Psoriasis: Classical vs. Paradoxical. The Yin-Yang of TNF and Type I Interferon

Abstract

Chronic plaque psoriasis is a common debilitating skin disease. The identification of the pathogenic role of the TNF/IL-23/T_H17 pathway has enabled the development of targeted therapies used in the clinic today. Particularly, TNF inhibitors have become a benchmark for the treatment of numerous chronic inflammatory diseases such as psoriasis. Although being highly effective in psoriasis treatment, anti-TNFs can themselves induce psoriasis-like skin lesions, a side effect called paradoxical psoriasis. In this review, we provide a comprehensive look at the different cellular and molecular players involved in classical plaque psoriasis and contrast its pathogenesis to paradoxical psoriasis, which is clinically similar but immunologically distinct. Classical psoriasis is a T-cell mediated autoimmune disease driven by TNF, characterised by T-cells memory, and a relapsing disease course. In contrast, paradoxical psoriasis is caused by the absence of TNF and represents an ongoing type-I interferon-driven innate inflammation that fails to elicit T-cell autoimmunity and lacks memory T cell-mediated relapses.

Keywords: IL-23; TH17; TNF; paradoxical psoriasis; plaque psoriasis; type I-interferon.

Figure 1

Pathogenesis of classical plaque psoriasis and paradoxical psoriasis. Antimicrobial peptides (AMPs), which are produced by keratinocytes upon skin injury or released by neutrophils, form complexes with nucleic acids (NAs) released by dying cells. These complexes activate plasmacytoid dendritic cells (pDC) to produce large amounts IFNα during the acute/early phase of psoriasis pathogenesis. IFNα activates conventional dendritic cells (cDCs), which in turn produce TNF and IL-23. TNF induces the maturation of cDCs and pDCs, which lose their ability to produce IFNα. Thus, in classical psoriasis, early IFNα production gets relayed by TNF that controls and limits the IFNα production by pDCs via a negative feedback loop (through induction of pDC maturation). Subsequently, IL-23 and other pro-inflammatory cytokines produced by cDCs drive the activation of potentially autoreactive T-cells, which proliferate and, particularly CD8⁺ T_C cells, migrate into the epidermis. Upon antigen recognition they produce the T_H17 cytokines IL-17 and IL-22 that induce keratinocyte hyperproliferation, attract neutrophils to the skin, and upregulate AMP production providing a positive feedback loop eventually resulting in the psoriatic phenotype (chronic/late phase). Normally, during anti-TNF therapy, the absence of TNF and consequently of downstream cytokines suppresses pathogenic T-cells thereby alleviating classical psoriasis. However, in patients developing paradoxical psoriasis, TNF blockade inhibits pDC maturation and leads to sustained IFNα production. In addition, as cDC cannot mature in absence of TNF, paradoxical psoriasis fails to elicit a T cell mediated autoimmune response. Thus, paradoxical psoriasis remains in an ongoing IFNα-driven acute immune inflammation independent of T-cells. The exact pathogenic downstream mechanism of IFNα-driven paradoxical psoriasis skin lesions remains to be fully elucidated.