Multicellular immune dynamics implicate PIM1 as a potential therapeutic target for uveitis

Area of Science:

• Immunology
• Ophthalmology
• Genomics

Background:

• Uveitis is a severe autoimmune eye disease and a leading cause of blindness.
• The precise cellular dynamics and pathogenic mechanisms of uveitis are not fully understood.

Purpose of the Study:

• To investigate the cellular and molecular mechanisms underlying experimental autoimmune uveitis (EAU) using single-cell RNA sequencing (scRNA-seq).
• To identify potential therapeutic targets for uveitis and related human conditions like Vogt-Koyanagi-Harada disease (VKH).

Main Methods:

• Performed scRNA-seq on experimental autoimmune uveitis (EAU) models.
• Analyzed disease-associated alterations in cell composition and transcriptional regulation.
• Investigated the role of the molecule PIM1 and its downstream signaling pathways (AKT/FOXO1).
• Assessed the effects of PIM1 inhibition on immune cell populations and pathogenicity in both EAU and human VKH models.

Main Results:

• Identified dynamic changes in immune cell composition and gene expression during EAU progression.
• Discovered that PIM1 is upregulated in CD4+ T cells and plasma cells in both EAU and human VKH.
• Demonstrated that PIM1 inhibition reduces pathogenic Th17 cells, increases regulatory T cells (Tregs), and decreases plasma cell differentiation.
• Showed that PIM1 inhibition limits CD4+ T and B cell expansion in VKH models.

Conclusions:

• Developed a comprehensive immune cellular atlas for uveitis.
• PIM1 plays a critical role in uveitis pathogenesis.
• PIM1 inhibition represents a potential therapeutic strategy for autoimmune uveitis, including VKH.