Background/Purpose: Systemic sclerosis (SSc) is a heterogenous autoimmune disease characterized by fibrosis, vascular abnormalities and immune dysregulation. Characterization of peripheral blood immune signatures in relation to disease stages and progression remains insufficiently defined. Understanding these immune signatures may shed light to SSc pathogenesis underpinning distinct disease stages and states.

Methods: The study included a cohort of SSc patients (n=15), age and sex matched to healthy controls (n=7). We compared immune signatures of SSc patients at different stages (“very early diagnosis of SSc” (VEDOSS), early < 3 years and late >5 years from disease onset) and ILD status (stable vs progressive). Clinical and laboratory parameters were recorded for auto-antibody profile, immunosuppressive treatment and disease activity including ILD status. Peripheral blood mononuclear cells of SSc patients were analysed by high dimensional Mass Cytometry (CyTOF) approach employing 73 unique markers to identify perturbations in SSc immunome in comparison to healthy controls. A high throughput analytical and discovery platform, EPIC (Extended Polydimensional Immune Characterization) was deployed for multi-dimensional data analysis and clustering to identify significantly perturbed immune cell subsets.

Results: Unsupervised clustering revealed significant differences in T and NK cell subsets. Supervised analysis revealed activated CD4+ cells expressing CXCR4 and type 1 IFNs (IFI44 and IFI44L) to be significantly increased in SSc compared to healthy controls. This was particularly more pronounced in the late stage of disease and for patients with stable ILD. CXCR4 are known to mediate migration of lymphocytes, endothelial progenitor cells and stem cells and may play a key role in tissue fibrosis. Conversely, a decreased number of cytotoxic NK cells expressing CX3CR1 were found in SSc. CX3CR1 is a mediator of chemotaxis for immune cells and a significant decrease could potentially indicate impaired immunosurveillance in SSc patients. This subset was significantly decreased in the early and late stages of disease and in stable ILD state.

Conclusion: These findings shed light on the heterogeneity of SSc and provide insights into the differential characteristics of disease stages. Understanding the mechanism underlying SSc disease progression and immune perturbations will aid in early diagnosis and intervention. This could contribute to the development of targeted therapeutic strategies and better management of this debilitating disease. Further investigations are warranted to explore the functional significance of increased activated CD4 cells expressing CXCR4 and decreased cytotoxic NK cells expressing CX3CR1 in SSc, as well as to identify potential therapeutic targets that could mitigate disease progression and restore immune homeostasis in affected individuals.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/decoding-the-peripheral-immune-landscape-of-systemic-sclerosis-to-investigate-disease-stages-and-interstitial-lung-disease-progression/