Deciphering Gene Dysregulation in the Immune System in ME/CFS

Despite our lack of understanding of ME/CFS, substantial evidence implicates immune dysregulation either as an underlying cause or major consequence of the disease.

Nevertheless, the identity of specific dysregulated leukocytes (white blood cells, WBCs) that are most implicated in ME/CFS is unclear. We are working to elucidate immune dysregulation in ME/CFS by comprehensively investigating gene-regulation defects in patients across all types of leukocytes.

We are using single-cell RNA sequencing (scRNA-seq) to interrogate the transcriptomes of leukocytes from peripheral blood collected from a cohort of ME/CFS patients and controls.¹ This novel approach offers multiple advantages over all previous gene-regulatory studies of the disease. Ongoing analysis aims to discover coordinated changes in gene regulation among different cell types.

We have extended our use of scRNA-seq to compare leukocyte profiles from patients and controls after exercise. These experiments are motivated by the need to better understand aberrant gene regulation in specific leukocytes resulting from exercise in ME/CFS patients, as post-exertional malaise is a defining symptom of the disease.

We have examined possible roles for microRNAs found in extracellular vesicles in ME/CFS. Extracellular vesicles are a newly discovered class of particles secreted by donor cells, which deliver cargoes, including miRNAs, to recipient cells, thereby altering the state of the recipient cell.

We have tested the hypothesis that miRNAs in extracellular vesicles are altered in ME/CFS, examining samples obtained before and after an exercise challenge, and investigating whether such alterations result in dysregulation of patient immune cells.

The unifying theme of this study is to provide definitive data on gene-regulatory changes in leukocytes from ME/CFS patients and investigate whether microRNAs in extracellular vesicles contribute to such changes.

This NIH-funded project (U54NS105541) was led by Dr. Andrew Grimson at Cornell University, whose lab specializes in the genomics of gene regulation. He has extensive experience in eukaryotic RNA biology, including small-RNA biology. Dr. Jen Grenier, Director of the TREx Facility and Genomics Innovation Hub at Cornell University, and her staff assisted in the single-cell RNA-seq data analysis.

Publication

1. Vu LT, Ahmed F, Zhu H, Iu DSH, Fogarty EA, Kwak Y, Chen W, Franconi CJ, Munn PR, Tate AE, Levine SM, Stevens J, Mao X, Shungu DC, Moore GE, Keller BA, Hanson MR, Grenier JK, Grimson A.
   Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation.
   Cell Reports Medicine. 2024 Jan 16;5(1):101373. doi: 10.1016/j.xcrm.2023.101373. PMID: 38232699; PMCID: PMC10829790.

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