Bimodal immune activation in psoriasis

Abstract

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.

Dynamics and Transcriptomics of Skin Dendritic Cells and Macrophages in an Imiquimod-Induced, Biphasic Mouse Model of Psoriasis

“…2E). This is reminiscent of psoriatic patients, in whom early lesions show an increase in neutrophils, whereas macrophages and cells from the adaptive immune system predominate in stable plaques (23,24).…”

442 European consensus statement on phenotypes of pustular psoriasis

“…Heterozygous IL36RN alleles were also found in some cases [18,19] of the pustular drug rash AGEP, which could suggest a close relation or overlap with PP. IL-36 is close to IL-1 that has been implicated as the early pathogenetic mechanism in the model of bimodal immune activation in psoriasis [20], acting as autoinflammatory factor. Whilst in PV this is followed by an adaptive immune response, it remains unclear what role adaptive immunity plays in PP.…”

The continuing evolution of targeted therapy for inflammatory skin disease

“…2,3 Triggers that initiate stable disease or exacerbate relapsing disease may be of exogenous or endogenous nature and provoke early inflammatory events that are distinct from the ones in late 4/20 inflammation responsible for stable disease. 4 Indeed, sterile inflammation in the initiation phase of inflammatory skin disease is mediated by the innate immune system and can thus be classified as autoinflammatory. 4,5 Therefore, by blocking IL-12/23p40, interference with both the autoimmune and the autoinflammatory phase is established and, consequently, successful treatment of psoriatic inflammation is observed clinically.…”

“…4 Indeed, sterile inflammation in the initiation phase of inflammatory skin disease is mediated by the innate immune system and can thus be classified as autoinflammatory. 4,5 Therefore, by blocking IL-12/23p40, interference with both the autoimmune and the autoinflammatory phase is established and, consequently, successful treatment of psoriatic inflammation is observed clinically. These reflections may also apply to the high efficacy of neutralizing IL-17 signaling in psoriasis, as IL-17 is increasingly understood to be an intricate part of both the early innate and the late adaptive immune response.…”