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Pathophysiology of plaque psoriasis

Pathophysiology of plaque psoriasis
Literature review current through: Aug 2023.
This topic last updated: Oct 18, 2021.

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 plaque psoriasis will be discussed here. The epidemiology, genetics, clinical features, diagnosis, and management of psoriasis, as well as the pathogenesis of the less common subtype of pustular psoriasis, are reviewed separately. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis" and "Treatment selection for moderate to severe plaque psoriasis in special populations" and "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis".)

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 [3,4]. A basic sequence of the immunologic events that are theorized to occur in psoriasis is described below [3,4]:

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 and migration of various myeloid dendritic cells in the skin.

Activated macrophages and myeloid dendritic cells produce cytokines, in particular interleukin (IL) 23, which stimulate the attraction, differentiation, and activation of effector T cells.

Recruited effector T cells, in particular T helper type 17 (Th17) and Tc17 cells, produce cytokines, importantly IL-17A, which synergizes with other cytokines to stimulate keratinocytes to proliferate and produce antimicrobial peptides and proinflammatory 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 the professional antigen-presenting cells (APCs), dendritic cells and macrophages, as well as 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 molecule phosphodiesterase 4 (PDE4) inhibitor apremilast and the small molecule Janus kinase (JAK) and tyrosine kinase 2 (Tyk2) inhibitors tofacitinib and deucravacitinib, respectively, has demonstrated benefit in the treatment of psoriasis [5-8]. (See "Treatment of psoriasis in adults", section on 'Emerging therapies' and "Treatment of psoriasis in adults", section on 'Apremilast'.)

Cellular components

Dendritic cells — Two types of dendritic cells (plasmacytoid dendritic cells and various myeloid dendritic cells) have been implicated as contributors to psoriasis:

Plasmacytoid dendritic cells – Plasmacytoid dendritic cells are a unique type of dendritic cell largely absent from normal human skin but are greatly increased in number in early lesions of psoriasis [9]. These cells are the primary producers of IFN-alpha, a key cytokine involved in the initiation phase of autoimmune responses and antiviral immunity. (See 'Interferon-alpha' below.)

Upregulation of IFN-alpha has been detected in early psoriatic lesions [10]. In addition, in a mouse xenograft model of psoriasis, the development of psoriatic lesions was dependent on IFN-alpha production by plasmacytoid dendritic cells [11].

Myeloid dendritic cells – The numbers of myeloid dendritic cells are markedly elevated in psoriatic skin. In particular, an inflammatory subset of myeloid dendritic cells (including TNF-alpha and iNOS-expressing dendritic cells [TIP-DCs], 6-sulfo LacNAc dendritic cells [slanDCs], and epidermal dendritic cells [eDCs]), recruited in response to the release of IFN-alpha and other proinflammatory cytokines and chemokines, has been detected in lesional, psoriatic skin [12-18]. Treatment with biologics, like secukinumab and guselkumab, decreases inflammatory dendritic cells within psoriatic skin [18].

Myeloid dendritic cells are potent APCs 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 and Tc17 cells, and IL-12, a cytokine that stimulates the development of Th1 cells [16,17,19] (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) [20]. (See 'Keratinocytes' below and 'Vascular changes' below.)

Macrophages and neutrophils — The importance of macrophages in psoriasis in humans has been evolving. Macrophages accumulate in psoriatic dermis near the basement membrane [21]. Inflammatory macrophages, and not myeloid dendritic cells, have been identified as the most abundant source of IL-23 in psoriatic skin [18]. Thus, these cells 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 [22]. These cells are also reduced with biologic treatment of psoriasis [18].

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 [23,24]. 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 [25]. (See 'Interleukin-17A' below.)

Cytokines

Interferon-alpha — Type I IFN pathways are upregulated in early lesions of psoriasis [10]. IFN-alpha present in psoriatic skin is largely derived from plasmacytoid dendritic cells [10]. (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 [26,27]. 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-like disease in mice [28,29]. Furthermore, mice that lack a transcription factor that represses type I IFN signaling develop psoriasis-like disease [30].

Tumor necrosis factor-alpha — TNF-alpha is a critical proinflammatory cytokine common to many inflammatory disease states, including psoriasis [31]. Activated dendritic cells, Th17/Tc17 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 [32].

Dramatic clinical improvement of psoriasis is seen with pharmacologic inhibitors of TNF-alpha (infliximab, adalimumab, etanercept, and certolizumab pegol) [33-36].

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 [14].

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 and Tc17 cells, which are important T cell subsets in many autoimmune diseases, including psoriasis and Crohn disease [37-39]. IL-23 is produced by inflammatory macrophages, inflammatory myeloid dendritic cells, and (at low levels) by keratinocytes [40,41]. Production of this cytokine by dendritic cells can occur through toll-like receptor signaling pathways [42,43]. (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 macrophages, dermal dendritic cells, and (to a lesser extent) keratinocytes; levels of IL-23 fall with effective treatment of psoriasis [44-48].

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 [44,49,50]. Blockade of IL-23 in a mouse model prevented development of psoriasis in human xenografted skin from patients with psoriasis [51].

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 [52].

Several monoclonal antibodies bind selectively to the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab), thereby blocking IL-23-mediated effects on Th17 and Tc17 cells. These drugs are highly effective for psoriasis [53-55]. Additionally, the biologic agent ustekinumab, which inhibits both IL-23 and IL-12 signaling by binding the shared p40 subunit of these cytokines, is effective for psoriasis [56]. (See "Treatment of psoriasis in adults", section on 'Ustekinumab'.)

Deucravacitinib inhibits IL-23 receptor-mediated signaling by selective blockade of Tyk2, a tyrosine kinase acting downstream of the IL-23 receptor. Treatment with this drug has resulted in improvement of psoriasis in clinical trials [7,8].

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 [57,58]. 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 [46]. Additionally, preclinical mouse models suggest a regulatory or protective role for IL-12 in counteracting the IL-23/Th17 immunologic pathway [59]. It is possible that ustekinumab, an effective biologic agent for psoriasis that targets both IL-12 and IL-23 [51,56], may function primarily through the drug's 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 [60]. 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 (APCs) and CD2 on T cells that is no longer commercially available), have been effective for psoriasis [61]. In addition, injection of lymphocytes from psoriatics can induce psoriatic features in nonlesional human skin transplanted onto severe combined immunodeficient (SCID) mice [62]. Inhibition of inflammatory cytokine production via phosphodiesterase 4 (PDE4) blockade or Janus kinase (JAK)/tyrosine kinase 2 (Tyk2) inhibition in lymphocytes has improved psoriasis as well [6-8,63,64]. (See "Treatment of psoriasis in adults", section on 'Emerging 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 [65]. 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 [66]. In addition, clinical improvement has occurred in patients with psoriasis treated with monoclonal antibodies against the CD4+ molecule on T cells [67].

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 known 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 T helper type 17 (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 interleukin (IL) 1, IL-6, transforming growth factor (TGF)-beta, and IL-23 produced by inflammatory dendritic cells and macrophages [68] (see 'Dendritic cells' above and 'Macrophages and neutrophils' 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 [49,69,70]. (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 [39], 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 [57,71,72].

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 [73].

Effective therapies for psoriasis, such as phototherapy, cyclosporine, etanercept, and infliximab, have all been shown to modulate the IL-23/T17 pathway in psoriasis [14,72,74-76].

Selective targeting of IL-17A (the main effector cytokine produced by Th17 cells) by secukinumab and ixekizumab, as well as duel blockade of IL-17A and IL-17F by bimekizumab, leads to dramatic improvement in psoriasis [77-79].

Similar success in clearing psoriatic skin is seen with blockade of the IL-17RA, a subunit of the IL-17A receptor, by brodalumab [80]. (See "Treatment of psoriasis in adults", section on 'Secukinumab' and "Treatment of psoriasis in adults", section on 'Emerging therapies'.)

Affecting Th17 cells via inhibition of IL-23 is also a proven therapeutic approach for psoriasis [53,81,82]. 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, guselkumab, tildrakizumab, and risankizumab are selective blockers of IL-23 that show high efficacy in clinical practice and 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 [6,7,64].

T helper type 1 cells — T helper type 1 (Th1) cells produce an array of proinflammatory cytokines, including interferon (IFN)-gamma, IL-2, and TNF-alpha [83]. IFN-gamma, the prototypic cytokine produced by these cells, can promote psoriasis-like changes in nonlesional, psoriatic skin [84]. Of note, infliximab, an effective anti-TNF therapy for psoriasis, is also capable of inhibiting IFN-gamma production by Th1 cells [85].

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 [46]. (See 'Dendritic cells' above and 'Interleukin-12' above.)

CD8+ T cells — Cytotoxic CD8+ T cells, especially Tc17 cells, are primarily found in the epidermis of psoriatic skin and are also considered to play a prominent role in psoriasis [86]. Although they produce cytolytic enzymes, their role in psoriasis is speculated to involve the elaboration of inflammatory cytokines, including IL-17A [87-90]. Interestingly, clonal restriction of resident memory epidermal T cells seems limited to the CD8+ compartment [91]. 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 [92,93].  

In addition, resident memory T cells that are long-lived CD69+, CD103+, IL-17A-producing epidermal CD8+ T cells have been linked to the recurrence of psoriasis in previously healed skin [94]. Further research on these cells may result in therapeutic strategies to target them, perhaps leading to greater long-term control of psoriasis in the future.

Regulatory T cells — CD18-knockout mice that are deficient in regulatory T cells develop skin with features of psoriasis [95]. T regulatory cells have also been found to limit psoriasiform inflammation in imiquimod-induced mouse skin via modulation of IFN-alpha [96]. Additionally, defects in the suppressive function of regulatory T cells have been found in psoriasis lesions [97]. 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 and Tc17 cells, is elevated in lesions of psoriasis and serum of patients with psoriasis [44,98]. 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 [49,70,99-105]. 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 [77,78]. Bimekizumab, a monoclonal antibody that blocks IL-17A and its close homolog IL-17F, shows promising results in clinical trials [106]. Similarly, high efficacy results in psoriasis are achieved with brodalumab, an antibody that blocks the binding of IL-17A to its receptor [80].

Interleukin-22 — IL-22 levels are increased in the blood of patients with psoriasis and in psoriatic plaques. Treatment of psoriasis decreases these levels [72,98,107].

IL-22 is produced by Th17 cells, Tc17 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 [50,107-110]. Of note, trials utilizing fezakinumab, an anti-IL-22 monoclonal antibody, failed in psoriasis, indicating this cytokine is not critical for maintenance of psoriatic lesions [111].

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 [112]. 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 interleukin (IL) 17 pathway in psoriatics [113]. 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 interferon (IFN)-alpha by plasmacytoid dendritic cells through Toll-like receptor (TLR)-9 [114]. 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 [115].

Keratinocyte hyperplasia characteristic of psoriasis may develop because of the effects of cytokines produced by immune cells. IL-22 is produced by Th17 and Tc17 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 [116,117]. 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 [118]. Therapeutics directed against both IL-22 and IL-20 have been tested in early clinical trials [111].

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 may 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 [119,120]. Transgenic mice overexpressing VEGF in the epidermis have been found to develop psoriasiform skin changes [121].

The activated vasculature promotes attraction and transmigration of the leukocytes discussed above. Antiangiogenic agents have demonstrated some success in psoriasis patients, but more investigation is needed [122].

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 interferon (IFN)-alpha by plasmacytoid dendritic cells. This process is dependent on the interleukin (IL) 23/T17 pathway [29].

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, 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. Interferon (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.)

Interleukin (IL) 23 and IL-12 produced by activated macrophages and myeloid dendritic cells promote the development of T helper type 17 (Th17)/Tc17 and T helper type 1 (Th1) cells, respectively. Th17 and Tc17 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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Topic 15277 Version 9.0

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