Plasma-derived exosomes from Graves' orbitopathy: Pathogenic entities causing tissue lesions.

Early human evidence such as case series or small samples is exploring possible benefits.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Graves' orbitopathy (GO) is an autoimmune disorder characterized by orbital inflammation, fibrosis, and adipogenesis. circulating exosomesomes, critical mediators of intercellular communication, are implicated in autoimmune pathologies through miRNA cargo delivery. However, their direct role in GO pathogenesis and mechanisms driving systemic-to-local disease progression remain unexplored. Plasma-derived exosomes from patients with Graves' orbitopathy (GO-Exos) and healthy controls (Con-Exos) were isolated and characterized. Functional assays assessed their impact on primary human orbital fibroblasts (OFs). A GO model was established via weekly intravenous administration of GO-Exos. Disease progression was evaluated through thyroid function tests, histopathology, MRI, and single-cell RNA sequencing. Mechanistic studies focused on miR-221-5p and its downstream CACNG4/AMPK pathway. In vitro, GO-Exos reprogrammed OFs into proinflammatory, profibrotic, and adipogenic phenotypes, while upregulating disease-associated receptors IGF-1R and TSHR, suggesting a feedforward mechanism for sustained autoimmunity. Strikingly, stable-phase GO-Exos retained bioactivity, inducing comparable cytokine elevations in control OFs. In vivo, weekly intravenous administration of GO-Exos in BALB/c mice over 150 days recapitulated human disease hallmarks, including thyroid dysfunction, exophthalmos, orbit

Evidence level

Early human evidence such as case series or small samples is exploring possible benefits.

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