DISCUSSION
SSc is characterized by skin sclerosis, which develops in the fingertips. Raynaud's phenomenon, which develops in almost all cases, is also a clinical feature observed in the fingertips. However, previous studies using human skin tissues have been commonly conducted on biopsy tissues from the forearms, which contain large numbers of mast cells (15-17). We here examined skin biopsy samples harvested from the distal extremities and fingers, the sites of symptoms at early stage of the disease, as well as the forearms. In contrast to previous studies, our results demonstrated digital and forearm accumulation of mast cells in the dermis and that digital dermal mast cell density reflected the severity of systemic skin sclerosis in patients with SSc.
Mast cells are strongly involved in allergic diseases by releasing histamine and causing symptoms such as itching following a process called degranulation. During the clinical course of SSc, swelling of the fingers is often observed at an early stage. This may be caused by histamine release after mast cell degranulation. In fact, previous studies reported elevated serum histamine levels in SSc patients (18). Mast cells can also induce fibroblast growth and collagen production to promote skin fibrosis (10, 19). Tight-skin mice (i.e., scleroderma model mice) show accumulation of mostly degranulated mast cells in the skin with fibrosis (20). Furthermore, skin biopsy samples from the forearms of SSc patients often show increase in dermal mast cells with degranulation of some of these cells (15-17, 21). Our results demonstrated a higher density of mast cells in the dermis of fingers than that of forearms and that digital dermal mast cell density correlated with the severity of skin sclerosis assessed by mRSS, especially in patients with sclerodactyly. Thus, our results suggest the possible involvement of digital dermal mast cell density in the pathogenesis of skin sclerosis.
Previous studies demonstrated certain discrepancies in the relevance of dermal mast cells to clinical features such as positivity of anti-Scl-70 antibody (19, 20). However, different from other studies, since our patients had not been treated with corticosteroids and the majority were treatment-naïve, our results could reflect more naïve clinical features that are not affected by therapies.
While the exact reason for the digital accumulation of mast cells in SSc remains unclear, several mechanisms have been proposed. First, stem cell factor (SCF), which is mainly produced by fibroblasts, is involved in migration, differentiation, growth and survival of mast cells (22, 23). Second, although tissue hypoxia is often observed and its severity depends on the extent of inflammation and ischemia-reperfusion damage, mast cells are generally tolerant to hypoxia and can survive and maintain their functions (24-26). Third, since Raynaud phenomenon and fingertip ulcer, which are partly caused by tissue hypoxia, are observed in the distal extremities in SSc, dermal mast cells can survive and produce tryptase and chymase under the hypoxemic condition in fingers (27).
Our results showed high density of dermal mast cells in the fingers and forearms in SSc patients. This is the first study that examined the involvement of digital dermal mast cells in SSc. In particular, digital dermal mast cell density, complicated with Raynaud's phenomenon and fingertip ulceration, reflects systemic skin sclerosis. The present study also indicates the importance of biopsy sites in the estimation of disease severity and the potential of mast cells as a new therapeutic target of SSc.
ACKNOWLEDGMENTS
The authors thank Ms. T. Adachi for the excellent technical assistance. This work was supported in part by a Grant-In-Aid for Scientific Research from the Ministry of Health, Labor and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the University of Occupational and Environmental Health, Japan, through UOEH Grant for Advanced Research.
CONFLICTS OF INTEREST
Y. Tanaka has received consulting fees, speaking fees, and/or honoraria from Mitsubishi-Tanabe Pharma Corporation, Abbott Japan Co., Ltd., Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Santen Pharmaceutical Co., Ltd., Pfizer Japan Inc., Astellas Pharma Inc., Daiichi-Sankyo Co., Ltd., GlaxoSmithKline K.K., Astra-Zeneca, Otsuka Pharmaceutical Co., Ltd., Actelion Pharmaceuticals Japan Ltd., Eli Lilly Japan K.K., Nippon Kayaku Co., Ltd., UCB Japan Co., Ltd., Quintiles Transnational Japan Co. Ltd., Ono Pharmaceutical Co., Ltd., and Novartis Pharma K.K. and has received research grants from Bristol-Myers Squibb, MSD K.K., Chugai Pharmaceutical Co., Ltd., Mitsubishi-Tanabe Pharma Corporation, Astellas Pharma Inc., Abbott Japan Co., Ltd., Eisai Co., Ltd. and Janssen Pharmaceutical K.K.