Spatial transcriptomic profiling identifies lacrimal-gland-epithelial cell-driven mechanisms underlying autoimmunity...

Area of Science:

• Immunology and Rheumatology
• Ocular Surface Disease
• Spatial Transcriptomics

Background:

• Sjögren's disease (SjD) is a prevalent autoimmune disorder affecting tear-producing lacrimal glands, causing ocular surface disease.
• Lacrimal gland pathology in SjD is not fully understood, hindering effective diagnosis and treatment.
• Identifying molecular mechanisms of lacrimal gland dysfunction is crucial for SjD management.

Purpose of the Study:

• To identify molecular signatures associated with epithelial cell dysfunction in SjD lacrimal glands using spatial transcriptomics.
• To explore the role of specific epithelial cell subtypes (acinar, ductal, myoepithelial) in SjD pathogenesis.
• To uncover potential biomarkers and therapeutic targets for SjD-related lacrimal gland pathology.

Main Methods:

• Spatial transcriptomics profiling of lacrimal glands from wild-type and SjD model mice (TSP-1-/-).
• Analysis of gene expression patterns in acinar, ductal, and myoepithelial cells.
• Integration of spatial and cellular data to understand cell-cell interactions and inflammation.

Main Results:

• Identified endoplasmic reticulum stress in acinar cells and mitochondrial dysfunction in ductal cells.
• Revealed secretory dysfunction in acinar/ductal cells and contractile impairment in myoepithelial cells.
• Found reduced polymeric immunoglobulin receptor (PIGR) expression in acinar cells, correlating with lower tear secretory IgA (sIgA) and ocular surface disease.
• Discovered a spatial relationship between ductal cells and antigen-presenting cells, suggesting ductal cells drive inflammation and autoantibody production.

Conclusions:

• Lacrimal gland epithelial cells exhibit distinct molecular dysfunctions in SjD, offering early disease markers.
• Tear sIgA levels may serve as a quantifiable biomarker for SjD glandular dysfunction.
• Ductal epithelial cells play an active role in SjD pathogenesis by promoting inflammation and autoantibody production.
• These findings provide a framework for targeted therapies addressing epithelial cell dysfunction and immune interactions in SjD.