Serum Proteomic Markers in Patients with Systemic Sclerosis in Relation to Silica Exposure

Abstract

Background: Systemic sclerosis (SSc) is a multisystem autoimmune disease characterised by fibrosis, vasculopathy, and immune dysfunction. Silica exposure has been associated with a more aggressive phenotype of the disease, including diffuse cutaneous involvement and interstitial lung disease. This study aims to identify proteomic differences between SSc patients exposed to silica and those not exposed to silica. Methods: An observational study of 32 SSc patients (11 silica-exposed and 21 non-exposed) was performed, with occupational history and quantitative proteomic analysis using SWATH-MS mass spectrometry. Differentially expressed proteins were analysed, and functional pathway enrichment was performed. Results: Eight proteins showed significant differences between groups, all with reduced levels in silica-exposed patients: adiponectin, immunoglobulins (IGLV3-19, IGLV2-18), complement C2, alpha-2-macroglobulin, vitronectin, cytoplasmic actin 2, and pigment epithelium-derived factor. Alterations in pathways related to fibrinolysis, complement activation, and inflammation were highlighted, suggesting that silica exposure may influence the pathogenesis of SSc and worsen its clinical course. Conclusions: This study supports the hypothesis that silica exposure is not only a triggering factor for SSc, but is also modulating its progression through inflammatory, procoagulant, and fibrotic pathways. The identification of proteomic biomarkers could contribute to the phenotypic classification of patients and the development of personalised therapies. Future studies should expand the cohort and further investigate the functional mechanisms of these proteins in SSc.

Keywords: Systemic sclerosis; etiopathogenesis; proteomics; scleroderma; silica.

Figure 4

Figure made with Reactome Pathway Browser. Both schemes integrate immune and inflammatory processes in defence and repair contexts, highlighting the interconnection between immunity and coagulation. (A): Immune activation and molecular recognition (left). This scheme shows immune activation pathways, including pattern recognition receptors (PRRs), which detect danger or damage signals (PAMPs and DAMPs). Some key points include the following: toll-like receptors (TLRs) to detect bacterial components such as lipopolysaccharide (LPS) and activate intracellular signalling, resulting in the production of inflammatory cytokines; Fc receptors to mediate the response to immune complexes (antibodies bound to antigens), activating phagocytes and other immune cells; complement cascade promotes the opsonization and destruction of pathogens, amplifying the inflammatory response; DAMP interactions involve mitochondrial or cytosolic DNA recognised by intracellular sensors, leading to inflammatory activation; and neutrophil degranulation releases antimicrobial factors and extracellular networks (NETs) to contain infection. (B): Hemostasis and platelet adhesion (right). This schematic illustrates platelet adhesion and clot formation in response to endothelial damage. Platelet adhesion: Platelets adhere to exposed collagen via receptors such as GPIb and GPIIb/IIIa, becoming activated. Platelet aggregation releases activating factors (e.g., ADP, thromboxane A2) that amplify platelet recruitment. Fibrin formation: thrombin converts fibrinogen to fibrin, stabilising the clot. Cell–vessel wall interactions: leukocytes adhere to endothelium via adhesion molecules such as selectins and integrins, contributing to inflammation.

Figure 1

Current hypotheses about the effects of silica on the immune system. Antigen-presenting cells (such as the macrophage) are stimulated by silica, producing three types of effects on the immune system: (1) Stimulation of the inflammasome, with the production of pro-inflammatory cytokines (IL-18, IL-1beta). (2) Stimulation of T lymphocytes (both the Th1 response, also pro-inflammatory, and the Th2 response and attenuation of regulatory T lymphocytes, which favour fibrosis. (3) Stimulation of the production of autoantibodies by B lymphocytes (own elaboration, based on data collected in [8,9,10].

Figure 2

Differential proteins between si-SSc and nosi-SSc groups. SSc; systemic sclerosis; Si-SSc: systemic sclerosis patients with silica exposure; nosi-SSc: systemic sclerosis patients without silica exposure; Adipo: adiponectin; LV319: immunoglobulin lambda variable 3–19; CO2: complement C2; A2MG: alfa 2-macroglobulin; VTNC: vitronectin; ACTG: cytoplasmic actin 2; PED: pigment epithelium-derived factor; LV218: immunoglobulin lambda variable 2–18.

Figure 3

Protein Interaction Network. ADIPOQ: adiponectin; ACTG1: actin, gamma 1; PLG: plasminogen; C9: complement component 9; C2: complement component 2; C4A: complement C4-A; SERPINF1: Serpin Family F Member 1; CPB2: Carboxypeptidase B2; VTN: vitronectin; A2M: alpha-2-macroglobulin; CFH: Complement Factor H.