Involvement of mast cells in fibrosis and pulmonary arterial hypertension in systemic sclerosis

Sonosuke Yukawa1), Kunihiro Yamaoka1), Norifumi Sawamukai1), Shohei Shimajiri2), Kazuyoshi Saito1), Yasuyuki Sasaguri2), Yoshiya Tanaka1)
1)The First Department of Internal Medicine, School of Medicine 2) The Department of Second Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Japan


Systemic sclerosis (SSc) is characterized by excessive and wide spread fibrosis of the skin and internal organs, vasculopathy and activation of the immune system. SSc is often complicated with pulmonary arterial hypertension (PAH) which causes poor prognosis. Interestingly, increased number of mast cells (MCs) can be observed at cutaneous lesions in both human and animal models of SSc. Moreover, MCs-derived tryptase has been implicated as a chemotactic factor for fibroblasts inducing cell proliferation and synthesis of type I collagen, suggesting the involvement of MCs in skin fibrosis. However, the precise role of MCs in the pathogenesis of SSc, especially involvement in PAH remains to be elucidated.


Aim of this study was to clarify the involvement of MCs in human SSc complicated with PAH.


We have evaluated skin biopsy specimens from SSc patients (54 cases), non-SSc patients (29 cases) and normal control (4 cases). NanoZoomer Digital Pathology (NDP), a system to convert a histology slide into high-resolution digital slides (190 million pixels) was utilized for analysis. NDP enables sequential pathological analysis of multiple sections and measurement of accurate specimen area. Density of MCs (/㎟) in each specimen was measured and statistical analysis was performed. Detection of MCs was performed by toluidine blue staining and c-kit immunostaining, tansforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) was detected by immunostaining and fluorescence immnohistochemistry.


First, we compared the number of MCs in skin biopsy specimens from SSc and non-SSc patients. Significantly increased density of MCs with degranulation was observed in dermis of SSc, compared to non-SSc patients and normal control, in concert with fibrosis. Accordingly, density of dermis MCs correlated with modified Rodnan Skin Thickness Score. In addition, increased number of dermis MCs were observed in patients with positive anti-Scl-70 antibody or diffuse cutaneous SSc, compared with patients with negative anti-Scl-70 antibody or limited cutaneous SSc, suggesting the relevance of MCs tothe progress of skin sclerosis. We further evaluated the correlation of the density of dermis MCs with comorbiditiy of multiple internal organ manifestation. .It is noteworthy that dermis MCs were increased in cases complicated with PAH showing strong relation with mean pulmonary arterial pressure and max pressure gradient measured by ultrasound. To further confirm the involvement of MCs in pathology of PAH, we evaluated the density of MCs in pulmonary interstitium in biopsy-samples obtained by a case with SSc-related PAH and found increased density of MCs nearly co-localizing with pulmonary artery, compared with a case with primary PAH. Furthermore, TGF-β1 and PDGF, cytokines known to be involved in fibrosis, were found to be secreted from MCs and both of them localized at dermis and pulmonary interstitium.


Taken together, dermis MCs are increased in SSc patients with a significant correlation with the severity of sclerosis, positive anti-Scl-70 antibody and the presence of PAH and TGF-β1 and PDGF produced by MCs are accumulated at sclerotic dermis and pulmonary interstitium of PAH. Imatinib mesylate, a kinase inhibitor inhibiting c-Abl and PDGF receptor, is known to improve digital ulcer and PAH as well as skin sclerosis in SSc. Recent reports indicate imatinib alsoinhibits c-kit, a cell surface marker for MCs. In conclusion, we here documentfor the first time that the massive involvement of MSc in the pathological processes of SSc, especially complicated with PAH and the results suggest that the inhibition of MCs by imatinib may have a potential of the treatment of SSc.