AB0190 Impaired activation of ataxia-telangiectasia mutated protein kinase in immune cells is associated with clinical features in patients with systemic sclerosis
Authors: K. Sakata, H. Yasuoka, K. Yoshimoto, K. Yamaoka, T. Takeuchi
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Ataxia-telangiectasia mutated (ATM) is a protein kinase associated with ataxia-telangiectasia (AT), which is an autosomal recessive disorder due to defective functional activity of ATM. Telangiectasia, seen in AT, is also well known as one of the major characteristics of systemic sclerosis (SSc). ATM plays an important role not only in DNA damage repairing system, but also in the process of regulation of oxidative stress.<sup>1</sup> Moreover, it has been reported that oxidative stress may contribute to disease process of SSc<sup>2 3</sup>. Based on these background, we hypothesised that ATM may play a substantial role in the pathogenesis of SSc. However, the possible association between ATM activity and SSc development is not fully understood. <h3>Objectives</h3> To clarify the role of ATM in the pathogenesis of SSc, we demonstrated the expression and activation level of ATM in circulating immune cells and analysed the association with clinical characteristics of the patients. <h3>Methods</h3> Whole blood samples were collected from twenty-four patients with SSc and 12 healthy controls (HC). Expression levels of total ATM and active phosphorylated ATM (pATM) were examined in each immune cell subset (neutrophil, monocyte, T cell, B cell and NK cell) by mean fluorescence intensity (MFI) using flow cytometer. Each MFI level of ATM and pATM was compared between patients with SSc and HC, and was analysed the correlation with clinical characteristics of SSc patients, retrospectively collected from patients' records. <h3>Results</h3> The expression level of pATM was significantly lower in monocytes, neutrophils, and T cells in SSc as compared with <sup>HC (1887</sup>±128 vs 2386±181, p=0.03; 10265±861 vs 16087±1218, p=0.0004; 1326±73 vs 1675±103, p=0.009; respectively), whereas no significant difference in total ATM level was observed in each cell subset between two groups. Notably, the expression levels of pATM in monocytes of the patients with interstitial lung disease (ILD) was lower than that of the patients without <sup>ILD (1663</sup>±136 vs 1999±96, p=0.05). Furthermore, there was a tendency of correlation between pATM level in monocyte and parameters of pulmonary function test, such as forced vital capacity. No significant differences and/or correlation between pATM expression level in other cell subsets and clinical parameters of the patients, such as SSc subtype, SSc-specific autoantibodies, presence of pulmonary arterial hypertension, gastrointestinal involvement, digital tip ulcer, pitting scar and modified Rodnan skin score were observed. <h3>Conclusions</h3> In SSc, phosphorylated level of ATM in monocytes, neutrophils, and T cells was significantly lower than that of HC. Importantly, we found that ATM activation was impaired in monocyte of the SSc patients with ILD. These results collectively suggest that the loss of ATM activation in monocytes may contribute to the disease process of SSc, and is possibly due to DNA damage and oxidative stress. <h3>References</h3> [1] Guo Z, et al. Science. 2010;330:517–521. [2] Sambo P, et al. J Invest Dermatol. 1999;112:78–84. [3] Gabrielli A, et al. Open Rheumatol J. 2012;6:87–95. <h3>Disclosure of Interest</h3> None declared