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

Role of T Cells in Psoriasis Immunopathology

The involvement of T cells in psoriasis was already demonstrated in 1986, when a study published by Fry and colleagues demonstrated clearance of psoriasis following administration of low-dose ciclosporin.[8] However, psoriasis was previously considered a primarily keratinocyte-driven disease for decades, until approaches involving anti-CD3 and anti-CD4 monoclonal antibodies specifically targeting T cells[9,10] produced a paradigm shift in our understanding of its immunopathology. In 1995, a landmark study by Gottlieb et al.[11] demonstrated psoriatic plaque reduction after the targeted depletion of activated interleukin (IL)-2 receptor (R)-expressing T cells by treatment with a fusion protein composed of IL-2 and diphtheria toxin. Although the observed mean reduction of 32% in Psoriasis Area and Severity Index (PASI 32) is low by present-day therapeutic standards, it was considerable at the time. This research suggested the primary role of T cells in psoriasis pathogenesis, and was further supported by studies identifying large numbers of activated CD4+ and CD8+ T cells in the skin lesions and peripheral blood of patients with psoriasis.[12,13] Xenograft studies on an immunosuppressed AGR129 mouse model demonstrated that T-cell proliferation and migration into the epidermis precedes the onset of psoriasis and is essential for disease development. Therefore, accumulating epidermal T cells are now seen as effectors in psoriasis pathogenesis rather than triggers.[14] Such T cells show oligoclonal expansion in psoriatic skin,[15,16] particularly in the epidermis,[17] indicating the potential for a common (epidermal) antigen for autoimmune T cells in psoriasis.

In the 1990s, characterization of the cells and cytokines involved in psoriasis pathogenesis demonstrated overexpression of the T helper (Th)1 cytokines interferon gamma (IFN-γ), tumour necrosis factor alpha (TNF-α) and interleukins in psoriatic lesions,[18,19] and led to the description of psoriasis as a Th1-type disease. However, when IL-17-producing CD4+ T cells (Th17 cells) were isolated from psoriatic plaques, focus shifted towards a novel T-cell subset.[20–25] In 2014–2015, specific T-cell responses against the autoantigen keratin 17, the cathelicidin antimicrobial peptide LL-37 and the melanocyte antigen ADAMTSL5 were identified in patients with psoriasis, supporting the hypothesis of plaque-type psoriasis as a T-cell mediated autoimmune disease.[26,27] Moreover, epidermal CD8+ T cells, which express the Th17 cytokines IL-17 and IL-22, were shown to play an essential role in the pathogenesis of psoriasis.[28,29] In fact, IL-17 and IL-22 represent key disease mediators, linking the adaptive immune response and epithelial dysregulation in psoriasis by inducing keratinocyte hyperproliferation via Th17 and LL-37 upregulation from activated keratinocytes.[30]

Whereas Th1 cell development is driven by IL-12, development and maintenance of Th17 cells is linked to IL-23. IL-12 is composed of a p35 and a p40 subunit, while IL-23 is composed of a p19 and a p40 subunit. Both cytokines therefore share the p40 subunit, and a therapeutic agent targeting the p40 subunit (ustekinumab) has shown clinical efficacy in patients with psoriasis.[31] In 2009, McGeachy et al. demonstrated that IL-23 was required for in vivo Th17 cell differentiation in autoimmunity, inflammation and infection, thus indicating a more central role for IL-23 in Th17 function than previously thought.[32] Interference with correct Th17 cell development inhibits psoriasis plaque formation, as shown in a psoriasis xenograft mouse model where antibodies directed against IL-21, a key cytokine in Th17 early development, had therapeutic effects.[33] In 2010, a study showed that specific IL-23 p19 inhibition blocked psoriasis development in the immunosuppressed AGR129 mouse model, suggesting that IL-23 plays a major role in the pathogenesis of psoriasis.[34] The relevance of the IL-23/Th17 pathway has been further supported by genome-wide association studies.[35,36] IL-23 appears to be critical in promoting the differentiation of pathogenic tissue-resident memory (TRM) T cells; this pathogenic subset of TRM cells has an important role in autoimmune inflammation in human skin.[37] This TRM cell differentiation via serum glucocorticoid-regulated kinase-1 induction of FOXO1 deactivation then leads to further IL-23R expression.[38]

In summary, the IL-23/Th17 axis has a central role in the pathogenesis of psoriasis.[39] (Figure 1), as well as in psoriatic arthritis and other spondyloarthritides.[40]

Figure 1.

Current model of psoriasis immunopathology 30,93,94 (1) Activation of plasmacytoid dendritic cells (pDCs) and interleukin (IL)-23-producing epidermal DCs due to keratinocyte damage. (2) T helper (Th)17 cell polarization and clonal expansion is triggered. T-cell activation leads to production of proinflammatory cytokines. IL-23 promotes Th17 cell clonal expansion and differentiation. (3) IL-17 +/– tumour necrosis factor alpha (TNF-α) induces further inflammation with terminal keratinocyte differentiation and proliferation – forming a psoriatic plaque. (4) A feedforward inflammatory response is induced, with IL-17 inducing psoriasis-related gene expression in keratinocytes, driving further inflammation. eDCs, epidermal DCs; IFN, interferon; LC, Langerhans cell; LL-37, cathelicidin antimicrobial peptide; TRM, tissue-resident memory cell.

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