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TH17 cells expressing CD146 are significantly increased in patients with Systemic sclerosis

Abstract : Systemic sclerosis (SSc) is an autoimmune disorder characterized by vascular damage, excessive fibrosis and abnormal T cells immune-regulation. CD146 is an adhesion molecule essentially expressed in the vascular system, but also on TH17 lymphocytes. In view of the recently described role of CD146 in SSc, we hypothesized an involvement of CD146 positive TH17 cells in this disease. Compared to healthy controls, we showed that both soluble form of CD146 (sCD146), and IL17A levels were increased in patients with SSc with a positive correlation between both factors. A significant increase in TH17 cells attested by an increase of RORγT, IL17A mRNA and CD4+ IL17A+ cell was observed in patients with SSc. Interestingly, the percentage of TH17 cells expressing CD146 was higher in patients with SSc and inversely correlated with pulmonary fibrosis. In vitro experiments showed an augmentation of the percentage of TH17 cells expressing CD146 after cell treatment with sCD146, suggesting that, in patients the increase of this sub-population could be the consequence of the sCD146 increase in serum. In conclusion, TH17 cells expressing CD146 could represent a new component of the adaptive immune response, opening the way for the generation of new tools for the management of SSc. Systemic sclerosis (SSc) is an autoimmune disease characterized by excessive fibrosis in the skin and internal organs, vascular damage and immune dysfunction. Two major clinical subsets, namely limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) forms have been described according to the extent of skin fibrosis 1. Pulmonary fibrosis and pulmonary arterial hypertension (PAH), are the most serious complications and constitute currently the major causes of death 2,3. The study of new molecular targets is essential in the understanding of the physiopa-thology of the disease, and the establishment of new therapeutic strategies. Among them, CD146 has been recently proposed as a new molecular target in SSc 4. This cell adhesion molecule , also called MUC18 and MCAM, is a membrane glycoprotein belonging to the Immunoglobulin super family 5. It is ubiquitously distributed on endothelium 6,7 , with a preferential localization at the endothelial junction 7. CD146 is involved in several functions such as cell adhesion 8 , inflammation 9 , and angiogenesis through different signaling pathways 8. CD146 also exists as a soluble form (sCD146) in the blood, resulting from the proteolysis of the membrane form 9-11. In a mice model of SSc induced by bleomycin, we showed that mice lacking CD146 were more susceptible to develop skin fibrosis than wild type animal. Fibrosis development could be prevented by subcutaneous sCD146 injection. We also evidenced the involvement of Wnt pathway since CD146 deficiency was associated with an up-regulation of the canonical Wnt pathway, leading to the profibrotic state 4. The expression of CD146 is not restricted to the endothelium since it is also expressed on other cell types such as melanoma cells 12 , extra villous trophoblastic cells 13 and TH17 cells 14. TH17 cells are involved in the pathogenesis of several autoimmune diseases including SSc 15. These cells play a critical role in the pathogenesis of autoimmune diseases, leading to production of several cytokines as IL17A, IL22, IL21 and IL26 14. The retinoic acid receptor-related-orphan-receptor-gamma T (RORγT), is the key transcription factor required for TH17 cell
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Amira Gabsi, Xavier Heim, Akram Dlala, Asma Gati, Haifa Sakhri, et al.. TH17 cells expressing CD146 are significantly increased in patients with Systemic sclerosis. Scientific Reports, Nature Publishing Group, 2019, 9 (1), ⟨10.1038/s41598-019-54132-y⟩. ⟨hal-02734077⟩

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