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Abstract
Atopic dermatitis (AD) is a protease-modulated chronic disorder with heterogenous clinical manifestations which may lead to an imprecise diagnosis. To date, there are no diagnostic protease tests for AD. We explored the gingival crevicular fluid (GCF) protease profile of individuals with moderate/severe AD compared to healthy controls. An exploratory case-control study was conducted. AD patients (n = 23) and controls (n = 21) were enrolled at the International Center for Clinical Studies, Santiago, Chile. Complete dermatological and periodontal evaluations (involving the collection of GCF samples) were made. The levels of 35 proteases were analyzed using a human protease antibody array in matching AD patients (n = 6) and controls (n = 6) with healthy periodontium. The GCF levels of zinc-binding ADAM8, ADAM9, MMP8, Neprilysin/CD10, aspartyl-binding Cathepsin E, serin-binding Protein convertase9, and uPA/Urokinase proteases were lower in moderate/severe AD patients compared to controls (p < 0.05). No inter-group differences in the levels of the other 28 proteases were found. MMP8, Cathepsin E, and ADAM9 were the biomarkers with the highest sensitivity and specificity regarding the detection of AD (p < 0.05). The area under receiver operating characteristic (ROC) curve for MMP8 was 0.83 and MMP8 + ADAMP9 was 0.90, with no significant differences (p = 0.132). A combined model of MMP8, Cathepsin E, and ADAM9 was not considered since it did not converge. Then, levels of MMP8 in GCF were determined using a multiplex bead immunoassay in 23 subjects with AD and 21 healthy subjects. Lower levels of MMP8 in the GCF from the AD group versus healthy group (p = 0.029) were found. This difference remained significant after adjustment by periodontitis (p = 0.042). MMP8 revealed the diagnostic potential to identify AD patients versus healthy controls, (ROC area = 0.672, p < 0.05). In conclusion, differences in the protease profile between AD and control patients were associated with MMP8, Cathepsin E, and ADAM9. Based on the multiplex assay results, MMP8 was lower in AD patients than controls, suggesting that MMP8 may be a diagnostic biomarker candidate.
Highlights
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in humans worldwide [1]
The disease is modulated by proteases, and greatly affects the quality of life of individuals who carry it through intractable manifestations and its severity
Clinical manifestations of AD greatly vary among subjects, at present there are no diagnostic tests that may give a better diagnosis and clinical classification of the moderate/severe AD status
Summary
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in humans worldwide [1]. The etiology of AD is multifactorial and involves the interaction of environmental, genetic, and immune system factors. The pathogenesis of AD is complex and combines cutaneous barrier dysfunction, systemic immune dysregulation, dysbiosis of the bacterial microbiome of the skin, and genetic factors. Atopic dermatitis patients have a predisposition to maintain the T helper (Th) 2 lymphocyte response, while a change in the response from Th2 to Th1 promotes the chronicity of the disease [1,3]. In addition to the immune-inflammatory response, the abnormal expression or activity of proteases has been associated with the pathogenesis of AD. Due to the proteolytic effects, external antigens of AD can invade the epidermis, resulting in dermatitis, coupled with the induction of Th2 cytokines [4,5,6]
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