Understanding the Role of Epithelial Cells in the Pathogenesis of Systemic Sclerosis

Systemic sclerosis (also called scleroderma, SSc) is a chronic autoimmune fibrotic disorder affecting the skin and internal organs to variable extent and categorized as limited cutaneous subset, when distal areas of skin are involved and diffuse cutaneous subset when more extensive proximal skin involvement is seen. Multiple pathogenic mechanisms have been demonstrated, including production of disease-specific autoantibodies, infiltration of involved tissues by immune cells, as well as environmental factors triggering the onset such as solvents and viruses. Although not strongly familial , susceptibility to SSc is associated with single nucleotide polymorphisms in immunoregulatory genes. In addition, several lines of evidence demonstrate abnormalities within the epithelial cell layer in SSc. Macroscopically the epidermis is pigmented, thickened and stiff and strongly promotes myofibroblasts in 3D co-culture. Moreover, multiple activating factors and pathways have been implicated in epithelium, including wound healing responses, induction of DAMPS and the release of pro-fibrotic growth factors and cytokines. Similar to SSc, data from studies of cutaneous wound healing indicate a major role for epidermal keratinocytes in promoting underlying fibroblast responses and coordinating resolution of the wound. Since the epithelium is strongly exposed to environmental factors and richly endowed with protective immune cells, we have proposed that disease initiating mechanisms in SSc involve dysregulation of this cell layer. Treatments designed to quiesce this cell layer or to block epithelial-fibroblast cross-talk could be of benefit in this severe and resistant disease.