Cell-type- and state-resolved transcriptomics uncovers distinct T cell and monocyte dysregulation in multiple...

Area of Science:

• Immunology
• Genomics
• Neuroscience

Background:

• Multiple sclerosis (MS) is a complex immune-mediated neurological disorder.
• Its polygenic and multicellular nature requires cell-specific molecular investigations.
• Understanding dysregulated pathways in peripheral immune cells is crucial.

Purpose of the Study:

• To identify cell-type-specific molecular signatures of peripheral immune cells in multiple sclerosis.
• To discover potential diagnostic or prognostic biomarkers for MS.
• To explore therapeutic targets for MS.

Main Methods:

• Transcriptome profiling of 1,075 samples from 167 MS patients and 42 healthy controls.
• Analysis across six peripheral immune cell-type-states, comparing primary and stimulated cells.
• Identification and replication of MS-associated gene modules and regulators.

Main Results:

• Transcriptional differences in MS are more prominent in primary (unstimulated) immune cells.
• Identified shared and cell-type-specific alterations in genes, pathways, and co-expressed gene modules.
• Top T cell module linked to MS susceptibility and proliferation; top monocyte module implicated TNF-α/NF-κB signaling.

Conclusions:

• Defined stable peripheral immune dysregulation signatures in MS.
• These signatures may function as diagnostic or prognostic biomarkers.
• Alvespimycin nominated as a potential modulator for MS treatment.