IL-17A is functionally relevant and a potential therapeutic target in bullous pemphigoid

Lenche Chakievska; Maike M. Holtsche; Axel Künstner; Stephanie Goletz; Britt Sabina Petersen; Diamant Thaci; Saleh M. Ibrahim; Ralf J. Ludwig; Andre Franke; Christian D. Sadik; Detlef Zillikens; Christoph Hölscher; Hauke Busch; Enno Schmidt

doi:10.1016/j.jaut.2018.09.003

IL-17A is functionally relevant and a potential therapeutic target in bullous pemphigoid

Lenche Chakievska, Maike M. Holtsche, Axel Künstner, Stephanie Goletz, Britt Sabina Petersen, Diamant Thaci, Saleh M. Ibrahim, Ralf J. Ludwig, Andre Franke, Christian D. Sadik, Detlef Zillikens, Christoph Hölscher, Hauke Busch, Enno Schmidt^*

^*Corresponding author for this work

101 Citations (Scopus)

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.

Original language	English
Journal	Journal of Autoimmunity
Volume	96
Pages (from-to)	104-112
Number of pages	9
ISSN	0896-8411
DOIs	https://doi.org/10.1016/j.jaut.2018.09.003
Publication status	Published - 01.01.2019

Funding

D.T. has received honoraria or fees for serving on advisory boards, as a speaker, as a consultant for Lilly, Leo-Pharma, Novartis and UCB, and grants from Novartis. D.Z. received honoraria from UCB and travel fees from Novartis and UCB. R.J.L. and E.S. received honoraria and travel fees from Novartis as well as honoraria from UCB. We are grateful to Vanessa Krull and Ingrid Dahlke, Lübeck, for excellent technical support. We thank Franziska Schulze, Lübeck, for help with the animal experiments and supervision of L.C. and Yask Gupta, Lübeck, 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 Schultheiß, animal care takers at the Christian-Albrechts-Universität 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). Appendix A

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SDG 9 Industry, Innovation, and Infrastructure

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10.1016/j.jaut.2018.09.003

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Chakievska, L., Holtsche, M. M., Künstner, A., Goletz, S., Petersen, B. S., Thaci, D., Ibrahim, S. M., Ludwig, R. J., Franke, A., Sadik, C. D., Zillikens, D., Hölscher, C., Busch, H., & Schmidt, E. (2019). IL-17A is functionally relevant and a potential therapeutic target in bullous pemphigoid. Journal of Autoimmunity, 96, 104-112. https://doi.org/10.1016/j.jaut.2018.09.003

@article{5670a0ce5a344920a34ebbe0c351a6be,

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.",

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",

year = "2019",

month = jan,

day = "1",

doi = "10.1016/j.jaut.2018.09.003",

language = "English",

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TY - JOUR

T1 - IL-17A is functionally relevant and a potential therapeutic target in bullous pemphigoid

AU - Chakievska, Lenche

AU - Holtsche, Maike M.

AU - Künstner, Axel

AU - Goletz, Stephanie

AU - Petersen, Britt Sabina

AU - Thaci, Diamant

AU - Ibrahim, Saleh M.

AU - Ludwig, Ralf J.

AU - Franke, Andre

AU - Sadik, Christian D.

AU - Zillikens, Detlef

AU - Hölscher, Christoph

AU - Busch, Hauke

AU - Schmidt, Enno

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85053150424

UR - http://www.mendeley.com/research/il17a-functionally-relevant-potential-therapeutic-target-bullous-pemphigoid

U2 - 10.1016/j.jaut.2018.09.003

DO - 10.1016/j.jaut.2018.09.003

M3 - Journal articles

C2 - 30219389

AN - SCOPUS:85053150424

SN - 0896-8411

VL - 96

SP - 104

EP - 112

JO - Journal of Autoimmunity

JF - Journal of Autoimmunity

ER -

IL-17A is functionally relevant and a potential therapeutic target in bullous pemphigoid

Abstract

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