Rationale and Early Clinical Data on IL-17 Blockade in Psoriasis

Steven M Nwe; Amanda H Champlain; Kenneth B Gordon


Expert Rev Clin Immunol. 2013;9(7):677-682. 

In This Article

Immunopathogenesis of Psoriasis

While psoriasis has been a well-described clinical entity for centuries,[11] the pathogenesis of the disease itself, and more specifically the immunopathogenesis, has only been clarified over the last few years. Given the more common clinical and phenotypic features of the disease state (skin erythema, scale and induration), early views centered primarily on the epidermis itself, and more specifically, keratinocyte abnormalities.[12] Evidence that psoriasis development and maintenance was more systemic and immunologic in nature occurred much later and incidentally. Rheumatologic studies evaluating the efficacy of cyclosporine A, which targets T-cell function, for the use in psoriatic arthritis, also observed clinical improvement in psoriatic lesions. Additional positive trials in the 1980s and early 1990s which looked specifically at cyclosporine and other medications that target T-cell function for use to treat psoriatic skin lesions, built on the observation and helped fuel the hypothesis that psoriasis could be an immune-mediated disease.[13–17] In concordance with this, the findings of abnormally large infiltrates of activated inflammatory cells were observed in psoriatic lesion biopsies. Despite this circumstantial evidence, the direct connection between the inflammatory environment of psoriatic lesions and the clinically apparent keratinocyte changes remained unclear.

The critical link between the immune response and the eventual keratinocyte alterations occurred when it was noted that psoriatic lesions expressed a high level of an activated signal transduction protein named STAT-3, also noted in epithelial cancers.[18] By this point, it was known that cytokines central to the IL-17 pathway were important regulators of STAT-3.[19] Several studies comparing psoriatic lesion biopsies with those of normal skin showed increased mRNA expression of these key cytokines including IL-17A, IL-17F, IL-20 and IL-22 (which have direct effects on keratinocyte behavior), as well as IL-23 in lesion samples.[20–31] Genome-wide association scans also linked risk of psoriasis with gene locus variants for IL-12 and IL-23 receptors, all of which further implicated the activation of the Th17 pathway in the pathogenesis of psoriasis.[32,33]

The Th17 CD4+ T cell and cytokine deregulation theory challenged the most common thought at the time, that psoriasis was primarily a Th1-mediated disease.[34] Since its discovery, and because of its key role in preferentially producing key cytokines (IL-17A, IL-17F, IL-22 and IL-21), the Th17 cell (and more specifically its dysregulation) has been implicated as a key component in the development of autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosis and rheumatoid arthritis.[35–39]

The present model of psoriasis builds upon these findings and the thought that a dysregulation of the innate and adaptive immune system results in lesion development.[40] The model proposes that an unknown antigen or environmental trigger activates natural killer T cells, plasmacytoid dendritic cells and macrophages to produce TNF-α, IL-1β and IFN-α and IL-6 in a genetically susceptible individual. These in turn activate local myeloid dendritic cells to secrete IL-12 and IL-23. While IL-12 goes on to enhance production of Th1 cells (which also drives keratinocyte activation in psoriasis through TNF-α and INF-γ production), IL-23, composed of IL-23p19 and IL-12p40 protein subunits, appears to be the key cytokine involved in Th17 cell differentiation and stabilization.

Differentiated Th17 cells migrate back into the epidermis (controlled by α1β1 integrin) and subsequently produce IL-22 and six different IL-17 cytokines (IL-17A–F).[41–43] The increase in these circulating cytokines, through the mediation of the STAT-3 signaling protein, induces the keratinocyte response, along with upregulation of other important chemokines including CC chemokine ligand (CCL-20), CXCL1, CXCL3, CXCL5, CXCL5 and CXCL8.[44,45] It is believed that the end result is the decreased maturation and increased proliferation of keratinocytes, as well as the vascular proliferation, that are hallmark to psoriasis.[45,46]