Table 1.

Function of the primary cell types implicated in SSc pathogenesis both in the blood circulation and at the site of fibrosis.

Cell Type	Function
Endothelial cell	Platelet adhesion activates fibrotic pathways. Increased microvascular permeability causes leukocyte adhesion to the endothelium, leading to increased inflammation [7].
Monocyte/Macrophage	A prominent M2 macrophage signature increases levels of pro-fibrotic cytokines such as IL-4, IL-6, and IL-13 and correlates with elevated tissue fibrosis [17,18,19,20].
Eosinophil	Elevated eosinophil counts in the peripheral blood are associated with severe lung disease and presence of skin ulcers [31,32,33].
Mast cell	Release of cytokines and growth factors such as IL-4, IL-6, IL-13, TNF-a, PDGF, and TGF-β activates myofibroblasts to produce collagen [37]. Tryptase and histamine release triggers fibroblast proliferation [38,39].
Innate lymphoid cell	Increased production of the ILC2 cytokines IL-25, IL-33, and TSLP in serum and skin mediates fibrosis in a TGF-β-dependent manner [43,44,45,46,47,48,49].
Plasmacytoid dendritic cell	Elevated numbers of CXCL4+- and IFN-a-producing pDCs in skin and lungs are involved in increased fibrotic manifestations mediated by TLR8 activation [28,50,52].
T lymphocyte	Skin is predominantly infiltrated by CD4+ and CD8+ cytotoxic T cells that produce pro-fibrotic cytokines and cause apoptosis to epithelial cells [6,72]. Increased IL-21-producing Tph cells promote plasmablast differentiation and increase activation of myofibroblasts [75,77]. In the peripheral blood, SSc patients are characterized by increased Th2 and Th17 numbers compared to healthy donors [4,60,63].
B lymphocyte	Elevated BAFF and APRIL are correlated with skin thickening [81,83]. Increased IL-6-producing Beffs increase inflammation, while decreased IL-10-producing Bregs exhibit a reduced capacity for immunosuppression [82]. In SSc peripheral blood, an increase in naïve and a decrease in activated memory B cells is observed compared to healthy controls [4,85,87,91].