@article{72bdbde19b504c50ab96eff49ed76b66,
title = "IL-17A is functionally relevant and a potential therapeutic target in bullous pemphigoid",
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. IL17A 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) IL17A-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.",
keywords = "Autoantibody, BP180, Bullous pemphigoid, IL-17A",
author = "Lenche Chakievska and Holtsche, {Maike M.} and Axel K{\"u}nstner and Stephanie Goletz and Petersen, {Britt Sabina} and Diamant Thaci and Ibrahim, {Saleh M.} and Ludwig, {Ralf J.} and Andre Franke and Sadik, {Christian D.} and Detlef Zillikens and Christoph H{\"o}lscher and Hauke Busch and Enno Schmidt",
note = "Funding Information: We are grateful to Vanessa Krull and Ingrid Dahlke, L{\"u}beck, for excellent technical support. We thank Franziska Schulze, L{\"u}beck, for help with the animal experiments and supervision of L.C. and Yask Gupta, L{\"u}beck, for generating the gene regulatory network. We also thank Yoichiro Iwakura for providing breeding pairs of IL-17A−/- mice and greatly appreciate the effort of Sarah Vieten, Gerhard Schulthei{\ss}, animal care takers at the Christian-Albrechts-Universit{\"a}t zu Kiel. The study was supported by Deutsche Forschungsgemeinschaft through the Research Training Group 1727 Modulation of Autoimmunity (to C.M.M.H., C.H., and E.S.), the Clinical Research Unit 303 Pemphigoid Diseases (to S.M.I., C.D.S., D.Z. and E.S), and structural funding through the Excellence Cluster Inflammation at Interfaces (to D.T., S.I., D.Z., R.L., and H.B.). The in vitro studies were funded in part by a research grant of Novartis (to E.S). Funding Information: We are grateful to Vanessa Krull and Ingrid Dahlke, L{\"u}beck, for excellent technical support. We thank Franziska Schulze, L{\"u}beck, for help with the animal experiments and supervision of L.C. and Yask Gupta, L{\"u}beck, for generating the gene regulatory network. We also thank Yoichiro Iwakura for providing breeding pairs of IL-17A −/- mice and greatly appreciate the effort of Sarah Vieten, Gerhard Schulthei{\ss}, animal care takers at the Christian-Albrechts-Universit{\"a}t zu Kiel. The study was supported by Deutsche Forschungsgemeinschaft through the Research Training Group 1727 Modulation of Autoimmunity (to C.M.M.H., C.H., and E.S.), the Clinical Research Unit 303 Pemphigoid Diseases (to S.M.I., C.D.S., D.Z. and E.S), and structural funding through the Excellence Cluster Inflammation at Interfaces (to D.T., S.I., D.Z., R.L., and H.B.). The in vitro studies were funded in part by a research grant of Novartis (to E.S). Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2019",
month = jan,
doi = "10.1016/j.jaut.2018.09.003",
language = "British English",
volume = "96",
pages = "104--112",
journal = "Journal of Autoimmunity",
issn = "0896-8411",
publisher = "Academic Press Inc.",
}
