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Background IgG4-Related Disease (IgG4-RD) is a multi-organ fibro-inflammatory disorder characterised by tumefactive lesions with well-defined histological features including lymphoplasmacitic infiltrate rich in IgG4+ plasma cells, storiform fibrosis and obliterative phlebitis1. Alternatively-activated macrophages (M2) have also been reported to abundantly infiltrate IgG4-RD lesions, but their role in IgG4-RD pathogenesis remains elusive. M2 macrophages have been recently shown to modulate innate and adaptive immune responses as well as tissue fibrosis by direct interaction with stromal cells2–4. Both these roles can be mediated by Mer tyrosine kinase (MerTK), a member of the TAM – Tyro3, Axl and MerTK- receptor family, which is highly expressed on M2 macrophages5. The relevance of MerTK and of its ligands Protein S (ProS) and Growth arrest-specific protein 6 (Gas6) in IgG4-RD has never been assessed before. Objectives To assess a pathogenetic relevance of the MerTK-ProS/Gas6 axis in IgG4-RD. Methods Immunohistochemical studies for CD68, CD163 and MerTK were performed on 8 cases of IgG4-RD involving different organs. MerTK expression within the different circulating monocyte subsets was quantified by flow cytometry both in 11 active untreated IgG4-RD patients and in 10 healthy controls (HC). Plasma levels of ProS, Gas6 and of their decoy receptor – soluble Mer (sMer) – were measured by ELISA in 34 IgG4-RD patients and 20 HC. Results MerTK was abundantly expressed in IgG4-RD lesions both within the inflammatory infiltrate and in the newly formed fibrous tissue. The pattern of MerTK expression was similar to that of the M2 macrophage marker CD163 (figure 1). Total circulating monocytes and their subsets were not expanded in active untreated IgG4-RD compared to HC. However, MerTK+ monocytes were significantly increased in the peripheral blood of patients with IgG4-RD compared to HC (p Conclusions A subset of MerTK+ M2 macrophages abundantly infiltrates IgG4-RD fibrotic lesions and their MerTK+ monocyte precursors are expanded in the peripheral blood of patients with active IgG4-RD. MerTK ligands are also increased in IgG4-RD, suggesting an augmented activation of MerTK signalling pathways. Further studies are needed to better characterise this monocyte/macrophage subpopulation, to understand its role in IgG4-RD and to identify possible biomarkers and therapeutic targets. References [1] Deshpande V, et al. Mod. Pathol2012. [2] Furukawa S, et al. Clin. Immunol2015. [3] Furukawa S, et al. Sci. Rep2017. [4] Ohta M. et al. Med2016. [5] Rothlin CV, et al. Annu. Rev. Immunol2015. Disclosure of Interest None declared |
