Identifying Dysregulated Immune-Related Gene Networks at the Single-Cell Level in Pediatric Morphea

Overview

Morphea, or localized scleroderma, is an idiopathic disorder of the skin and underlying tissue that produces permanent disability and functional impairment due to joint contracture and soft tissue loss. Notably, pediatric-onset morphea is associated with more severe features compared to adult-onset morphea, such as worsened morbidity and prolonged duration of disease, impairing growth and resulting in disfigurement. Morphea has remitting and relapsing periods of activity, marked by inflammation and fibrosis, and damage which produces atrophy. Activity is characterized by an inflammatory dermal and subcutaneous lymphocytic infiltrate manifesting clinically as erythema and edema. Inflammatory activity often overlaps with a fibrotic phase distinguished by dense collagen deposition with infiltration of inflammatory cells manifesting clinically as hardened, discolored plaques. Fibrosis and resultant atrophy of the skin, soft tissue, and bone result in functional impairment. As with other autoimmune disorders, the predominant driver of long-term morphea damage and disability is thought to be the magnitude and duration of the initial active phase, which likely facilitates subsequent damaging fibrosis. However, the dysregulation of immune and fibrotic pathways at single-cell resolution that contribute to these changes has not been systematically studied. The only widely tested treatment for morphea is a combination of corticosteroids and methotrexate, the use of which is substantially limited by toxicity, particularly in the pediatric population. Therefore, characterization of immune pathway aberrations at the single-cell level is quintessential in the identification of molecular targets for therapeutic development.

Aim 1: Identify dysregulated immune networks in morphea relative to matched healthy control skin.

Aim 2: Utilize identified dysregulated immune networks to determine association with disease trajectory and therapeutic response.

Status

This project was funded through a 2021 PeDRA Research Fellowship Grant.