Gingival Crevicular Fluid Zinc- and Aspartyl-Binding Protease Profile of Individuals with Moderate/Severe Atopic Dermatitis

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.

MMP-9 Levels in the Gingival Crevicular Fluid of Chilean Rosacea Patients

“…In our study, we also found higher MMP-9 levels in the GCF of individuals with rosacea versus healthy controls, confirming that rosacea induces changes in biomarkers associated with the inflammation of this disease at a distance from the facial skin. Although higher levels of MMP-9 were reported in atopic dermatitis skin wash samples compared to normal controls [ 49 ], our investigation group did not detect a difference in the MMP-9 levels in GCF between Atopic Dermatitis patients and healthy controls [ 25 ]. Therefore, we suggest that the MMP-9 present in the facial skin of individuals with rosacea enters the circulation due to increased vascular permeability (provided by MMP-9 itself), driving it to the periodontal tissues.…”

“…Therefore, according to these studies, rosacea could cause changes in the composition of proteins in bodily fluids. Our group also reported that psoriasis and atopic dermatitis could influence the GCF’s concentrations of cytokines and MMP, respectively [ 25 , 36 ]. Since rosacea shares specific inflammation mechanisms with psoriasis and atopic dermatitis [ 37 , 38 ], we hypothesized that rosacea might also modify the protein composition in the GCF.…”

“…MMPs are zinc-dependent endopeptidases that degrade different extracellular matrix constituents in chronic skin diseases [ 23 ]. Dermal keratinocytes and fibroblasts synthesize MMPs in response to chronic exposure to several stimuli such as ultraviolet radiation and pro-inflammatory cytokines [ 24 , 25 ]. Among the different types of MMPs, MMP-2 and -9 have been implicated as participants in the pathogenesis of rosacea [ 26 , 27 ].…”

Lack of iron, zinc, and vitamins as a contributor to the etiology of atopic diseases

“…No associations were determined with the levels of vitamins A and E ( 131 , 136 , 137 ) (NCT01861548). Still, low levels of zinc in serum, hair, and erythrocytes are consistently reported in subjects affected by atopic dermatitis ( 138 , 139 ) (RMC 14193/14 and HREC 473/2017), with zinc transporter ( 140 ) and zinc-dependent enzymes being decreased in atopic lesions ( 141 ). However, zinc levels do not change with the severity of the disease ( 142 ).…”

Association of Periodontitis and Atopic Dermatitis with the Levels of IL-13, IL-31, and TSLP in the Gingival Crevicular Fluid

“…Few studies have explored the association between AD and periodontal diseases [23,24]. Although AD and periodontitis share etiopathogenetic mechanisms and comorbidities, the existing literature does not provide enough evidence to ascertain whether AD can influence the immunoinflammatory response of periodontal tissues [25]. In this context, a recent publication successfully associated AD with gingival inflammation and periodontitis (adjusted OR = 1.69, 95% CI: 1.38 to 2.08 and 1.42, 95% CI: 1.13 to 1.77, respectively) [23], whereas a second study reported that AD influences the gingival crevicular fluid levels of MMP-8 independently of periodontal status [25].…”