Fig. 6 |. Mechanisms of fibrotic tissue remodelling in systemic sclerosis.
As-yet-unidentified triggers promote apoptosis of microvascular endothelial cells as the first histopathological change in systemic sclerosis (SSc). Microvascular injury promotes leukocyte infiltration and type 2 immune responses, with release of profibrotic mediators from alternatively activated (M2) macrophages, T helper 2 (TH2) cells and innate lymphoid cells (ILCs). Injured endothelial cells as well as activated platelets also release profibrotic factors. The resulting profibrotic milieu activates resident fibroblasts and induces transdifferentiation of various cell types to myofibroblasts. Myofibroblasts in turn release soluble mediators that may aggravate vascular manifestations and modulate inflammation in SSc. Progressive tissue remodelling induces self-sustaining activation loops that maintain fibroblast activation even in the absence of exogenous stimuli.