AB0172 PSGL-1 and ADAM8 on dendritic cells are associated with systemic sclerosis and could act as biomarkers for interstitial lung disease
Authors: J Silván, R González-Tajuelo, E Vicente-Rabaneda, A Pérez-Frías, M Espartero-Santos, E García-Lorenzo, I González-Alvaro, S Castañeda, A Urzainqui
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Systemic sclerosis (SSc) is a chronic autoimmune disorder with cutaneous, vascular and immune cells abnormalities that lead to extensive cutaneous and visceral fibrosis with high morbidity and mortality. P-Selectin glycoprotein ligand-1 (PSGL-1) is the major ligand for P-selectin. PSGL-1 mediates the initial contacts with endothelial cells during extravasation to inflamed tissues or homing to several tissues in homeostatic conditions. In addition, PSGL-1/P-Selectin interaction contributes to the homeostasis of the immune system by generating regulatory T cells<sup>1</sup>. Importantly, the metalloprotease ADAM8 interacts with PSGL-1 and proteolytically processes it, what could be a regulatory mechanism to control the expression of PSGL-1<sup>2</sup>. Interestingly, mice lacking PSGL-1 develop a progressive SSc-like syndrome<sup>3</sup>. <h3>Objectives</h3> To investigate whether PSGL-1 and ADAM8 expression on leukocytes could be implicated in the pathogenesis of SSc. <h3>Methods</h3> PBLs from 47 SSc patients and 35 healthy donors were analyzed by flow cytometry. The percentage of cells expressing PSGL-1, HLA-DR and ADAM8, as well as the membrane (without cell permeabilization) and total (after cell permeabilization) expression were assessed for each leukocyte subset. For cell permeabilization, cells were incubated for 15 min at room temperature with a fixation/permeabilization solution. Positivity was stablished using isotype control antibodies. Comparisons between groups were analyzed with Student t tests or Mann-Whitney U test. For pairwise multiple comparisons one-way ANOVA with Tukey9s post hoc test was applied (p&lt;0.05, 95% CI). To analyze the possible contribution of PSGL-1, ADAM8 and HLA-DR to SSc pathogenesis, and to explore whether they could be used as biomarkers for SSc, we studied the influence of these molecules using a multivariate logistic regression model. <h3>Results</h3> SSc patients showed increased expression of HLA-DR in antigen presenting cells (B cells, monocytes and dendritic cells), indicating a higher activation of these cells. PSGL-1 expression in B cells was decreased in SSc patients but increased in monocytes, dendritic cells (DC) and T cells. ADAM8 was increased in B and T lymphocytes, monocytes and DC from SSc patients. Overall, we have identified three variables that are associated with SSc: high percentage of ADAM8-expressing pDC, high PSGL-1 expression in cDC and high HLA-DR expression in CD16+ monocytes. Remarkably, highest PSGL-1 expression on conventional DC (cDC) and high levels of ADAM8 on plasmacytoid DC (pDC) associate with interstitial lung disease (ILD), one of the most severe SSc clinical manifestations, suggesting that PSGL-1 and ADAM8 could be prognostic markers of ILD. <h3>Conclusions</h3> This study highlights that PSGL-1 and ADAM8 expression on DC, monocytes and lymphocytes could be implicated in SSc pathogenesis and particularly on DC might act as biomarkers for ILD. <h3>References</h3> Urzainqui et al., J. Immunol 2007; Domínguez-Luis et al., Eur J Immunol 2011. Pérez-Frías et al., Arthritis Rheumatol 2014. <h3>Disclosure of Interest</h3> None declared