Immunopathogenesis of Juvenile Systemic Sclerosis

Abstract

Juvenile-onset systemic sclerosis (jSSc) is a rare and severe autoimmune disease with associated life-threatening organ inflammation and evidence of fibrosis. The organ manifestations of jSSc resemble adult SSc, but with better outcomes and survival. The etiology of jSSc appears to reflect adult-onset SSc, with similar inflammatory mediators and autoantibodies, but with a significant population of children with uncharacterized anti-nuclear antibodies. The genetics of patients with jSSc differ from women with SSc, resembling instead the genes of adult males with SSc, with additional HLA genes uniquely associated with childhood-onset disease. Current treatments are aimed at inhibiting the inflammatory aspect of disease, but important mechanisms of fibrosis regulated by dermal white adipose tissue dendritic cells may provide an avenue for targeting and potentially reversing the fibrotic stage.

Keywords: Pediatric Rheumatology; autoimmune disease; disease etiology; fibrosis; genetics; skin; systemic sclerosis.

Figure 1

Adipose-derived stromal cells (ADSC) maintenance by dendritic cell-derived lymphotoxin in fibrotic skin and enhancing ADSC therapy with lymphotoxin stimulation to treat fibrosis. (A) Reparative and regenerative ADSCs are lost with skin fibrosis and are maintained in fibrotic skin by dendritic cell-derived lymphotoxin. (B) Adding lymphotoxin stimulation to therapeutic ADSC injection enhances survival and effectiveness of the injected ADSCs in skin repair in a model of skin fibrosis. This model may be helpful to investigate its potential application for the treatment of fibrosis.

Figure 2

Schematic representation of proposed disease pathogenesis of pediatric SSc.