Peripheral immune landscape for hypercytokinemia in myasthenic crisis utilizing single-cell transcriptomics

Area of Science:

• Immunology
• Genomics
• Cell Biology

Background:

• Myasthenia gravis (MG) is a prevalent autoimmune neuromuscular junction disorder.
• Myasthenic crisis (MC) is a life-threatening complication of MG characterized by rapid respiratory muscle deterioration.
• The complex pathogenesis of MC involves various immune cells and hypercytokinemia, with underlying mechanisms largely unexplored.

Purpose of the Study:

• To investigate the cellular and molecular mechanisms underlying myasthenic crisis (MC) in acetylcholine receptor antibody-positive (AChR+) MG patients.
• To identify specific immune cell subsets and inflammatory pathways involved during and after MC using single-cell transcriptomics.

Main Methods:

• Single-cell RNA sequencing and immune repertoire sequencing of peripheral blood mononuclear cells (PBMCs) from MG patients during and after MC.
• Cell type annotation using transfer-learning models and RNA velocity analysis to infer cellular state progression.
• Analysis of cell communication, cytokines, and chemokines to identify inflammation initiators.

Main Results:

• A unique subset of FCGR3B+ monocytes (monocytes 3) showed significant differential expression of pro-inflammatory pathways during and after MC.
• A high neutrophil-lymphocyte ratio (NLR), indicative of innate immune activation, was associated with MG clinical scores.
• Oligoclonal expansions were observed in age-associated B cells and CD4+/CD8+ T cells exhibiting autoimmune activity and T exhaustion, respectively.

Conclusions:

• Integrated single-cell analysis highlights the role of innate immune activation and hypercytokinemia in MC.
• The identified monocyte cluster may provide insights into the etiology and pathology of MC.
• Further functional studies are necessary to establish causality.