only pathological immune reactions and do not
suppress protective cellular immunity. However, we still need a deeper
understanding of upstream and downstream molecular interactions of
inflammatory cytokines, chemokines and regulatory receptors in this
disease.
Unresolved issues and questions
How do we move forward to gain a greater understanding of this unique
disease of humans? First, it is likely that we have much to learn from
careful mechanistic studies of existing targeted therapeutics in transla-
tional (clinical) studies. The introduction of new immune antagonists to
additional targets will help to refine our understanding of the complex
interactions that exist in psoriasis. Fortunately, an array of powerful
molecular biological and genetic tools can be brought to the study of
human tissue in an accessible organ within the context of therapeutic
manipulation of disease activity.
Second, animal models of skin inflammation, even if they do not pre-
cisely reproduce psoriasis, have tremendous potential to help establish
how complex inflammatory circuits are regulated. Animal models can
also help us determine how psoriasis susceptibility genes might influ-
ence or dysregulate normal immune reactions or responses of skin-resi-
dent cells to immune triggers. In this case it is extremely helpful to model
molecular or cellular changes that are consistently detected in psoriatic
lesions. It would also be useful to have better information about how
molecular alterations in murine model systems parallel the broad set
of gene transcriptional alterations detected in psoriatic lesions through
genome-level expression analyses. Unfortunately, none of the model
systems have the level of genomic information that exists in psoriatic
lesions studied from patients. In addition, it is not at all clear whether
the repertoire of leukocyte subsets, including several distinct types of
DC seen in psoriatic lesions, is represented in mouse skin
58
.
Third, xenotransplantation of normal versus genetically affected skin
of patients with psoriasis is a means of testing cellular or molecular inter-
actions in ways that might not be possible in clinical studies, and this
approach does have the advantage that the relevant human cell subsets
are directly studied
13
. We are not yet at the point at which skin tissue
can be fully reconstructed from cultured skin cells, but much progress
is being made in this area and might be applied to pathogenic or thera-
peutic dissection in the future.
Hopefully, it can be appreciated that we have only begun to scratch
the surface of an important skin disease. The progress we have made in
understanding psoriasis leads only to a set of larger and more difficult
questions for the future. The outstanding issues and questions might
be broadly considered in five categories. First, what are the key triggers
of the cellular inflammatory response going on in the skin and how do
they interact with genetic susceptibility factors? Is this an autoimmune
disease with self-reactivity to a conventional antigen, or a disease driven
by endogenous or exogenous activators of innate immunity?
Second, why do wound healing responses of keratinocytes or immune-
activation responses of leukocytes fail to terminate in psoriatic lesions,
as they would normally upon successful wound repair or elimination of
an immune-activating pathogen? Or, to put it another way, is psoriasis a
disease of too much immune stimulation or a problem in the response or
downregulation of cell reactions to ‘normal’ stimulation? The potential
for defective function of regulatory T cells, DCs or other cells that cross-
regulate immune responses needs continued study.
Third, how do psoriasis susceptibility genes actually cause the broader
set of cellular and transcriptional alterations that define psoriasis and
make it different from other inflammatory diseases that also have genetic
links, some of which overlap with psoriasis
33
?
Fourth, how can we predict which patients might respond to expen-
sive biological therapies? In psoriasis and other autoimmune diseases
substantial genetic heterogeneity is apparent between patients. Although
some genetic factors might encode components of the same biochemi-
cal pathway, and thus not require a different treatment regimen to halt
disease, it is likely that genetic heterogeneity leads to subtle differences
in disease pathogenesis, requiring different treatment regimens. As with
other complex traits, the results of genome-wide methods, which will
elucidate the genetic variations responsible for disease susceptibility and
drug response, will allow personalized medicine to begin in earnest.
Finally, what are the differential effects of new targeted agents on path-
ological versus protective cellular immunity and, as a related issue, will we
be able to safely alter the activity of the immune system over potentially
decades of treatment? Whatever the ultimate answers to these questions
hold, we are at an exciting time at which science and medicine converge
to produce direct benefit to millions of affected individuals.
Note added in proof: A recent study
66
shows that IL-23 induces marked
hyperplasia in epidermal keratinocytes in murine skin, and results sug-
gest that this effect is mediated to a significant extent through IL-22
produced by T
H
17 T cells. However, keratinocyte hyperplasia is still
present on an Il22-null background, which suggests that IL-23 or other
factors independent of IL-22 also stimulate keratinocyte proliferation.
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Acknowledgements The authors and their primary research have been supported
by grants from the NIH.
Author Information Reprints and permissions information is available at
npg.nature.com/reprintsandpermissions. The authors declare competing
financial interests: details accompany the paper at www.nature.com/nature.
Correspondence should be addressed to J.G.K. (jgk@rockefeller.edu).
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... Further, keratinocytes also produce vascular endothelial growth factors (VEGF), and platelet-derived growth factors (PDGF) leading to the formation and growth of blood vessels [1,19,20]. The activation of endothelial cells leads to the production of keratinocytes growth factor (KGF) which promotes keratinocytes proliferation and vasodilation of dermis capillaries, thereby granting the extravasation of circulating immune cells [21]. ...
... The interaction between keratinocytes and mononuclear leucocytes is responsible for the eruption of the psoriatic lesion [21]. Psoriasis susceptibility genes influence the gene expression program in these diverse cell types [21,22]. ...
... The interaction between keratinocytes and mononuclear leucocytes is responsible for the eruption of the psoriatic lesion [21]. Psoriasis susceptibility genes influence the gene expression program in these diverse cell types [21,22]. Keratinocytes actively participate in the recruitment and activation of leukocytes in the psoriatic lesion [21,22]. ...
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Psoriasis is a typical dermal condition that has been anticipated since prehistoric times when it was mistakenly implicit in being a variant of leprosy. It is an atypical organ-specific autoimmune disorder, which is triggered by the activation of T-cells and/or B-cells. Until now, the pathophysiology of this disease is not completely explicated and still, many research investigations are ongoing. Different approaches have been investigated to treat this dreadful skin disease using various anti-psoriatic drugs of different modes of action through smart drug-delivery systems. Nevertheless, there is no ideal therapy for a complete cure of psoriasis owing to the dearth of an ideal drug-delivery system for anti-psoriatic drugs. The conventional pharmacotherapy approaches for the treatment of psoriasis demand various classes of anti-psoriatic drugs with optimum benefit/risk ratio and insignificant untoward effects. The advancement in nanoscale drug delivery had a great impact on the establishment of a nanomedicine-based therapy for better management of psoriasis in recent times. Nanodrug carriers are exploited to design and develop nanomedicine-based therapy for psoriasis. It has a promising future in the improvement of the therapeutic efficacy of conventional anti-psoriatic drugs. The present manuscript aims to discuss the pathophysiology, conventional pharmacotherapy, and contemporary research in the area of nanoscale topical drug delivery systems for better management of psoriasis including the significance of targeted pharmacotherapy in psoriasis.
... Psoriasis is an immune and/or inflammatory skin disease caused by the dysregulation of complex interactions among immune cells [11,12]. There are two classes of psoriasis: cutaneous and systemic. ...
... Based on the pathological characteristics, which are related to skin symptoms, the onset and development of psoriasis result from overactivated immune systems, in which components of the innate and adaptive immune systems interplay [12,14]. IFN-α and cytokines produced by innate immune cells [IL-1, IL-6, tumor necrosis factor-α (TNF-α), and IFN-γ] induce the activation and maturation of DCs to link innate and adaptive immune systems. ...
... Regulatory T cells (Tregs) play an essential role in immune tissue homeostasis and self-tolerance because they can stop the activation and proliferation of effector T cells via IL-10 production, thus regulating inflammatory processes in the body. Several experiments have indicated a malfunction of and/or a reduced number of Tregs in psoriatic lesions [12]. ...
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Psoriasis is a skin disease characterized by scaly erythema, parakeratosis, and epidermal hyperplasia. Application of imiquimod (IMQ), a ligand for Toll-like receptor 7, produces a mouse model for psoriasis. IMQ application induces scaling, erythema, and thickness in skin lesions, and the symptoms are milder in interleukin-23 p19 (Il23p19)-deficient and Il17a-deficient mice than in wild-type mice; this suggests that the interleukin-23 (IL-23)/T helper 17 (Th17) axis and Th17 cell-secreting cytokines play essential roles in the IMQ-induced psoriasis model. It is notable that a genome-wide association study identified the human tyrosine kinase 2 (TYK2) gene within the psoriasis susceptibility locus. After IMQ application, mice lacking Tyk2, a mouse homologue of the human TYK2 gene, exhibited significantly lower symptom scores of psoriasis and diminished inflammatory cell infiltration in the skin lesions. Tyk2-deficient mice also failed to increase CD4+IL-17+ or CD4+ interferon-γ+ (IFN-γ+) T cells in the draining lymph nodes or to produce Th17 cell-related cytokines after IMQ application. Furthermore, Tyk2 deficiency led to diminished skin inflammation induced by IL-23 and IL-22 injections. These results indicate that Tyk2-mediated signals in mice contribute to multiple steps of immune and inflammatory responses during the development of psoriasis; therefore, TYK2 targeting may be a promising strategy to treat patients with psoriasis. Recent clinical trials have shown that TYK2 inhibitors have a high overall response rate with good tolerability in the management of psoriasis. This review describes the fundamental mechanisms of Tyk2 inhibition in immune/inflammatory diseases.
... Activation of transcription via the STAT3 pathway appears to be the primary mechanism of IL-22 signal transduction by which IL-22 promotes IL-23-induced acanthosis and cutaneous inflammation in psoriasis through the activation of STAT3 (53,94,95). Also, dendritic cells produce IL-23 and IL-20, which can activate and differentiate T cells and keratinocytes, to express high levels of TNFa and innate immunity-related inducible nitric oxide synthase (iNOS) (13,(96)(97)(98). In this study, there was also a marked decrease in psoriasis-associated STAT3 activation in epidermal cells of IMQ-induced C57BJ6 mice after fisetin treatment, suggesting that fisetin disrupts the positive immune to skin trafficking feedback that drives psoriasiform dermatitis. ...
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Psoriasis is a chronic autoimmune inflammatory skin disorder characterized by epidermal hyperplasia and aberrant immune response. In addition to aberrant cytokine production, psoriasis is associated with activation of the Akt/mTOR pathway. mTOR/S6K1 regulates T-lymphocyte activation and migration, keratinocytes proliferation and is upregulated in psoriatic lesions. Several drugs that target Th1/Th17 cytokines or their receptors have been approved for treating psoriasis in humans with variable results necessitating improved therapies. Fisetin, a natural dietary polyphenol with anti-oxidant and anti-proliferative properties, covalently binds mTOR/S6K1. The effects of fisetin on psoriasis and its underlying mechanisms have not been clearly defined. Here, we evaluated the immunomodulatory effects of fisetin on Th1/Th17-cytokine-activated adult human epidermal keratinocytes (HEKa) and anti-CD3/CD28-stimulated inflammatory CD4+ T cells and compared these activities with those of rapamycin (an mTOR inhibitor). Transcriptomic analysis of HEKa revealed 12,713 differentially expressed genes (DEGs) in the fisetin-treated group compared to 7,374 DEGs in the rapamycin-treated group, both individually compared to a cytokine treated group. Gene ontology analysis revealed enriched functional groups related to PI3K/Akt/mTOR signaling pathways, psoriasis, and epidermal development. Using in silico molecular modeling, we observed a high binding affinity of fisetin to IL-17A. In vitro, fisetin significantly inhibited mTOR activity, increased the expression of autophagy markers LC3A/B and Atg5 in HEKa cells and suppressed the secretion of IL-17A by activated CD4+ T lymphocytes or T lymphocytes co-cultured with HEKa. Topical administration of fisetin in an imiquimod (IMQ)-induced mouse psoriasis model exhibited a better effect than rapamycin in reducing psoriasis-like inflammation and Akt/mTOR phosphorylation and promoting keratinocyte differentiation and autophagy in mice skin lesions. Fisetin also significantly inhibited T-lymphocytes and F4/80+ macrophage infiltration into skin. We conclude that fisetin potently inhibits IL-17A and the Akt/mTOR pathway and promotes keratinocyte differentiation and autophagy to alleviate IMQ-induced psoriasis-like disease in mice. Altogether, our findings suggest fisetin as a potential treatment for psoriasis and possibly other inflammatory skin diseases.
... Psoriasis, a chronic immunoinflammatory skin disease, is characterized by epidermal hyperplasia, microvascular dilation and excessive angiogenesis, and affects approximately 2% of the global population. 1 Altered endothelial cell function has been linked to the increased proliferation and migration of endothelial cells, and angiogenesis and vascular permeability in psoriasis. 2 Our previous study showed that alterations in psoriatic human dermal microvascular endothelial cell (HDMECs) functions, including proliferation, migration, and angiogenesis, are associated with microvascular dilation in psoriasis. ...
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Background: Cell proliferation, migration, and angiogenesis are aberrant in psoriatic human dermal microvascular endothelial cells (HDMECs), resulting in abnormal endothelial function and microvascular dilation in psoriasis. Objective: To explore the role of Integrin subunit alpha 9 (ITGA9) in proliferation and migration of dermal microvascular endothelial cells. Methods: HDMECs were isolated from the skin of 6 psoriatic patients and 6 healthy controls. Expression levels of ITGA9 mRNA and protein were assessed with qRT-PCR and Western blot, respectively, while miqRT-PCR was used to determine expression levels of miR-146a-3p. Cell proliferation and migration were assessed in human microvascular endothelial cell line (HMEC-1), following overexpression of either ITGA9 or miR-146a-3p, or co-transfection with miR-146a-3p-mimic and pLVX - ITGA9. Cell viability was detected by Cell Counting Kit-8 assay and 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay. Cell apoptosis was assessed, using annexin V-FITC/PI apoptosis detection kit, while cell migration was detected by wound healing and transwell assay. Results: Expression levels of ITGA9 were significantly decreased in psoriatic HDMECs compared to normal controls. Moreover, expression levels of miR-146a-3p were higher in psoriatic HDMECs than in normal controls. Overexpression of miR-146a-3p lowered expression levels of ITGA9, accompanied by increased proliferation and migration of HMEC-1 in vitro. In contrast, overexpression of ITGA9 inhibited proliferation and migration of HMEC-1, while increasing expression levels of cdc42, ki67, focal adhesion kinase (FAK), c-Src tyrosine kinase (Src), RAC1 and RhoA. Conclusion: ITGA9 can repress the proliferation and migration of HMEC-1, suggesting utility of ITGA9 as a potential therapeutic intervention for psoriasis.
... HaCaT cells were subjected to immunofluorescent staining, western blot, or 3D skin culture. About 2 × 105 HaCaT cells were seeded on the transwell (CORNING cat. 3493) in DMEM/high glucose (HyClone cat. ...
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Protein Phosphatase 6 down-regulation in keratinocytes is a pivotal event that amplifies the inflammatory circuits in psoriasis, indicating that restoration of protein phosphatase 6 can be a rational strategy for psoriasis treatment. Through the phenotypic screen, we here identify L-menthol that ameliorates psoriasis-like skin inflammation by increasing protein phosphatase 6 in keratinocytes. Target identification approaches reveal an indispensable role for the transcription factor hairy and enhancer of split 1 in governing the protein phosphatase 6-upregulating function of L-menthol in keratinocytes. The transcription factor hairy and enhancer of split 1 is diminished in the epidermis of psoriasis patients and imiquimod-induced mouse model, while L-menthol upregulates the transcription factor hairy and enhancer of split 1 by preventing its proteasomal degradation. Mechanistically, the transcription factor hairy and enhancer of split 1 transcriptionally activates the expression of immunoglobulin-binding protein 1 which promotes protein phosphatase 6 expression and inhibits its ubiquitination. Collectively, we discover a therapeutic compound, L-menthol, for psoriasis, and uncover the dysfunctional the transcription factor hairy and enhancer of split 1- immunoglobulin-binding protein 1- protein phosphatase 6 axis that contributes to psoriasis pathology by using L-menthol as a probe. Psoriasis is an inflammatory disease which has proven difficult to cure. Prof. Honglin Wang’s team describes L-menthol for treating models of psoriasis and uncovers the dysfunctional HES1- IGBP1-PP6 axis in psoriasis pathology by using L-menthol as a probe.
Article
Psoriasis is a common chronic inflammatory skin disease characterized by inflammatory cell infiltration and epidermal hyperplasia. However, the regulatory complexity of cytokine and cellular networks still needs to be investigated. Here, we show that the expression of FXYD3, a member of the FXYD domain-containing regulators of Na+/K+ ATPases family, is significantly increased in the lesional skin of psoriasis patients and mice with imiquimod (IMQ)-induced psoriasis. IL-17A, a cytokine important for the development of psoriatic lesions, contributes to FXYD3 expression in human primary keratinocytes. FXYD3 deletion in keratinocytes attenuated the psoriasis-like phenotype and inflammation in an IMQ-induced psoriasis model. Importantly, FXYD3 promotes the formation of the IL-17R-ACT1 complex by competing with IL-17R for binding to TRAF3 and then enhances IL-17A signaling in keratinocytes. This promotes the activation of the NF-κB and MAPK signaling pathways and leads to the expression of proinflammatory factors. Our results clarify the mechanism by which FXYD3 serves as a mediator of IL-17A signaling in keratinocytes to form a positive regulatory loop to promote psoriasis exacerbation. Targeting FXYD3 may serve as a potential therapeutic approach in the treatment of psoriasis.
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Nanotechnology has been widely applied in the development of traditional Chinese medicine (TCM). Interestingly, we found that nanostructures intrinsically existed in 12 clinically applied TCM mixtures (TCMMs). However, the role of these nanostructures in TCMMs and their potential value in improving the development of TCMMs remain unknown. Taking Qingxuechushi mixture as an example, we demonstrated that nanoparticles could be the most efficient part through the pharmacodynamics study on psoriasis model. By imitating the physical properties and chemical composition of isolated nanoparticles in Qingxuechushi mixture, a novel nanoformulation with definite components and good therapeutic effect was developed, which not only mimicked the prescription composition rules in the original TCMMs but also possessed the advantage of nanotechnology. This novel nanoformulation could notably alleviate the psoriasis-like manifestations and reduce the levels of pro-inflammatory factors in serum in the psoriasis mouse model. This work organically integrates the advantages of TCMMs and nanotechnology, which may provide a new approach and inspiration for the development of TCM.
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Psoriasis is a chronic disabling complex inflammatory disorder prevalent worldwide with environmental and genetic components that involve predominantly skin in addition to nails and joints associated with various systemic comorbidities having periods of exacerbations and remissions. Psoriasis is characterized by hyper-proliferation as well as abnormal differentiation of epidermal keratinocytes and lymphocyte infiltration (mainly T cells) with resultant inflammatory cytokines and chemokines. Immunological and genetic studies over the last decade have identified genetic susceptibility risk alleles, molecular, cellular and immunological mechanisms involved in immunopathogenesis of psoriasis. The current disease model emphasizes the role of aberrant Th1 and Th17 responses regulated by a complex network of different cytokines, including TNF-α, IL-17 and IL-23; signal transduction pathways downstream to the cytokine receptors; and various activated transcription factors, including NF-κB, interferon regulatory factors and signal transducer and activator of transcriptions. Cytokines targeting biologics (IL-17, IL-23 and TNFα) therapies have revolutionized the management of severe skin disease having beneficial effects on joints and systemic inflammation of psoriasis as well. Further better understanding of immunopathogenesis of psoriasis will pave way for precision medicine based on specific immunopathogenic targets in a given phenotype of disease. Complex interplay of psoriasis with associated comorbidities is also a future area of research for overall better patient management and to improve their quality of life.
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The contribution of nutrient availability to control epidermal cell proliferation, inflammation, and hyperproliferative diseases remains unknown. Here, we studied extracellular serine and serine/glycine metabolism using human keratinocytes, human skin biopsies, and a mouse model of psoriasis-like disease. We focused on a metabolic enzyme, serine hydroxymethyltransferase (SHMT), that converts serine into glycine and tetrahydrofolate-bound one‑carbon units to support cell growth. We found that keratinocytes are both serine and glycine auxotrophs. Metabolomic profiling and hypoxanthine supplementation indicated that SHMT silencing/inhibition reduced cell growth through purine depletion, leading to nucleotide loss. In addition, topical application of an SHMT inhibitor suppressed both keratinocyte proliferation and inflammation in the imiquimod model and resulted in a decrease in psoriasis-associated gene expression. In conclusion, our study highlights SHMT2 activity and serine/glycine availability as an important metabolic hub controlling both keratinocyte proliferation and inflammatory cell expansion in psoriasis and holds promise for additional approaches to treat skin diseases.
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Cytokines in the interleukin (IL)-23/IL-17 axis are central to psoriasis pathogenesis. Janus kinase (JAK) signal transducer and activator of transcription (STAT) regulates intracellular signalling of several cytokines (including IL-12, 23, 22, 6, 17, and interferon (IFN)-γ) in the IL-23/IL-17 axis, and, as a result, has become a therapeutic target for psoriasis treatment. Although several JAK1-3 inhibitors, with varying degrees of selectivity, have been developed for immune-mediated inflammatory diseases, use in psoriasis is limited by a low therapeutic index as anticipated by signals from other disease indications. More selective inhibition of the JAK family is an area of interest. Specifically, selective tyrosine kinase (TYK)2 inhibition suppresses IL-23/IL-17 axis signalling, and at therapeutic doses, has a favorable safety profile compared to therapeutic doses of JAK1-3 inhibitors. Phase III efficacy and safety data for the selective allosteric TYK2-inhibitor, deucravacitinib, in adult patients with moderate-to-severe plaque psoriasis is promising. Furthermore, phase II clinical trials for ropsacitinib (PF-06826647), a selective TYK2 inhibitor, and brepocitinib (PF-06700841), a JAK1/TYK2 inhibitor, have also demonstrated efficacy and an acceptable safety profile in adult patients with moderate-to-severe plaque psoriasis. Other novel TYK2 allosteric inhibitors, NDI-034858 and ESK-001, are currently being investigated in adult patients with plaque psoriasis. This article reviews the details of the JAK-STAT pathway in psoriasis pathophysiology, the rationale for selective targeting of JAKs in the treatment of psoriasis, and provides clinical perspective on clinical trial data for JAK and TYK2 inhibitors.
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Psoriasis is a frequent, inflammatory disease of skin and joints with considerable morbidity. Here we report that in psoriatic lesions, epidermal keratinocytes have decreased expression of JunB, a gene localized in the psoriasis susceptibility region PSORS6. Likewise, inducible epidermal deletion of JunB and its functional companion c-Jun in adult mice leads (within two weeks) to a phenotype resembling the histological and molecular hallmarks of psoriasis, including arthritic lesions. In contrast to the skin phenotype, the development of arthritic lesions requires T and B cells and signalling through tumour necrosis factor receptor 1 (TNFR1). Prior to the disease onset, two chemotactic proteins (S100A8 and S100A9) previously mapped to the psoriasis susceptibility region PSORS4, are strongly induced in mutant keratinocytes in vivo and in vitro. We propose that the abrogation of JunB/activator protein 1 (AP-1) in keratinocytes triggers chemokine/cytokine expression, which recruits neutrophils and macrophages to the epidermis thereby contributing to the phenotypic changes observed in psoriasis. Thus, these data support the hypothesis that epidermal alterations are sufficient to initiate both skin lesions and arthritis in psoriasis.
Article
Psoriasis is a frequent, inflammatory disease of skin and joints with considerable morbidity. Here we report that in psoriatic lesions, epidermal keratinocytes have decreased expression of JunB, a gene localized in the psoriasis susceptibility region PSORS6. Likewise, inducible epidermal deletion of JunB and its functional companion c-Jun in adult mice leads (within two weeks) to a phenotype resembling the histological and molecular hallmarks of psoriasis, including arthritic lesions. In contrast to the skin phenotype, the development of arthritic lesions requires T and B cells and signalling through tumour necrosis factor receptor 1 (TNFR1). Prior to the disease onset, two chemotactic proteins (S100A8 and S100A9) previously mapped to the psoriasis susceptibility region PSORS4, are strongly induced in mutant keratinocytes in vivo and in vitro. We propose that the abrogation of JunB/activator protein 1 (AP-1) in keratinocytes triggers chemokine/cytokine expression, which recruits neutrophils and macrophages to the epidermis thereby contributing to the phenotypic changes observed in psoriasis. Thus, these data support the hypothesis that epidermal alterations are sufficient to initiate both skin lesions and arthritis in psoriasis.
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This article has no abstract; the first 100 words appear below. Autoimmune diseases, with the exception of rheumatoid arthritis and autoimmune thyroiditis, are individually rare, but together they affect approximately 5 percent of the population in Western countries.¹,² They are a fascinating but poorly understood group of diseases. In this review, we define an autoimmune disease as a clinical syndrome caused by the activation of T cells or B cells, or both, in the absence of an ongoing infection or other discernible cause. We will discuss a classification of autoimmune disease that distinguishes diseases caused by generalized defects in lymphocyte selection or homeostasis from those caused by aberrant responses to . . . Supported by grants from the National Institutes of Health (AI47291-01 and AI31229, to Dr. Davidson, and AR32371 and AI31229, to Dr. Diamond). Source Information From the Departments of Microbiology and Immunology and Medicine, Albert Einstein College of Medicine, Bronx, N.Y. Address reprint requests to Dr. Diamond at Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, or at diamond@aecom.yu.edu.