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J Allergy Clin Immunol. 2017 Mar;139(3):923-932.e8. doi: 10.1016/j.jaci.2016.06.038. Epub 2016 Aug 5.

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

Author information

1
Novartis Institutes for BioMedical Research Shanghai, China.
2
Novartis Pharma, Basel, Switzerland, and Shanghai, China.
3
HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H., and the Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University Graz, Graz, Austria.
4
Novartis Institutes for BioMedical Research Shanghai, China. Electronic address: dhavalkumar.patel@novartis.com.

Abstract

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. 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).

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.

KEYWORDS:

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

PMID:
27502297
DOI:
10.1016/j.jaci.2016.06.038
[Indexed for MEDLINE]
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