Background DNAM-1 (CD226) is well known as a genetic risk factor of many autoimmune diseases such as systemic sclerosis (SSc). More recently, Avouac et al. have reported that mice deficient for DNAM-1 are protected from bleomycin-induced dermal fibrosis. In human, however, the roles of DNAM-1 in SSc are still unknown.
Objectives To evaluate cell surface expression of DNAM-1 on peripheral blood lymphocytes from SSc patients and to identify the roles of DNAM-1 in the pathogenesis of SSc.
Methods The expression of DNAM-1 was analyzed by flow cytometry (FCM) on surface of CD4+ T cells, CD8+ T cells and CD19+ B cells from 41 SSc patients (median age, 59 years; female, 37) and 23 healthy controls (HCs). We evaluated the relationship between DNAM-1 expression level on CD8+ T cells and clinical manifestations of SSc. Intracellular and extracellular cytokine production in CD8+ T cells with or without DNAM-1 was measured by FCM (intracellular staining and multiplex bead array, respectively) after stimulation with PMA/Ionomycin. The cytotoxic capacity of CD8+ T cells against human umbilical vein endothelial cells (HUVECs) was assessed in the presence or absence of anti-DNAM-1 neutralizing antibody in SSc patients and HCs.
Results The proportion of DNAM-1high CD8+ T cells was increased in SSc patients (median, 52.5%) compared to HCs (29.7%, P=0.0002). We found no significant difference between SSc patients and HCs in CD4+ T cells and CD19+ B cells. The expression of DNAM-1 on CD8+ T cells was higher in patients with diffuse cutaneous subtype than those with limited cutaneous subtype (P=0.0009) and was higher in those with interstitial pneumonia than those without (P=0.0016). The percentage of DNAM-1high CD8+ T cells was significantly correlated with modified Rodnan skin thickness score (r =0.4295, P=0.0071). The production of IL-13 was significantly increased in DNAM-1 positive CD8+ T cells compared with DNAM-1 negative ones and the neutralization of DNAM-1 impaired the IL-13 production from CD8+ T cells. The cytotoxic ability of CD8+ T cells was significantly elevated in SSc patients and positively correlated with the percentage of DNAM-1high CD8+ T cells. The cytotoxicity against HUVECs was partially inhibited in the presence of anti-DNAM-1 neutralizing antibody.
Conclusions These findings indicate that DNAM-1high CD8+ T cells are involved in the pathogenesis of SSc via the production of profibrotic IL-13 and endothelial cell injury.
Avouac J, Elhai M, Tomcik M, et al. Critical role of the adhesion receptor DNAX accessory molecule-1 (DNAM-1) in the development of inflammation-driven dermal fibrosis in a mouse model of systemic sclerosis. Ann Rheum Dis. 2013;72:1089-98.
Disclosure of Interest None declared
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.