Highly Effective New Treatments for Psoriasis Target the IL-23/Type 17 T Cell Autoimmune Axis

Abstract

Psoriasis vulgaris, affecting the skin, is one of the most common organ-specific autoimmune diseases in humans. Until recently, psoriasis was treated by agents or approaches discovered largely through serendipity. Many of the available drugs were inherently quite toxic when used as continuous treatment for many years in this chronic disease. However, an increasing understanding of disease-specific immune pathways has spurred development of pathway-targeted therapeutics during the past decade. Psoriasis is now the most effectively treated human autoimmune disease, with high-level clinical improvements possible in ∼90% of patients using a new generation of drugs that selectively target the IL-23/Type 17 T cell axis. Thus, psoriasis is a model for the success of a translational-medicine approach based on cellular and molecular dissection of disease pathogenesis in humans.

Psoriasis pathogenesis and the development of novel targeted immune therapies

“…trauma or infection) in the pre-psoriatic skin, T17-producing cells in the skin produce substantial amounts of IL-17 (IL-17A/IL-17F), as well as TNF, IL-26, and IL-29 (IFN-λ1). 46 Together, these cytokine signals create a “feed forward” inflammatory response in keratinocytes by activating CCAAT-enhancer-binding protein beta (C/EBPβ) or delta (C/EBPδ), signal transducer and activator of transcription 1 (STAT1), and nuclear factor kappa B (NFκB), which lead to the upregulation of a number of keratinocyte-derived inflammatory products (Figure 2). This “feed forward” response is self-amplifying and, ultimately, drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, regulating epidermal cell proliferation, and recruiting leukocyte subsets into the skin.…”

“…46 The increased proliferation of epidermal keratinocytes is likely further potentiated by IL-22, and possibly IL-20, as both of these cytokines are also activators of STAT3. 52, 53 This marked thickening of the rapidly proliferating epidermis is accompanied by retention of the keratinocyte nucleus (parakeratosis), as well as upregulation of IL-17-induced transcription factors (e.g.…”

Standard dose of Ustekinumab for childhood-onset deficiency of interleukin–36 receptor antagonist

“…DITRA and non-monogenic psoriasis may have pathophysiological features in common,5 meaning that complex interactions between innate and adaptive immune systems may be involved 6–10. Failure to thrive in DITRA children may be explained by exudative cutaneous protein loss, systemic inflammatory activity, gastrointestinal inflammatory involvement and/or the late repercussions of a lack of early maternal attachment.…”

IL-23 Inhibits Melanoma Development by Augmenting DNA Repair and Modulating T Cell Subpopulations

“…IL-23 plays a pivotal role in the pathogenesis of psoriasis (40) and one study (41) describes patients with psoriasis who showed a reduction in nevus numbers in the psoriatic lesions. Another study (42) observed that compared with control subjects, psoriatic patients had fewer nevi overall, fewer nevi less than 5 mm, and fewer congenital nevi.…”