IL-17A is functionally relevant and a potential therapeutic target in bullous pemphigoid. (January 2019)

• Record Type: Journal Article
• Authors: Chakievska, Lenche; Holtsche, Maike M.; Künstner, Axel; Goletz, Stephanie; Petersen, Britt-Sabina; Thaci, Diamant; Ibrahim, Saleh M.; Ludwig, Ralf J.; Franke, Andre; Sadik, Christian D.; Zillikens, Detlef; Hölscher, Christoph; Busch, Hauke; Schmidt, Enno
• Is Part Of: Journal of autoimmunity. Volume 96(2019)
• Page Start: 104
• Page End: 112
• Publication Date: 2019-01
• Subjects: Autoantibody -- BP180 -- Bullous pemphigoid -- IL-17A; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2018.09.003
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: IL-17A has been identified as key regulatory molecule in several autoimmune and chronic inflammatory diseases followed by the successful use of anti-IL-17 therapy, e.g. in ankylosing spondylitis and psoriasis. Bullous pemphigoid (BP) is the most frequent autoimmune blistering disease with a high need for more specific, effective and safe treatment options. The aim of this study was to clarify the pathophysiological importance of IL-17A in BP. We found elevated numbers of IL-17A + CD4 + lymphocytes in the peripheral blood of BP patients and identified CD3 + cells as major source of IL-17A in early BP skin lesions. IL1 7A and related genes were upregulated in BP skin and exome sequencing of 51 BP patients revealed mutations in twelve IL-17-related genes in 18 patients. We have subsequently found several lines of evidence suggesting a significant role of IL-17A in the BP pathogenesis: (i) IL-17A activated human neutrophils in vitro, (ii) inhibition of dermal-epidermal separation in cryosections of human skin incubated with anti-BP180 IgG and subsequently with anti-IL-17A IgG-treated leukocytes, (iii) close correlation of serum IL-17A levels and diseases activity in a mouse model of BP, (iv) IL1 7A-deficient mice were protected against autoantibody-induced BP, and (v) pharmacological inhibition of lL-17A reduced the induction of BP in mice. Our data give evidence for a pivotal role of IL-17A in the pathophysiology of BP and advocate IL-17A inhibition as potential novel treatment for this disease. Highlights: CD3 + cells were identified as major source of IL-17A in early bullous pemphigoid skin lesions. IL1 7A and related genes were upregulated in the skin of bullous pemphigoid patients. Exome sequencing of bullous pemphigoid patients revealed mutations in twelve IL-17-related genes in one third of patients. IL1 7A-deficient mice were protected against antibody-induced experimental bullous pemphigoid. Anti-IL-17A treatment significantly reduced skin lesions in antibody-induced experimental bullous pemphigoid in adult mice.