IL-23/IL-17A Dysfunction Phenotypes Inform Possible Clinical Effects from Anti-IL-17A Therapies

Abstract

Biologics that neutralize specific cytokines have improved outcomes for several immune-mediated disorders but may also increase risks for particular side effects. This article postulates potential immunologic consequences of inhibiting components of the IL-23/T-helper cell 17 pathway-the target of next-generation biologics for treating psoriasis-based on clinical phenotypes of inherent or acquired deficiencies in this pathway. Generally, downstream deficiencies (e.g., IL-17A, IL-17F) are associated with fewer disorders compared with upstream deficiencies, suggesting that selectively blocking downstream targets may result in a narrower range of side effects. However, safety of these specific inhibitions must be established in long-term studies.

Figure 1

Role of cytokines in psoriasis pathophysiology and immune defense against infections. (a) Pathophysiology of psoriasis, with indications for the relative positions of key cytokines and their inhibitors. (b) Signaling pathways associated with specific increases in susceptibility to pathogens. HSV, herpes simplex virus; NEMO, NF-kappaB essential modulator; STAT, signal transducer and activator of transcription; TIR, Toll-like receptor/IL-1 receptor; TNF-R, tumor necrosis factor receptor; TYK, tyrosine kinase (Bustamante et al., 2008). Adapted from Bustamante et al., 2008, with permission from Elsevier.