β-Defensin 2 is a responsive biomarker of IL-17A-driven skin pathology in patients with psoriasis

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:139

Article

Kolbinger, Frank^1,2  Loesche, Christian^1,2  Valentin, Marie-Anne^1,2  Jiang, Xiaoyu^1,2,7  Cheng, Yi^3,4  Jarvis, Philip^3,4  Peters, Thomas^1,2  Calonder, Claudio^1,2  Bruin, Gerard^1,2  Polus, Florine^1,2  Aigner, Birgit^5,6  Lee, David M.^1,2,8  Bodenlenz, Manfred⁵  Sinner, Frank^5,6  Pieber, Thomas Rudolf^5,6  Patel, Dhavalkumar D.^1,2 

[1] Novartis Inst BioMed Res, Basel, Switzerland

[2] Novartis Inst BioMed Res, Shanghai, Peoples R China

[3] Novartis Pharmaceut, Basel, Switzerland

[4] Novartis Pharmaceut, Shanghai, Peoples R China

[5] Joanneum Res Forsch Gesell MbH, HLTH Inst Biomed & Hlth Sci, Weiz, Austria

[6] Med Univ Graz, Div Endocrinol & Metab, Dept Internal Med, Graz, Austria

[7] Merrimack Pharmaceut, Cambridge, MA USA

[8] Roche, Basel, Switzerland

关键词: IL-17;    psoriasis;    secukinumab;    beta-defensin 2;    biomarker;    dermal interstitial fluid;    microperfusion;    psoriatic arthritis;    ankylosing spondylitis;    rheumatoid arthritis;    multiple sclerosis;    autoimmunity;   

DOI  :  10.1016/j.jaci.2016.06.038

来源: Elsevier

【 摘 要 】

Background: IL-17A is a key driver of human autoimmune diseases, particularly psoriasis. Objective: We sought to determine the role of IL-17A in psoriasis pathogenesis and to identify a robust and measurable biomarker of IL-17A-driven pathology. Methods: We studied 8 healthy subjects and 8 patients with psoriasis before and after administration of secukinumab, a fully human anti-IL-17A mAb, and used a combination of classical techniques and a novel skin microperfusion assay to evaluate the expression of 170 proteins in blood, nonlesional skin, and lesional skin. For validation, we also tested stored sera from 601 patients with a variety of autoimmune diseases. Results: IL-17A was specifically expressed in lesional compared with nonlesional psoriatic skin (9.8 vs 0.8 pg/mL, P <.001). Proteomic and gene transcription analyses revealed dysregulated antimicrobial peptides, proinflammatory cytokines, and neutrophil chemoattractants, levels of which returned to normal after treatment with secukinumab. beta-Defensin 2 (BD-2) was identified as a biomarker of IL-17A-driven pathology by comparing protein expression in patients with psoriasis versus that in healthy subjects (5746 vs 82 pg/mL in serum, P <.0001; 2747 vs <218 pg/mL in dermis, P <.001), responsiveness to secukinumab therapy, and synergistic induction by IL-17A and TNF-alpha in epidermal keratinocytes. In a validation set of sera from 601 patients with autoimmune diseases thought to be IL-17A driven, we found that BD-2 levels are most highly increased in patients with psoriatic skin lesions, and in patients with psoriasis, BD-2 levels correlated well with IL-17A levels (r = 0.70, n = 199, P <.001) and Psoriasis Area and Severity Index scores (r = 0.53, n 5 281, P <.001). Conclusion: IL-17A is a primary driver of skin pathology in patients with psoriasis, and serum BD-2 is an easily measurable biomarker of IL-17A-driven skin pathology.

【 授权许可】

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