Pathophysiology of psoriasis uptodate

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Pathophysiology of psoriasis - UpToDate

Authors: Andrew Blauvelt, MD, MBA, Benjamin D Ehst, MD, PhD
Section Editor: Kristina Callis Duffin, MD
Deputy Editor: Abena O Ofori, MD
Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: Apr 28, 2017.
INTRODUCTION — Psoriasis is a complex immune-mediated inflammatory disease that occurs in genetically
susceptible individuals and presents with the development of inflammatory plaques on the skin (picture 1A-B).
Although early concepts of the pathogenesis of psoriasis focused primarily on keratinocyte hyperproliferation,
dysregulation of the immune system is now recognized as a critical event in this disease. The evolving
knowledge of the role of the immune system in psoriasis has had a significant impact on treatment
development. Many new and emerging therapeutic agents target specific immunologic aspects of psoriatic
disease. (See "Treatment of psoriasis in adults".)
The pathophysiology of psoriasis will be discussed here. The epidemiology, genetics, clinical features,
diagnosis, and management of psoriasis are reviewed separately. (See "Epidemiology, clinical manifestations,
and diagnosis of psoriasis" and "Treatment selection for moderate to severe plaque psoriasis in special
populations".)
OVERVIEW — Involvement of the immune system in psoriasis was first indicated in early studies that identified
complex infiltrates of leukocytes involved in both innate and adaptive immunity in psoriatic skin [1,2].
Subsequent studies have supported the concept that interactions between dendritic cells, T cells, keratinocytes,
neutrophils, and the cytokines released from immune cells likely contribute to the initiation and perpetuation of
the cutaneous inflammation that is characteristic of psoriasis [3]. A basic sequence of the immunologic events
that are theorized to occur in psoriasis is described below [3]:
● Antigenic stimuli contribute to the activation of plasmacytoid dendritic cells and other innate immune cells
in the skin.
● Proinflammatory cytokines produced by innate immune cells, including interferon (IFN)-alpha, stimulate the
activation of myeloid dendritic cells in the skin.
● Myeloid dendritic cells produce cytokines, in particular interleukin (IL)-23, that stimulate the attraction,
activation, and differentiation of T cells.
● Recruited T cells produce cytokines, importantly IL-17A, which synergizes with other cytokines to stimulate
keratinocytes to proliferate and produce proinflammatory antimicrobial peptides and cytokines.
● Cytokines produced by immune cells and keratinocytes perpetuate the inflammatory process via
participation in positive feedback loops.
The specific components of this pathway are reviewed below.
THE INNATE IMMUNE RESPONSE — The cellular components of the innate immune system that have been
linked to the pathophysiology of psoriasis include dendritic cells as well as macrophages and neutrophils. The
cytokines produced by these cells that appear to play major roles in the development of psoriasis include
interferon (IFN)-alpha, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-23. Modulating the production of
these inflammatory cytokines and the innate immune cells responsible for their production with the small
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molecule phosphodiesterase 4 (PDE4) inhibitor apremilast and the small molecule Janus kinase (JAK)
inhibitors tofacitinib and baricitinib has demonstrated benefit in the treatment of psoriasis [4-6]. (See "Treatment
of psoriasis in adults", section on 'Future therapies' and "Treatment of psoriasis in adults", section on
'Apremilast'.)
Cellular components
Dendritic cells — Two types of dendritic cells (plasmacytoid dendritic cells and myeloid dendritic cells) have
been implicated as contributors to psoriasis.
● Plasmacytoid dendritic cells – Plasmacytoid dendritic cells are largely absent from normal human skin,
but are increased in number in early lesions of psoriasis [7]. These cells are the primary producers of IFNalpha, a key cytokine involved in the initiation of autoimmune responses and antiviral immunity. (See
'Interferon-alpha' below.)
Upregulation of IFN-alpha has been detected in early psoriatic lesions [8]. In addition, in a mouse xenograft
model of psoriasis, the development of psoriatic lesions was dependent on IFN-alpha production by
plasmacytoid dendritic cells [9].
● Myeloid dendritic cells – The numbers of myeloid dendritic cells are markedly elevated in psoriatic skin.
In particular, an inflammatory subset of myeloid dendritic cells that is likely recruited in response to the
release of IFN-alpha and other proinflammatory cytokines and chemokines has been detected in psoriasis
[10-13].
Myeloid dendritic cells are potent antigen presenting cells that produce an array of inflammatory cytokines
that influence T cell activity, such as TNF-alpha (see 'Tumor necrosis factor-alpha' below). Myeloid
dendritic cells also produce IL-23, a cytokine that causes the differentiation of precursor CD4+ cells into
Th17 cells, and IL-12, a cytokine that stimulates the development of Th1 cells and effector CD8+ T cells
[14] (see 'Interleukin-23' below and 'Interleukin-12' below). Myeloid dendritic cells also affect keratinocytes
and the skin vasculature through the production of IL-20 (a modulator of keratinocyte function) and nitric
oxide (a vasodilating agent) [15]. (See 'Keratinocytes' below and 'Vascular changes' below.)
Macrophages and neutrophils — The importance of macrophages in psoriasis in humans is not well
understood. Macrophages accumulate in psoriatic skin near the basement membrane [16] and may contribute
to psoriasis through antigen presentation to T cells as well as cytokine production. The depletion of
macrophages can reverse psoriasis-like skin changes in mouse models [17].
Neutrophils are prominent in lesions of psoriasis, and are found in collections throughout the epidermis that are
referred to as Munro microabscesses. The neutrophil chemoattractant IL-8 is highly elevated in psoriatic skin
[18,19]. Like macrophages, neutrophils are believed to participate in psoriatic inflammation. Studies highlight
their potential role as producers of IL-17A, an important cytokine with multiple effects in psoriatic plaques [20].
(See 'Interleukin-17A' below.)
Cytokines
Interferon-alpha — Type I interferon pathways are upregulated in early lesions of psoriasis [8]. IFN-alpha
present in psoriatic skin is largely derived from plasmacytoid dendritic cells [8]. (See 'Dendritic cells' above.)
Evidence in support of a key role for IFN-alpha in psoriasis includes the observation that systemic treatment
with IFN-alpha can exacerbate psoriasis [21,22]. In addition, topical treatment with imiquimod, which induces
local production of IFN-alpha in the skin, has stimulated the development of psoriasis in humans and psoriasis-

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like disease in mice [23,24]. Furthermore, mice that lack a transcription factor that represses type I interferon
signaling develop psoriasis-like disease [25].
Tumor necrosis factor-alpha — TNF-alpha is a critical proinflammatory cytokine common to many
inflammatory disease states, including psoriasis [26]. Activated dendritic cells, Th17 and Th1 cells, and
keratinocytes in psoriatic skin produce TNF-alpha and respond to its effects. TNF-alpha also functions
synergistically with other cytokines to promote disease pathogenesis.
The following observations support an important role for TNF-alpha in psoriasis:
● Elevated levels of TNF-alpha are found in lesional skin of psoriatic patients [27].
● Dramatic clinical improvement of psoriasis is seen with pharmacologic inhibitors of TNF-alpha (infliximab,
adalimumab, and etanercept) [28-30].
● Removal of circulating TNF-alpha via the administration of etanercept (a TNF-alpha inhibitor) results in
decreased numbers of dendritic cells and T cells along with a reduction of epidermal hyperplasia in
psoriatic skin [12].
The central role of TNF-alpha in both innate and adaptive immune responses makes this cytokine a key target
for therapeutic blockade. (See "Treatment of psoriasis in adults", section on 'Biologic agents'.)
Interleukin-23 — IL-23 is the regulatory cytokine responsible for proliferation and survival of Th17 cells,
which is an increasingly important T cell subset in many autoimmune diseases, including psoriasis and Crohn's
disease [31-33]. IL-23 is produced by myeloid dendritic cells and at low levels by keratinocytes [34,35].
Production of this cytokine by dendritic cells can occur through toll-like receptor signaling pathways [36,37].
(See "Toll-like receptors: Roles in disease and therapy".)
The importance of IL-23 to the pathogenesis of psoriasis has been demonstrated by the following:
● In psoriatics, IL-23 is elevated in lesions of psoriasis compared with unaffected skin and localizes to dermal
dendritic cells and keratinocytes; levels of IL-23 fall with effective treatment of psoriasis [38-42].
● Injection of IL-23 into normal mouse skin produces changes that are clinically and histologically similar to
psoriasis; this process depends on downstream production of IL-22 and IL-17A [38,43,44]. Blockade of IL23 in a mouse model prevented development of psoriasis in human xenografted skin from patients with
psoriasis [45].
● Polymorphisms in the genes encoding a component of the IL-23 receptor, IL23R, and the p40 and p19
subunits of IL-23 have been linked to psoriasis [46].
● Ustekinumab, a monoclonal antibody that blocks IL-23 effects on Th17 cells by inhibiting binding of IL-23 to
the IL-23 receptor, has shown great efficacy in treating psoriasis [47]. Additional biologic agents that
selectively block IL-23 actions, tildrakizumab, guselkumab, and risankizumab, have also proven beneficial
in clinical trials [48-50]. (See "Treatment of psoriasis in adults", section on 'Ustekinumab'.)
Interleukin-12 — IL-12, like IL-23, is produced by activated myeloid dendritic cells, and this cytokine
promotes the differentiation of Th1 cells. Indirect evidence for a contributory role for IL-12 in psoriasis comes
from findings of increased Th1 cells and IFN-gamma (a product of Th1 cells) in psoriatic skin [51,52]. However,
the degree to which IL-12 contributes to psoriasis is brought into question by the failure of a study to detect
upregulation of the p35 subunit of IL-12 in psoriatic skin [40]. It is possible that ustekinumab, an effective
biologic agent for psoriasis that targets both IL-12 and IL-23 [45,47], may function primarily through the drug's

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effects on the IL-23 pathway. (See 'T helper type 1 cells' below and 'Interleukin-23' above and "Treatment of
psoriasis in adults", section on 'Ustekinumab'.)
THE ADAPTIVE IMMUNE RESPONSE — The importance of T cells and their effector cytokines in psoriasis
was established early on with the success of medications that inhibit global T cell responses, such as
cyclosporine [53]. Therapies that block T cell activation or induce T cell death, such as alefacept (an inhibitor of
the T cell-activating interaction between LFA3 on antigen presenting cells and CD2 on T cells that is no longer
commercially available), have been effective for psoriasis [54]. In addition, injection of lymphocytes from
psoriatics can induce psoriatic features in nonlesional human skin transplanted onto severe combined
immunodeficient (SCID) mice [55]. Inhibition of inflammatory cytokine production via phosphodiesterase 4
(PDE4) blockade or Janus kinase (JAK) inhibition in lymphocytes has improved psoriasis as well [56]. (See
"Treatment of psoriasis in adults", section on 'Future therapies' and "Treatment of psoriasis in adults", section
on 'Apremilast'.)
Cellular components
CD4+ T cells — CD4+ helper T cells are found throughout dermal inflammatory infiltrates in psoriatic skin
[57]. Data in support of a role for these cells include the finding that the injection of CD4+ (but not CD8+) T cells
from patients with psoriasis into graft sites on SCID mice transplanted with human skin induces psoriatic
changes in the engrafted skin [58]. In addition, clinical improvement has occurred in patients with psoriasis
treated with monoclonal antibodies against the CD4+ molecule on T cells [59].
The Th17 subset of CD4+ T cells, and to a lesser extent Th1 and Th22 cells, has been implicated in psoriasis.
Early investigational studies presumed a dominating role for Th1 cells; however, Th17 cells are now believed to
play the more critical role. The effects of these cells and other components of the adaptive immune system in
psoriasis are reviewed below.
T helper type 17 cells — The discovery of Th17 cells has led to important insights on the
pathophysiology of psoriasis and new target-specific approaches to treatment. Th17 cells develop in psoriatic
skin under the polarizing effects of IL-1, IL-6, transforming growth factor (TGF)-beta, and IL-23 produced by
inflammatory dendritic cells [60] (see 'Dendritic cells' above). The activation of Th17 cells by IL-23 stimulates
these cells to produce IL-17A and IL-22, cytokines that promote keratinocyte activation and growth [43,61,62].
(See 'Interleukin-17A' below and 'Interleukin-22' below.)
The following study results highlight the role of these cells in psoriasis:
● Th17 cells produce an array of proinflammatory cytokines, including IL-17A, IL-17F, IL-21, IL-22, IL-6, and
TNF-alpha [33], all of which have been linked to psoriasis.
● Th17 cells are found in lesional skin and at elevated levels in the circulation in patients with psoriasis, and
IL-17A is abundantly expressed by these cells [51,63,64].
● Transgenic mice overexpressing the p19 subunit of IL-23, a key factor for Th17 cell functioning, have
severe widespread inflammatory disease that includes inflammation of the skin [65].
● Effective therapies for psoriasis, such as phototherapy, cyclosporine, etanercept, and infliximab, have all
been shown to modulate the Th17 pathway in psoriasis [12,64,66-68].
● Selective targeting of IL-17A (the main effector cytokine produced by Th17 cells) by secukinumab and
ixekizumab leads to dramatic improvement in psoriasis [69,70]. Similar success in clearing psoriatic skin is
seen with blockade of the IL-17RA, a subunit of the IL-17A receptor, by brodalumab [71]. (See "Treatment

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of psoriasis in adults", section on 'Secukinumab' and "Treatment of psoriasis in adults", section on 'Future
therapies'.)
Affecting Th17 cells via inhibition of IL-23 or the IL-23 receptor also is a promising therapeutic approach for
psoriasis [50,72,73]. Ustekinumab, a highly effective drug that is in use for psoriasis, is a monoclonal antibody
that binds to p40, a subunit of both IL-23 and IL-12, which leads to death of Th17 cells. Similarly, tildrakizumab,
risankizumab, and guselkumab are selective blockers of IL-23 that show high efficacy in clinical trials. Agents
that interrupt JAK/STAT signaling pathways (key intracellular events in Th17 cytokine production) are also
under investigation for the treatment of psoriasis [5,6].
T helper type 1 cells — Th1 cells produce an array of proinflammatory cytokines, including IFN-gamma,
IL-2, and TNF-alpha [74]. IFN-gamma, the prototypic cytokine produced by these cells, can promote psoriasislike changes in nonlesional psoriatic skin [75]. Of note, infliximab, an effective anti-TNF therapy for psoriasis, is
also capable of inhibiting IFN-gamma production by Th1 cells [76].
IL-12, a cytokine produced by activated myeloid dendritic cells, promotes the differentiation of Th1 cells. The
degree to which IL-12-mediated effects contribute to psoriasis is uncertain [40]. (See 'Dendritic cells' above and
'Interleukin-12' above.)
CD8 T cells — Cytotoxic CD8+ T cells are found primarily in the epidermis of psoriatic skin and are generally
considered to play a less prominent role in psoriasis than CD4+ T cells [77]. Although they produce cytolytic
enzymes, their role in psoriasis is speculated to involve the elaboration of inflammatory cytokines, including IL17A [78-81]. Interestingly, clonal restriction of resident memory epidermal T cells seems limited to the CD8+
compartment [82]. This finding might suggest a link between viral or self-antigens in the epidermis and
triggering of psoriasis, since these types of MHC class I-restricted antigens are typically presented to CD8+ T
cells, and not CD4+ T cells [83,84].
Regulatory T cells — CD18-knockout mice that are deficient in regulatory T cells develop skin with features
of psoriasis [85]. Additionally, defects in the suppressive function of regulatory T cells have been found in
psoriasis lesions [86]. In the absence of properly functioning regulatory cells, downregulation of immune
responses is inadequate. This may contribute to unchecked inflammation in psoriasis.
Cytokines
Interleukin-17A — IL-17A, an effector cytokine produced by Th17 cells, is elevated in lesions of psoriasis
and serum of patients with psoriasis [38,87]. IL-17A has many functions that are relevant to psoriasis, including
the activation, recruitment, and inhibition of apoptosis in neutrophils; the enhancement of angiogenesis; the
promotion of the release of other inflammatory cytokines (TNF-alpha, IL-1, and IL-6); and the direct activation of
keratinocytes leading to increased production of chemokines [43,62,88-94]. Therapeutic agents for psoriasis
that block IL-17A production or the downstream effects of IL-17 are commercially available. The anti-IL-17A
monoclonal antibodies secukinumab and ixekizumab have shown efficacy results equivalent to or better than
other available biologic agents for moderate to severe plaque psoriasis [69,70]. Similarly high efficacy results in
psoriasis are achieved with brodalumab, an antibody that blocks the binding of IL-17A to its receptor [71].
Interleukin-22 — IL-22 levels are increased in the blood of patients with psoriasis and in psoriatic plaques.
Treatment of psoriasis decreases these levels [64,87,95].
IL-22 is produced by Th17 cells and Th22 cells. This cytokine stimulates the growth and activation of
keratinocytes and has little effect on immune cells. In keratinocytes, IL-22-mediated signaling via STAT3
stimulates cell hyperproliferation, secretion of antimicrobial peptides, and production of matrix
metalloproteinases that support increased cell mobility [44,95-98]. Molecular therapies that target IL-22 are in
clinical trials [99].
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KERATINOCYTES — A role for epidermal keratinocytes as triggers for the initiation of psoriasis is a subject of
much debate. Keratinocyte-derived antimicrobial peptides (AMPs), including beta-defensins, cathelicidins, and
psoriasin (S100A7), may be induced by trauma, and are upregulated in psoriatic epidermis early in the course
of lesion development [100]. AMPs have both chemoattractant and immunomodulatory effects on dendritic cells
and T cells and may contribute to cutaneous inflammation. Similarly, the melanocyte-derived ADAMTS-like
protein 5 may also function as an antigenic trigger of the IL-17 pathway in psoriatics [101]. One theory on the
initiation of psoriasis involves the upregulation of the AMP cathelicidin LL-37 in skin. LL-37 may bind self DNA
and stimulate the production of IFN-alpha by plasmacytoid dendritic cells through Toll-like receptor (TLR)-9
[102]. LL-37 has also been shown to be antigenic in psoriasis; LL-37 stimulates both CD4+ and CD8+ T cells in
an HLA-restricted manner [103].
Keratinocyte hyperplasia characteristic of psoriasis may develop as a result of the effects of cytokines produced
by immune cells. IL-22 is produced by Th17 cells and promotes many of the epidermal changes that occur in
psoriatic lesions (see 'Interleukin-22' above). Additionally, IL-20 production by keratinocytes plays an important
synergistic role downstream of IL-22.
Both IL-22 and IL-20 are highly expressed in psoriatic skin and promote alterations in epidermal thickness,
maturation defects, and upregulation of AMPs [104,105]. A role for IL-20 in psoriasis is supported by the
observation that blocking IL-20 in a SCID xenotransplant model of psoriasis induces resolution of psoriasis and
blocks initiation of disease [106]. Therapeutics directed against both IL-22 and IL-20 have been tested in early
clinical trials [99].
The cytokines and chemokines produced by activated keratinocytes contribute to the sustainment of the
inflammatory response in psoriasis via their effects on innate and adaptive immune cells. Topical vitamin D
analogs as well as topical and oral retinoids primarily affect this pathway in psoriasis. Methotrexate was
originally thought to modulate the epidermal component of psoriasis as well, although current thinking suggests
that its direct effects on the immune system are more important. (See "Treatment of psoriasis in adults", section
on 'Topical vitamin D analogs' and "Treatment of psoriasis in adults", section on 'Tazarotene' and "Treatment of
psoriasis in adults", section on 'Methotrexate'.)
VASCULAR CHANGES — Endothelial cells within psoriatic plaques express elevated levels of vascular
endothelial growth factor (VEGF), prostaglandins, and nitric oxide, all contributing to the characteristic leaky
and tortuous vessels that are abundant in psoriatic skin [107,108]. Transgenic mice overexpressing VEGF in
the epidermis have been found to develop psoriasiform skin changes [109].
The activated vasculature promotes attraction and transmigration of the leukocytes discussed above.
Antiangiogenic agents have actually demonstrated some success in psoriasis patients, but more investigation is
needed [110].
ENVIRONMENTAL FACTORS — Medications, trauma, alcohol, cigarette smoking, stress, and infections have
all been linked to the onset of autoimmune inflammatory conditions and are also known to trigger psoriasis. The
current understanding of this process is rudimentary.
A proposed pathogenic model highlights the possibility of innate recognition of conserved sequences in
microbes through TLR signaling as one possible explanation for infectious triggers. The TLR-7/8 antagonist
imiquimod can induce a psoriasis-like skin disease in mice through production of IFN-alpha by plasmacytoid
dendritic cells. This process is dependent on the Th17 pathway [24].
SUMMARY
● Psoriasis is a complex immune-mediated disorder that presents as inflammatory plaques in the skin
(picture 1A-B). Dysregulation or alteration of components of the innate and adaptive immune systems,
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keratinocyte function, and vascular structure contribute to the manifestations of this disease. (See
'Overview' above.)
● Plasmacytoid and myeloid dendritic cells are key contributors to development of inflammation in psoriasis.
IFN-alpha produced by plasmacytoid dendritic cells stimulates the activation of myeloid dendritic cells,
which contribute to the adaptive immune response through the activation of T cells. (See 'The innate
immune response' above.)
● IL-23 and IL-12 produced by activated myeloid dendritic cells promote the development of Th17 and Th1
cells, respectively. Th17 cells play a major role in the pathogenesis of psoriasis. (See 'The adaptive
immune response' above.)
● Keratinocytes may contribute to the initiation of psoriasis via the production of antimicrobial peptides.
Epidermal hyperplasia is driven by cytokines that stimulate keratinocyte activation and proliferation. (See
'Keratinocytes' above.)
● Knowledge of the pathophysiology of psoriasis is evolving. Advances in the understanding of the
mechanisms of disease will likely contribute to the development of new therapeutic agents and improved
patient outcomes. (See 'Introduction' above and "Treatment of psoriasis in adults".)
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