The Journal of allergy and clinical immunology |August 5, 2016

Kolbinger F, Loesche C, Valentin MA, Jiang X, Cheng Y, Jarvis P, Peters T, Calonder C, Bruin G, Polus F, Aigner B, Lee DM, Bodenlenz M, Sinner F, Pieber TR and Patel DD.

The Journal of allergy and clinical immunology. 2017;139:923-932.e8.

DOI: https://doi.org/10.1016/j.jaci.2016.06.038

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.