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

• Published in: Journal of allergy and clinical immunology Vol. 139; no. 3; pp. 923 - 932.e8
• Main Authors: Kolbinger, Frank, Loesche, Christian, Valentin, Marie-Anne, Jiang, Xiaoyu, Cheng, Yi, Jarvis, Philip, Peters, Thomas, Calonder, Claudio, Bruin, Gerard, Polus, Florine, Aigner, Birgit, Lee, David M., Bodenlenz, Manfred, Sinner, Frank, Pieber, Thomas Rudolf, Patel, Dhavalkumar D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2017
• Subjects: Adult; Allergy and Immunology; ankylosing spondylitis; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Autoimmune Diseases - blood; autoimmunity; beta-Defensins - blood; biomarker; Biomarkers - blood; dermal interstitial fluid; Female; Humans; IL-17; Interleukin-17 - blood; Male; microperfusion; multiple sclerosis; psoriasis; Psoriasis - blood; Psoriasis - drug therapy; Psoriasis - immunology; psoriatic arthritis; rheumatoid arthritis; secukinumab; Skin - immunology; Skin - pathology; β-defensin 2; LLOQ; IHC; dermal interstitial fluid; secukinumab; ankylosing spondylitis; microperfusion; dISF; β-defensin 2; CD; PASI; multiple sclerosis; GM; MS; qRT-PCR; biomarker; rheumatoid arthritis; RA; MMP; AS; autoimmunity; psoriasis; IL-17; BD-2; psoriatic arthritis; PsA; RQ; Immunohistochemistry; Quantitative RT-PCR; Matrix metalloproteinase; Psoriasis Area and Severity Index; Geometric mean; Relative quantity; Crohn disease; Lower limit of quantification
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2016.06.038

IL-17A is a key driver of human autoimmune diseases, particularly psoriasis. 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. 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. 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. β-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-α 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 = 281, P < .001). 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.