Systems immunology for systemic sclerosis (SSc): assessment of innate immune memory and immune aging as basis for individualised prevention and treatment modalities in SSc

Systemic sclerosis (SSc) is a progressive debilitating and life-altering connective tissue
disease with a pathogenesis that involves a complex interplay between microangiopathy, immun
dysfunction and fibrosis, leading to various and heterogenous disease manifestations that warrant a personalized therapeutic approach. However, current treatment guidelines primarly focus on symptomatic treatment based on disease subsets and type of internal organ involvement, rather than addressing the predominant underlying pathogenic mechanisms of action. Several reports suggest that innate immunity modulates SSc pathophysiology from an early stage of the disease, leading to fibroblast activation and subsequent fibrosis. Long-term innate immune memory (Trained immunity – TI) was also suggested to play a role in SSc. Moreover, immune aging (IA) research has identified shared features between immunological aging and cellular phenotype in SSc, including a single-cell RNA-sequencing based senescence signature in skin fibroblasts of SSc patients. We propose that innate immunological reprogramming takes place in the circulating cells/fibroblasts of SSc patients. This process may contribute to immune aging through the release of inflammatory factors and could alter tissue and organ homeostasis. This disruption could aggravate the immune dysregulation and SSc-related end-organ complications.