Single Cell Transcriptomics Implicate Novel Monocyte and T Cell Immune Dysregulation in Sarcoidosis

Area of Science:

• Immunology
• Genomics
• Systemic inflammatory diseases

Background:

• Sarcoidosis is a systemic inflammatory disease characterized by granuloma formation.
• Previous studies using mixed cell populations lacked cell-type-specific insights into immune dysregulation.

Purpose of the Study:

• To perform the first single-cell RNA-sequencing study on peripheral immune cells in sarcoidosis.
• To identify cell-type-specific immune dysregulation and novel inflammatory pathways in sarcoidosis patients.

Main Methods:

• Single-cell RNA-sequencing of peripheral immune cells from 48 sarcoidosis patients and controls.
• Unbiased clustering to identify cell types and differentially expressed genes.
• Bioinformatic assessment of gene function, pathway enrichment, and predictive modeling.

Main Results:

• Persistent activation of circulating classical monocytes with upregulation of trafficking molecules and enrichment of HMGB1, mTOR, and ephrin receptor signaling pathways.
• Dysregulation in T cell subsets, including CD4 naïve T cells (apoptosis, Th17/Treg differentiation) and effector T cells (anergy pathways).
• Identification of dysfunctional p53, cell death, and TNFR2 signaling in regulatory T cells.

Conclusions:

• Novel cell-type-specific inflammatory and regulatory pathways identified in sarcoidosis.
• Proposed model of sarcoidosis immunopathology involving hyperactivated innate/adaptive immunity, Treg dysfunction, and T cell anergy.
• Identification of potential novel therapeutic targets for sarcoidosis.