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Single-cell RNA-seq data of human PBMC from Myasthenia Gravis patients

ABSTRACT: Myasthenia Gravis (MG) is a chronic autoimmune disorder characterized by severe muscle weakness. However, the seronegative MG patient subgroup, which accounts for about 15% of MG patients, remains challenging diagnosis, and the immunopathology is understudied. Therefore, we performed single-cell RNA-sequencing analysis by peripheral blood and plasma proteome analysis for the seronegative MG patients. Numerical abnormalities were observed in multiple immune cells including B-cells compared to healthy controls (HC) and correlated with disease activities. Additionally, plasma protein of CD22 that was reported to be expressed in the lineage of B-cell maturation, such as mature B-cells and memory B-cells was decreased compared to HC, and had correlation with disease severity, B-cells frequency, and the RNA expression level. These results suggest that the seronegative MG patients have immune disorders centered on B-cells. This is the first large-scale and innovative study to elucidate the immunopathology of the seronegative MG patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227835 | GEO | 2024/04/03

REPOSITORIES: GEO

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Project description:Myasthenia gravis (MG) is an autoimmune disease affecting the neuromuscular junction, whose clinical hallmark is muscle weakness and early fatigability. Azathioprine (AZA) is commonly used in Myasthenia Gravis therapy. AZA is a purine antagonist, which inhibits the cell cycle in the resting and DNA synthesis phases. It is usually used as an immunosuppressant to block T- and B-cell proliferation. AZA, bioconverted to 6-mercaptopurine by glutathione S-transferase (GST), can be metabolized either through the hypoxanthine phosphoribosyl transferase pathway to active 6-thioguanine nucleotides (6-TGN) or through the thiopurine S-methyltransferase (TPMT) pathway to inactive methyl-thiopurine metabolites. The incorporation of active 6-TGNs into DNA, causing breaks in DNA strands resulting in interference with RNA production and thereby protein synthesis, is responsible for the drug effect. The response to AZA is determined by which metabolic pathway is being favored. While balanced use of both HPRT and TPMT pathways results in responsiveness to AZA, hyperactivity of TPMT skews the balance towards the TPMT pathway and results in unresponsiveness to AZA with no pharmacological effect. In contrast, low TPMT activity skews the balance towards the HPRT pathway, resulting in increasing side-effects due to the accumulation of 6-TGNs. Current treatments for MG therapy are often inadequate because less than 40% of patients achieve complete remission with available drugs. This reflects the lack of drugs acting on target sites for which there is strong evidence of pathogenicity and the inability to identify responder patients. No criteria for responsiveness are available, exposing patients to unpredictable failures and unpredictable side effects. These individuals are at particular risk for adverse drug reaction (ADRs) or therapeutic failure. Genetic profiling with the Affymetrix drug metabolizing enzymes and transports genotyping array offers the ability to determine 1,931 variants and 225 genes involved in drug metabolism and disposition. Accordingly, the study of well-known drug-metabolizing genes can be involved in the specific metabolic pathway of a drug, which is more likely to define genotype-phenotype association and thereby genotype profiles relevant to drug response that can be applied as predictive biomarkers for pharmacological treatment.

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Single-cell RNA-seq data of human PBMC from Myasthenia Gravis patients

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