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Summary

  1. Top of page
  2. Summary
  3. Early psoriasis
  4. Microabscesses and nail pitting
  5. A bimodal immunopathology of psoriasis
  6. Autoinflammatory immune reactivity in psoriasis
  7. Autoinflammatory immune reactivity in psoriasis-related disease
  8. References

Psoriasis is an immune-regulated skin disease with various clinical subtypes and disease activities. The majority of patients present with predominantly stable plaques. At the onset of new lesions, plaque-type psoriasis frequently demonstrates pin-sized and highly inflammatory papules sometimes with an inflammatory border. The histopathology of initial psoriasis differs from stable plaque-type psoriasis. Early lesions demonstrate innate immune cells with neutrophils, degranulating mast cells and macrophages. These are followed by interleukin (IL)-1-dependent T helper (Th)17 cells, finally resulting in the Th1-dominated immunopathology of stable plaque-type psoriasis, where mononuclear cells predominate with interspersed neutrophilic (Munro) microabscesses. These features suggest a bimodal immune pathway where alternate activation of either innate (autoinflammatory) or adaptive (autoimmune) immunity predominates. Neutrophilic infiltrations appear during early psoriasis with Munro abscesses. They are time limited and occur periodically, clinically best seen in linear nail pitting. These features strongly suggest a critical role for an IL-1–Th17-dominated autoinflammation in the initiation of psoriasis, followed by a Th1-dominated late-phase reaction. The concept of bimodal immune activation helps to explain results from therapeutic interventions that are variable and previously only partly understood.

Psoriasis is a common, immune-mediated inflammatory disease of the skin and joints that is genetically predetermined and strongly influenced by endogenous and exogenous trigger factors.[1, 2] Clinical phenotypes range from stable plaque-type psoriasis to highly inflamed eruptive erythematous papules or rapidly arising pustules.[3, 4] The histopathology of the skin, together with the various clinical subtypes, suggests that the underlying immune mechanisms are more complex than in other inflammatory diseases such as eczema or lichen planus.

Stable plaque-type psoriasis is the most common form and is considered as a prototype of psoriasis. Pathophysiological and therapeutic studies are generally conducted in patients with stable plaque-type psoriasis. Yet the clinical subtypes include not only various morphologies but also different types of inflammation. Depending on the type of inflammation, which is reflected by the intensity of the erythema or scaling (Fig. 1a), the eruption of plaques and pustules (Fig. 1a–c) or the development of pustules on infiltrated erythemas (Fig. 1c), the infiltrate is dominated either by tissue neutrophils in exanthematic and pustular psoriasis, or by mononuclear cells and T cells in stable plaque-type psoriasis. Thus, the histopathology basically reflects different stages of psoriasis and its inflammatory activity.[5, 6]

image

Figure 1. Newly developing early psoriasis papules, either as rapidly expanding papules, ‘pinpoint’ lesions (a), as papulopustular lesions (b) or as pustular psoriasis (c). (d) Linear nail pitting demonstrating the periodically dysregulated keratin production at the dorsal nail fold, indicated by white arrows. Nail photo courtesy of Prof. Dr R. Baran, Nice.

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We have previously suggested that the inflammatory pathology underlying various psoriasis phenotypes may switch from an innate immunopathology in pustular psoriasis to an adaptive phenotype in plaque-type psoriasis and vice versa.[4] Accordingly, two contrasting T helper (Th) cell phenotypes, either the innate interleukin (IL)-17-dominated Th17 phenotype or the interferon (IFN)-γ-dominated Th1 phenotype, seem to prevail and to determine the clinical manifestation.

Here we will discuss how different features of psoriasis reflect the natural undulation between an initial ‘autoinflammatory’ phase, leading to neutrophil recruitment, and, subsequently, an adaptive phase, where T cells and mononuclear cells predominate. During the ‘autoinflammatory’ initiation, innate inflammatory cells predominate together with cytokines related to the IL-1 family: IL-1α, IL-1β and IL-36.[7-10] This first flare is followed by CD4+ cells that, in the beginning, are most likely IL-17- or IL-22-producing Th17 cells.[6]

Following the initiation by neutrophils and Th17 cells, IFN-γ-producing Th1 cells become increasingly important in the developing plaque-type psoriasis.[11] Thus, clinical development of single psoriasis lesions seems to follow periodic waves, where autoinflammatory bursts of neutrophils and Th17 cells initiate the disease that then turns into an IFN-γ–Th1-associated inflammation that obviously predominates in psoriasis plaques.[5, 6, 11] In addition, periodic clusters of neutrophils characterize these stable psoriasis plaques, firstly in the dermis, known as squirting papillae [papillae that are enriched with polymorphonuclear neutrophils (PMNs)], and then above the papillae, in the epidermis (Munro abscesses). These neutrophilic bursts suggest that autoinflammatory activation is an inherent feature of the psoriatic pathology.

Early psoriasis

  1. Top of page
  2. Summary
  3. Early psoriasis
  4. Microabscesses and nail pitting
  5. A bimodal immunopathology of psoriasis
  6. Autoinflammatory immune reactivity in psoriasis
  7. Autoinflammatory immune reactivity in psoriasis-related disease
  8. References

Although histopathology studies of early psoriatic lesions have remained scarce, the predominant findings unravel features distinct from plaque-type psoriasis.[12, 13] In so-called pre-pinpoint lesions Jablonska[13] noted that neutrophils are first located in the dermal papillae around the papillary vessels, where they seem to emigrate. This emigration of PMNs from the vessels into the dermis is regulated by innate cytokines such as tumour necrosis factor (TNF), which induces the expression of PMN-binding adhesion molecules by stimulating TNF receptor-1-expressing endothelial cells.[14, 15] Subsequently, these PMNs migrate from the perivascular region towards the subcorneal zone of the epidermis, forming microabscesses leading to slightly more advanced lesions, followed by PMN emigration into the epidermis (Figs 2 and 3). Leucocyte migration is associated with loss of the granular layer and parakeratosis, and a minor thickening of the epidermis. At this stage neutrophils appear to be the predominant cells migrating into the epidermis (Fig. 2a).

image

Figure 2. Histology of a developing psoriasis plaque. (a) An early manifestation of psoriasis, the squirting papillae, with multiple polymorphonuclear neutrophils (PMNs, indicated by white arrowheads) and (b) a later plaque-type psoriasis, showing mainly lymphocytes. (c) Schematic illustration of the cells and cytokines involved at the different phases of psoriasis. Initially, a toll-like receptor (TLR) trigger in combination with rapidly released cytokines of the interleukin (IL)-1 family activate and recruit dendritic cells (DCs), namely plasmacytoid DCs (pDCs). Together with keratinocyte-derived IL-1, the pDCs release chemokines that recruit PMNs and IL-17-producing T helper cells (Th17). Subsequently, the DCs switch towards cells that produce large amounts of interferon (IFN)-α and thus tune the Th17-dominated immune responses with multiple PMNs into a classical T-cell-mediated immune response, where the T helper cells are of the IFN-γ-producing Th1 phenotype. Mø, macrophage.

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image

Figure 3. Psoriasis plaque with squirting papillae, harbouring multiple polymorphonuclear neutrophils (PMNs, indicated by white arrowheads) that may extravagate from the papillae into the epidermis. The inset shows the changing dominance of PMNs within the squirting papillae of early psoriasis lesions towards the predominantly T-cell-dominated infiltrate with small mononuclear T lymphocytes in the late phase characterized by the stable psoriasis plaque. Mø, macrophage; MR, mannose receptor.

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These changes are similar to psoriasis triggered or sustained by a Koebner phenomenon. In both these types of early psoriasis, T cells or mononuclear cells are rare. At this initial phase the histopathology of psoriasis has all of the features characterizing an autoinflammatory disease, similar to IL-1-induced autoinflammation. In line with this, mature IL-1α prevails in early psoriasis papules.[8] Most recent insights support a key role of IL-1α in triggering the disease manifestation, and Gross et al.[10] surprisingly revealed that keratinocytes produce mainly biologically active IL-1α in response to innate signals such as bacterial danger.

This view is strongly supported by studies of psoriatic plaques relapsing after corticosteroid withdrawal. In one such study,[12] 10 days of occlusive corticosteroid treatment showed that psoriatic plaques first clear with a glossy erythema remaining. Subsequently, within a week, psoriasis tends to relapse. Biopsies taken 3 days after the end of occlusive corticosteroid therapy revealed activated macrophages lining the epidermis, and degranulated mast cells to be the earliest changes following corticosteroid removal. As in very early psoriasis, this is followed by infiltrating neutrophils and subsequently, at the time of recurrence, the development of plaque-type psoriasis with macrophages and T lymphocytes. In this context it is important that preclinical studies have proven a key role for mast cells in the realization of T-cell-mediated skin inflammation.[14]

In clinical practice, the majority of patients present with stable plaque-type psoriasis without obvious signs of growth. When psoriasis progresses, patients frequently develop new papules in unaffected skin. Most new papules consist of sharply delineated pin-sized lesions, yet in patients with strong eruptions, the papules show a slight erythematous border and oedema, with the maximal variant being pustular psoriasis (Fig. 1a vs. b,c). In the newly developing oedematous papules neutrophilic inflammation prevails. Thus, during progression of stable plaque-type psoriasis two types of inflammation may coexist within the same patient: an obviously IL-1-driven autoinflammation, capable of neutrophil recruitment into highly inflammatory early lesions (Fig. 1b,c), and a Th1–IFN-γ-associated inflammation[5, 6, 11] that prevails within stable psoriasis plaques (Fig. 1a).

Microabscesses and nail pitting

  1. Top of page
  2. Summary
  3. Early psoriasis
  4. Microabscesses and nail pitting
  5. A bimodal immunopathology of psoriasis
  6. Autoinflammatory immune reactivity in psoriasis
  7. Autoinflammatory immune reactivity in psoriasis-related disease
  8. References

As a second feature, Munro microabscesses and the spongiform pustules of Kogoj link psoriasis to both IL-1- and IL-17-mediated inflammation. These are hallmarks of the psoriatic tissue reaction.[5] Microabscesses are rich in neutrophils that migrate up into and inside the epidermis. They originate from one or two dermal papillae and have been designated as ‘squirting papillae’ by Pinkus and Mehregan.[16] Interestingly, inside psoriasis plaques, microabscesses and ‘squirting papillae’ occur intermittently at timely intervals, indicating that this type of inflammation recurs periodically.

Investigating the mode of action of glucocorticosteroids in plaque-type psoriasis, Griffin et al.[17] showed that psoriasis plaques are clinically and histologically inhomogeneous. Treated lesions reveal both ‘acute and chronic inflammatory areas’, and both areas respond differently to topical corticosteroid therapy. Areas of ‘chronic’ inflammation that are characterized by mononuclear infiltrates respond well to topical corticosteroids, while the neutrophil-dominated sites of acute autoinflammation (‘hot spots’) are largely steroid resistant.[17] These findings not only underline the simultaneous presence of seemingly opposing inflammatory phenotypes within the same lesion, but also demonstrate that responsiveness to therapy, in this case topical corticosteroids, differs inside the psoriasis plaque.

A further clinical phenomenon suggesting periodic inflammatory activation is psoriatic nail pitting. These lesions often show a linear pattern in which single pits are aligned in a strictly linear pattern and are separated from each other at constant distances (Fig. 1d). Psoriatic nail pitting originates at the dorsal nail fold. Periodic bursts of psoriasis that attract PMNs and release them through the epidermis cause the production of nonadherent keratin masses. These keratin–PMN masses are released and cause small defects, the pits in the nails. As a consequence, the linearity and periodicity of psoriatic nail pits indicate that each given spot at the dorsal nail fold results from a periodic inflammatory psoriasis burst (Fig. 2a,c). Such a periodicity is considered to be a hallmark of autoinflammatory diseases.[18]

A bimodal immunopathology of psoriasis

  1. Top of page
  2. Summary
  3. Early psoriasis
  4. Microabscesses and nail pitting
  5. A bimodal immunopathology of psoriasis
  6. Autoinflammatory immune reactivity in psoriasis
  7. Autoinflammatory immune reactivity in psoriasis-related disease
  8. References

Current studies on the immunopathology of psoriasis tend to analyse entire plaques without discriminating between the ‘hot spots’ or squirting papillae and the plaque areas dominated by mononuclear cells. More information comes from experimental and clinical studies on immune activation in early psoriasis, although they provide conflicting data. One piece of data suggests that a type I IFN, namely IFN-α, acts as a prominent mediator leading to the early development of psoriasis plaques.[19] Plasmacytoid dendritic cells (pDCs), which secrete significant amounts of IFN-α in response to innate stimulation by DNA, and differ from classical IL-12-producing DCs, are found in early psoriasis.[19-22] A functional role of pDCs in the pathogenesis of psoriasis is further supported by the identification of a chemotactic factor, chemerin, which induces migration of pDCs into early psoriasis lesions.[23] Chemerin is lost during later stages of plaque development,[23] and pDCs disappear in fully developed psoriasis plaques.

While the description of DNA-stimulated pDCs provides an interesting explanation for the development of Th1 responses in psoriasis, the data have created some problems when trying to unify the data on innate immunity with those from adaptive immunity. One problem was that pDCs appear with the very early autoinflammation-like reactions, when neutrophils and activated mast cells predominate. Then they disappear, exactly at the time when the Th1-dominated mononuclear infiltrate appears. Thus, IFN-α-producing pDCs, which promote Th1 responses, are surprisingly found in close association with neutrophils and mast cells.[19, 21] This apparent discrepancy can now be resolved by recent data showing that type I IFNs, namely IFN-α, antagonize IL-1 production and inflammasome activation in macrophages, monocytes and DCs.[19] These insights now suggest a model of bimodal or consecutive immune activation in psoriasis. According to this theory, psoriasis is first initiated by an innate IL-1–Th-17-dominated innate response, followed by an infiltrate of mononuclear cells causing a Th1-dominated adaptive immune response.

According to these findings, subepidermal pDCs are activated together with IL-1α-producing keratinocytes in response to toll-like receptor (TLR) triggers, such as DNA. The production of IFN-α by the early immigrating pDCs suppresses IL-1 induction and production.[24] Simultaneously, they place the keratinocyte back into the focus of innate inflammation. In parallel, pDCs attract and initiate the mononuclear Th1 response, which persists in adaptive immunity, especially as T cells start replacing the neutrophilic infiltrate. In line with this, it is possible to improve psoriasis efficiently but slowly by abrogating exclusively the innate response either with small molecules that suppress IL-1, IL-12 or IL-23, such as fumarates, or with anti-IL-17 or anti-IL-23p19 antibodies.[25-28] It remains to be established under what conditions Th1 immunity causes increased tissue proliferation, as in the case of psoriatic keratinocytes, and under what conditions Th1 immunity causes cell-cycle arrest and senescence.[29]

Autoinflammatory immune reactivity in psoriasis

  1. Top of page
  2. Summary
  3. Early psoriasis
  4. Microabscesses and nail pitting
  5. A bimodal immunopathology of psoriasis
  6. Autoinflammatory immune reactivity in psoriasis
  7. Autoinflammatory immune reactivity in psoriasis-related disease
  8. References

Understanding innate immune mechanisms is becoming increasingly important in order to understand the clinical course of various diseases.[18] Originally, the description of IL-1 and the discovery of the inflammasome were closely connected with new insights into the disease pathogenesis of periodic fever syndromes.[18] These diseases may affect the skin, joints, eyes and various mucosal surfaces, and occur, at least in the initial phases, without any evidence for autoantibodies or antigen-specific T lymphocytes.[18, 30-32]

Classical periodic fever syndromes are different from classical autoimmune diseases, because they do not involve adaptive immunity. They reveal that the mechanisms leading to autoinflammation are fundamentally distinct from classical T- or B-cell-mediated inflammation. These diseases are frequently caused by mutations either in genes associated with regulation of inflammasomes or in genes regulated by the inflammasome. Many of these genes are involved in the production or metabolism of IL-1β, TNF or related molecules involved in early immune responses.[18, 32-36] The primary inflammatory cells leading to autoinflammation are neutrophils, macrophages and possibly also mast cells.

More recent data suggest that the concept of autoinflammation can be extended beyond the group of monogenetic periodic fever syndromes. Thus, various common immune-mediated inflammatory disorders, including psoriasis, show a mixed pattern of inflammation with components of both adaptive immunity and autoinflammation. Such diseases were recently coined as ‘mixed pattern diseases’.[32-36]

Autoinflammation is self-limited, and the inflammatory response/disease directly wanes when the stimulus disappears.[34] Thus, innate immune responses are short lived. Yet they have a strong tendency to relapse at variable time intervals, as demonstrated by the periodic fever syndromes.

In the skin, innate autoinflammation seems primarily to cause pustular diseases such as palmoplantar pustulosis, acrodermatitis continua or generalized pustular psoriasis.[37] These diseases can now be considered innate variants of psoriasis. Related diseases that also should involve autoinflammation in their development include other neutrophilic skin diseases such as subcorneal pustulosis, Sweet syndrome, pyoderma gangrenosum and Behçet disease, all of which share the association of tissue neutrophilia and a strong tendency to periodical relapses.

In contrast to the abovementioned group of classical autoinflammatory diseases, plaque-type psoriasis shows a mixed pattern of inflammation. Autoinflammatory foci such as squirting papillae or ‘hot spots’, and the subsequently developing Munro abscesses, are periodically interspersed into areas of mature, T-cell-driven plaque-type psoriasis. This shows that T-cell-driven autoimmune pathology coexists with periodic bursts of innate autoinflammation, which present as an inherent principle of psoriasis plaques.

This bimodality of psoriasis is supported by numerous clinical data. Thus, drug-induced agranulocytosis completely clears psoriasis.[38] Innate stimuli that initiate IL-23–Th17-mediated immunity, such as the TLR7 agonist imiquimod, can directly provoke psoriasis,[39] while inhibition of Th17 cells or Th17-driving innate cytokines is highly efficient in treating psoriasis.[26-28] On the other hand, treatment with type I IFNs in order to promote Th1 immunity in chronic hepatitis aggravates Th1-mediated autoimmune diseases, including lichen planus, type 1 diabetes and psoriasis.[40-42] Such a pattern of clinical associations can be reconciled only if the development of psoriasis includes both an autoinflammatory and an autoimmune component. This also explains why inhibition of the autoinflammatory cytokine TNF improves psoriasis by only about 75%, and why TNF antagonists are more efficient in improving pustular psoriasis than in improving the more Th1-associated psoriasis plaques.

Autoinflammatory immune reactivity in psoriasis-related disease

  1. Top of page
  2. Summary
  3. Early psoriasis
  4. Microabscesses and nail pitting
  5. A bimodal immunopathology of psoriasis
  6. Autoinflammatory immune reactivity in psoriasis
  7. Autoinflammatory immune reactivity in psoriasis-related disease
  8. References

Importantly, model diseases in mice have clearly demonstrated the critical role of the autoinflammatory and the nucleotide-binding oligomerization domain (NOD)-IL-1-signalling pathways in inflammatory bowel disease.[34, 43-45] This points towards a heterogeneous group of diseases, even inside the psoriasis disease family, that share the aberrant activation of the inflammasome.[44, 45] In line with this, McGonagle et al.[45] underline that psoriasis-associated nail and joint diseases (e.g. enthesitis) are distinct from human leucocyte antigen-Cw6-associated type I psoriasis. Whereas type I psoriasis is more closely linked to autoimmunity, aberrant autoinflammation seems to dominate in psoriatic nail and joint diseases. Consequently, these manifestations of psoriasis respond very efficiently to treatments with TNF antagonists.[46]

More recently it has become clear that aberrant activation of IL-1 and inflammasomes is also connected with the development of a variety of other, more closely T-cell-associated autoimmune diseases, namely type 1 diabetes, vitiligo and others. These recent data show that autoinflammation is not only a key driver initiating neutrophil-dominated autoimmune diseases, but also extends more broadly to T-cell-mediated autoimmune diseases.[34, 44, 45]

These insights should have important consequences for further studies and their design. Given that psoriasis is a bimodal disease, where autoinflammation initiates a disease that is subsequently sustained by T-cell-dominated Th1 immunity, it is not surprising that a classical study design focusing on Psoriasis Area and Severity Index (PASI) improvement during a 6–12-week period of treatment is effective only in a cohort of patients and cannot clear psoriasis in all patients treated. Instead of analyzing the improvement of established plaque-type psoriasis, one can alternatively question whether IL-1 antagonists are capable of preventing new flares of psoriasis. Such a study has not been performed. Future studies focusing on recent insights into psoriasis pathophysiology and the critical role of IL-1 in initiating this disease may allow development of therapies that safely prevent psoriasis by preventing the initial trigger. It is intriguing that fumarates, which improve PASI scores only very slowly and, in daily practice, seem rather to prevent than to improve psoriasis, inhibit not only the development of Th1 and Th17 responses, but obviously also IL-1α.[26, 27]

References

  1. Top of page
  2. Summary
  3. Early psoriasis
  4. Microabscesses and nail pitting
  5. A bimodal immunopathology of psoriasis
  6. Autoinflammatory immune reactivity in psoriasis
  7. Autoinflammatory immune reactivity in psoriasis-related disease
  8. References