Use high-dimensional immune profiling to study peripheral immune system and ALS progression

Title Use High-dimensional Immune Profiling to Study Peripheral Immune System and ALS Progression Topic Neuromuscular and Clinical Neurophysiology (EMG) Presentation(s) P6 - Poster Session 6 (8:00 AM-9:00 AM) Poster/Presentation Number 11-006 Objective Identify immune signatures and their association with ALS progression. Background ALS exhibits remarkable phenotypic variabilities in disease progression rate and survival time. Understanding the biological differences in this phenomenon can help identify predictive biomarkers and new therapeutic targets. Increasing evidence has emerged to support the role of immune system dysregulation in the pathophysiology of ALS. Clonally expanded CD4+ FoxP3+ regulatory T lymphocytes in the central nervous system inversely correlate with ALS progression. However, the mechanism underlying ALS progression disparity is still unclear. Design/Methods We utilize a high-dimensional immune profiling method-mass cytometry- to analyze the peripheral immune system and its correlation with ALS progression. Mass cytometry has advantages over traditional flow cytometry in that it can simultaneously analyze >40 cell surface markers and thereby identify unique immune cell subpopulations and effector status. Fast progressors are defined as ALSFRS-R decline per month (ΔFRS/mo) >1.5, and slow progressors as ΔFRS/mo <0.5 and typical progressors as ΔFRS/mo of 0.5-1.5. Patients’ whole blood is banked and undergoes mass cytometry for in-depth immunophenotyping. We implement manual gating and machine learning to identify immune signatures. Manual analyses were performed in CytoBank. Unsupervised computational analysis was performed using VoPo Cell analysis (Stanley et al., 2020 Nature Communications). Results We found CD8 terminal effector memory T cells (TEMRA) in peripheral blood are expanded in slowly progressing ALS group; conversely, CD4-CD8-ϒδT cells are associated with fast-progressing diseases. We also found a statistically significant inverse correlation between TEMRA and ϒδ T cells. The functions of TEMRA and ϒδ T cells have not been well characterized in ALS. Further, We also found fewer circulating late NK cells in faster-progressing ALS. Conclusions Our results indicate diverse immune perturbations in ALS that may play a role in disease progression. We plan to expand it to larger cohorts, laying the foundation for discovering new biomarkers and therapeutic targets.

Duke Scholars

Author Xiaoyan Li Neurology, Neuromuscular Disease