Systemic sclerosis (SSc) is a rare systemic autoimmune disorder marked by high morbidity and increased risk of mortality. Our study aimed to analyze metabolomic profiles of plasma from SSc patients by using targeted and untargeted metabolomics approaches. Furthermore, we aimed to detect biochemical mechanisms relevant to the pathophysiology of SSc. Experiments were performed using high-performance liquid chromatography coupled to mass spectrometry technology. The investigation of plasma samples from SSc patients (n = 52) compared to a control group (n = 48) allowed us to identify four different dysfunctional metabolic mechanisms, which can be assigned to the kynurenine pathway, the urea cycle, lipid metabolism, and the gut microbiome. These significantly altered metabolic pathways are associated with inflammation, vascular damage, fibrosis, and gut dysbiosis and might be relevant for the pathophysiology of SSc. Further studies are needed to explore the role of these metabolomic networks as possible therapeutic targets of SSc.

Systemic sclerosis (SSc) is an autoimmune disease with fibrosis of the skin and/or internal organs, causing a decrease in quality of life and survival. There is no causative therapy, and the pathophysiology of the SSc remains unclear. Studies showed that lipid metabolism was relevant for autoimmune diseases, but little is known about the role of lipids in SSc. In the present study, we sought to explore the phospholipid profile of SSc by using the lipidomics approach. We also aimed to analyze lipidomics results for different clinical manifestations of SSc. Experiments were performed using high-performance liquid chromatography coupled to mass spectrometry for the lipidomic profiling of plasma samples from patients with SSc. Our study showed, for the first time, significant changes in the level of phospholipids such as plasmalogens and sphingomyelins from the plasma of SSc patients as compared to controls. Phosphatidylcholine plasmalogens species and sphingomyelins were significantly increased in SSc patients as compared to controls. Our results also demonstrated a significant association of changes in the metabolism of phospholipids (phosphatidylcholine and phosphatidylethanolamine plasmalogens species and sphingomyelins) with different clinical manifestations of SSc. Further lipidomic studies might lead to the detection of lipids as new biomarkers or therapeutic targets of SSc.

Background: Despite novel therapeutic options, the long-term management of cutaneous T-cell lymphoma (CTCL) remains challenging. Extracorporeal photopheresis (ECP) is an immunomodulating photochemotherapy associated with higher overall survival when used for the treatment of leukaemic forms of CTCL. Its exact mode of action has not been fully elucidated. Immunogenic cell death (ICD) is pivotal in cancer immunotherapy, marked by the release of damage-associated molecular patterns that enhance dendritic cell (DC) maturation and cytotoxic T-lymphocyte responses. Objectives: To explore ICD in patients with leukaemic forms of CTCL during ECP and its effect on DC activation. Methods: We conducted in vitro studies with peripheral blood mononuclear cells (PBMCs) from healthy donors and ex vivo experiments with white blood cells (WBCs) from patients with leukaemic forms of CTCL undergoing ECP. We assessed cell viability, apoptosis and ICD markers [ATP, high mobility group box 1 protein (HMGB1), calreticulin] using flow cytometry, enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. Engulfment assays evaluated DC activation by ECP-treated CD4+ T cells. Results: ECP-treated healthy PBMCs and WBCs from patients with leukaemic forms of CTCL showed a significant induction of ICD hallmarks, including ATP release, HMGB1 secretion and calreticulin surface exposure. In patients with leukaemic forms of CTCL, calreticulin exposure was mainly present in CD4+CD26– T cells, indicating greater ICD susceptibility of malignant T cells. ECP-treated CD4+ T cells were phagocytosed by DCs, a process that was found to be dependent on ICD signals. Conclusions: ECP induces ICD in malignant T cells and, to a lesser extent, in healthy T cells, facilitates DC activation. These findings suggest that ECP enhances targeted immune responses against malignant T cells in leukaemic forms of CTCL, offering new insights into its therapeutic mechanisms and potential applications in cancer immunotherapy.

Systemic sclerosis (SSc) is a rare autoimmune systemic disease that leads to decreased survival and quality of life due to fibrosis, inflammation, and vascular damage in the skin and/or vital organs. Early diagnosis is crucial for clinical benefit in SSc patients. Our study aimed to identify autoantibodies in the plasma of SSc patients that are associated with fibrosis in SSc. Initially, we performed a proteome-wide screening on sample pools from SSc patients by untargeted autoantibody screening on a planar antigen array (including 42,000 antigens representing 18,000 unique proteins). The selection was complemented with proteins reported in the literature in the context of SSc. A targeted antigen bead array was then generated with protein fragments representing the selected proteins and used to screen 55 SSc plasma samples and 52 matched controls. We found eleven autoantibodies with a higher prevalence in SSc patients than in controls, eight of which bound to proteins associated with fibrosis. Combining these autoantibodies in a panel could lead to the subgrouping of SSc patients with fibrosis. Anti-Phosphatidylinositol-5-phosphate 4-kinase type 2 beta (PIP4K2B)- and anti-AKT Serine/Threonine Kinase 3 (AKT3)-antibodies should be further explored to confirm their association with skin and lung fibrosis in SSc patients.