The pathogenesis of systemic sclerosis (SSc) is still not clear and is considered to be related to the following mechanisms:

1. Vascular Involvement

The vascular changes usually cause Raynaud's phenomenon and involve not only extremities but also internal organs. Histopathological findings show contracture and intimal hyperplasia of small vessels (arteries) in lesional skin and internal organs, therefore someone consider it a primary vasculitis. Since vascular damage is not present in all patients, it is considered to be not the only pathogenic factor in SSc.   

2. Metabolic Abnormality in Connective Tissue

Histopathological examination of patients manifests extensive connective tissue changes. Collagen content elevates in the skin and fibroblast culture shows that Activation of collagen synthesis is prominently enhanced.

3. Humoral Autoimmunity

It is generally believed that SSc is a Th2 mediated autoimmune disease. Humoral immune function of SSc patients is remarkably activated. Experiments showed that bcl-2 expression is significantly enhanced in lymphocytes infiltrating the lesional skin and in peripheral blood. As a product of an apoptosis-inhibiting gene, it can inhibit clonal deletion of autoimmune reactive B-cells, thereafter increases the number of memory B-cells, prolongs the life span of mature B-cells and generates huge amount of auto-antibodies. A variety of auto-antibodies are detected in the patients, such as antinuclear antibody, anti-Scl-70 antibody, anti-ribonuclear protein antibody, anti-endothelial cell antibody and anti-collagen I or IV antibodies. Over 50% patients show positive test results with circulating immune complexes. Most patients develop hypergammaglobulinemia. In some cases, SSc is often complicated by lupus erythematosus, dermatomyositis, rheumatoid arthritis, sicca syndrome and Hashimoto’s thyroiditis in some cases.

4. Abnormal Cellular Immunity

Resent study shows that Th1 mediated cellular immunity plays a critical role in formation and progress of the disease. After being stimulated, T helper lymphocytes in the skin secrete cytokines which can activate skin fibroblasts. αβ T cells collected from SSc patients produce Th2 cytokine. γδT cells, however, secrete majorly Th1 cytokine, which considerably enhances the cytotoxin activeness of cytotoxic T-lymphocyte. Another in vitro study displays that mutual effect of vascular endothelial cells andγδT cells from damaged skin can generate enormous cytotoxin activeness. In fibroblasts, collagenocytes and monocytes from involved skin of SSc patients, over expressed monocyte chemotactic protein 1(MCP-1) can be detected, which can recruit and direct leukocytes to the lesional site. Sakkas et al. found that monoclonal T-cells infiltrate SSc lesional skin. These cells may have in situ cell proliferation and clonal expansion in response to some unknown antigens.