The Biological Basis of Disease Recurrence in Psoriasis

A Historical Perspective and Current Models

Lluís Puig; Antonio Costanzo; Ernesto J. Muñoz-Elías; Maria Jazra; Sven Wegner; Carle F. Paul; Curdin Conrad

Disclosures

The British Journal of Dermatology. 2022;186(5):773-781. 

In This Article

Molecular Scarring

The concept of a residual disease gene expression profile in psoriasis was first proposed in 2011 by Suárez-Fariñas et al.[69] in a landmark study of 20 patients with psoriasis who were treated with the TNF inhibitor etanercept. In post-treatment biopsy specimens, epidermal thickness improved by 92%, Ki67 staining (a general marker of cellular proliferation) improved by 119%, and all samples were negative for keratin 16 (a marker of keratinocyte hyperproliferation). However, a subset of 248 genes did not return to normal levels, including those coding for proinflammatory molecules IL-12, IFN-induced guanosine triphosphate-binding protein Mx1 (MX1), IL-22, IL-17 and IFN-γ, and genes encoding cutaneous structural or regulatory components such as lymphatic vessel endothelial hyaluronic acid receptor-1, Wnt-5a, Ras-related protein Rab-31 and aquaporin-9. Taken together, these findings suggested the concept of a 'molecular scar' within the epidermis of healed lesions.

In 2014, Cheuk et al.[70] reported a detailed analysis of gene expression and cytokine production in T cells within the epidermis and dermis of resolved psoriasis lesions after successful treatment with three different therapies: narrowband ultraviolet B, the IL-12/23 inhibitor ustekinumab and the TNF-α inhibitor infliximab. A population of epidermal CD8+ T cells expressing CLA, CCR6, CD103 and IL-23R was highly enriched in resolved psoriasis lesions, where those expressing CD103 responded to ex vivo stimulation with IL-17 production. The presence of these CD49a-expressing epidermal CD8+ cells suggested a stable, resting population of TRM cells in resolved psoriasis lesions, where they retain the ability to produce IL-17. The authors proposed a model in which, following the appropriate trigger in resolved lesions, skin-residing CD4+ T cells would drive keratinocyte pathology through IL-22 production, and CD8+ T cells would drive recurrent local inflammation by recruiting circulating leucocytes through IL-17A production.[70]

Matos et al.[71] hypothesized in 2017 that skin-resident T cells in resolved psoriatic lesions are derived from expanded clonal or oligoclonal populations of the original IL-17-producing pathogenic T cells that mediated the disease. Using both high-throughput screening of T-cell receptor (TCR) CDR3 regions (antigen recognition domains) and immunostaining to evaluate the clonality and cytokine production of T cells in resolved lesions, clinically resolved psoriatic lesions were found to contain oligoclonal populations of IL-17-producing αβ T cells. A total of four TCRα and 15 TCRβ antigen receptor sequences were found to be shared between patients with psoriasis and were not observed in healthy controls or other inflammatory skin conditions.

Additional evidence for the role of IL-17 expression in lesional memory came from a 2018 study by Gallais Sérézal et al.[72] using transcriptomic analyses to explore whether T cells had different gene expression patterns in psoriatic skin compared with healthy skin. Skin explants treated with the pan-T-cell activating antibody OKT-3 responded with IFN-γ-induced pathways regardless of the inflammatory status of the skin, whereas IL-17-induced pathways were preferentially activated in psoriatic skin and persisted in the epidermis of resolved lesions. As with healed skin, never-lesional skin explants from patients with psoriasis contained resident CD8+ T cells with the potential to produce IL-22, IL-17 and IFN-γ.[72]

The gene expression studies discussed above are subject to a number of important limitations. For example, the use of specific cut-offs to define what constitutes increased gene expression or clinical response is arbitrary, and results may vary substantially if different cut-offs are employed. Moreover, the results reflect gene expression only at the time of biopsy, meaning the timing of the biopsy in relation to the start of treatment may also substantially influence results. Nonetheless, with these limitations in mind, the evidence from these studies overall does suggest that pathogenic TRM cells can create a proinflammatory environment in the skin of patients with psoriasis, and could be responsible for local disease relapse by priming tissue response, driven by IL-22 and IL-17A production by skin-resident CD4+ and CD8+ T cells, respectively.[70,72] As previously mentioned, CD103+ CD8 TRM cells are enriched in both lesional and non-lesional disease-naïve skin, and increase IL-17A-generating potential with disease duration.[66] A current model for disease recurrence in psoriasis is shown in Figure 2.

Figure 2.

Current model of disease recurrence in resolved psoriatic lesions 70,95 In resolved lesions, CD4+ tissue-resident memory cells (TRMs) remain in the dermis, and CD8+ TRMs and epidermal Langerhans cells (eLCs) remain in the epidermis. Upon the disease trigger, eLCs and TRMs actively produce proinflammatory cytokines [interleukin (IL)-23, IL-17A and IL-22] that induce keratinocyte hyperproliferation and recurrent disease.

More recently, a number of RNA transcriptomics analyses have provided further insights into the molecular basis of psoriasis pathophysiology. A recent paper reported the re-emergence of developmental gene programmes by vascular endothelial cells and macrophages in psoriasis pathophysiology, similar to what has been observed in carcinogenesis and metastasis of tumours.[73] Other studies have reported alterations in T-cell expression of inflammatory markers such as ratios of IL-17A vs. IL-17F expression, IFN-γ vs. IL-10 expression and disease severity-dependent expression of the chemokine CXCL13.[74,75]

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