Immunopathogenesis of Pediatric Localized Scleroderma.

Kathryn S Torok,Francesco Zulian,Sarah F Taber,Heidi M Jacobe,Suzanne C Li,Theresa T Lu,Anne M Stevens

doi:10.3389/fimmu.2019.00908

Abstract

Localized scleroderma (LS) is a complex disease characterized by a mixture of inflammation and fibrosis of the skin that, especially in the pediatric population, also affects extracutaneous tissues ranging from muscle to the central nervous system. Although developmental origins have been hypothesized, evidence points to LS as a systemic autoimmune disorder, as there is a strong correlation to family history of autoimmune disease, the presence of shared HLA types with rheumatoid arthritis, high frequency of auto-antibodies, and elevated circulating chemokines and cytokines associated with T-helper cell, IFNγ, and other inflammatory pathways. This inflammatory phenotype of the peripheral blood is reflected in the skin via microarray, RNA Sequencing and tissue staining. Research is underway to identify the key players in the pathogenesis of LS, but close approximation of inflammatory lymphocytic and macrophage infiltrate with collagen and fibroblasts deposition supports the notion that LS is a disease of inflammatory driven fibrosis. The immune system is dynamic and undergoes changes during childhood, and we speculate on how the unique features of the immune system in childhood could potentially contribute to some of the differences in LS between children and adults. Interestingly, the immune phenotype in pediatric LS resembles to some extent the healthy adult cellular phenotype, possibly supporting accelerated maturation of the immune system in LS. We discuss future directions in better understanding the pathophysiology of and how to better treat pediatric LS.

Highlights

Localized scleroderma (LS) is a complex disease characterized by a mixture of inflammation and fibrosis of the skin that, especially in the pediatric population, affects extracutaneous tissues ranging from muscle to the central nervous system
Developmental origins have been hypothesized, evidence points to LS as a systemic autoimmune disorder, as there is a strong correlation to family history of autoimmune disease, the presence of shared HLA types with rheumatoid arthritis, high frequency of auto-antibodies, and elevated circulating chemokines and cytokines associated with T-helper cell, IFNγ, and other inflammatory pathways
Besides the obvious difference in age of disease onset, there are several major differences between pediatric and adult onset disease. These include a different subtype predominance, higher frequency of deep tissue and extracutaneous involvement in pediatric disease, and longer disease duration in pediatric disease [reviewed in [4]]. These differences contribute to the higher frequency of serious morbidity in patients with pediatric compared to adult onset disease [4, 7], with morbidity including arthropathy, uveitis, facial hemiatrophy, seizures, and neuropathy [7, 8]

Summary

Introduction

Localized scleroderma (LS) is the most common form of pediatric scleroderma, a disease whose histologic pathology involves inflammation and fibrosis, similar to that of systemic sclerosis (SSc), the clinical phenotypes are markedly different. Histopathologic Evidence for Immune Involvement In a cross-sectional study of 83 patients with localized scleroderma in which 101 biopsy specimens were examined the authors found that the microanatomical location and degree of inflammation and sclerosis were associated with the stage of evolution of the lesion as well as clinical disease manifestations.

Results

Conclusion