Dataset Information

Stereotypic T cell receptor clonotypes in the thymus and peripheral blood of Myasthenia gravis patients.

ABSTRACT: Myasthenia Gravis (MG) patients with anti-acetylcholine receptor (AChR) antibodies frequently show hyperplastic thymi with ectopic germinal centers, where autoreactive B cells proliferate with the aid of T cells. In this study, thymus and peripheral blood (PB) samples were collected from ten AChR antibody-positive MG patients. T cell receptor (TCR) repertoires were analyzed using next-generation sequencing (NGS), and compared with that of an age and sex matched control group generated from a public database. Certain V genes and VJ gene recombination pairs were significantly upregulated in the TCR chains of αβ-T cells in the PB of MG patients compared to the control group. Furthermore, the TCR chains found in the thymi of MG patients had a weighted distribution to longer CDR3 lengths when compared to the PB of MG patients, and the TCR beta chains (TRB) in the MG group's PB showed increased clonality encoded by one upregulated V gene. When TRB sequences were sub-divided into groups based on their CDR3 lengths, certain groups showed decreased clonality in the MG group's PB compared to the control group's PB. Finally, we demonstrated that stereotypic MG patient-specific TCR clonotypes co-exist in both the PB and thymi at a much higher frequency than that of the clonotypes confined to the PB. These results strongly suggest the existence of a biased T cell-mediated immune response in MG patients, as observed in other autoimmune diseases.

SUBMITTER: Lee Y

PROVIDER: S-EPMC10901099 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Stereotypic T cell receptor clonotypes in the thymus and peripheral blood of Myasthenia gravis patients.

Lee Yonghee Y Kim Seung Woo SW Lee Eunjae E Shin Ha Young HY Kim MinGi M Lee Chang Young CY Park Byung Jo BJ Kim Ha Eun HE Yang Young Ho YH Choi Jinny J Ju Soyeon S Park Jungheum J Kim Namphil N Choi Jaewon J Lee Jin Gu JG Kwon Sunghoon S Chung Junho J

Heliyon 20240219 4

Myasthenia Gravis (MG) patients with anti-acetylcholine receptor (AChR) antibodies frequently show hyperplastic thymi with ectopic germinal centers, where autoreactive B cells proliferate with the aid of T cells. In this study, thymus and peripheral blood (PB) samples were collected from ten AChR antibody-positive MG patients. T cell receptor (TCR) repertoires were analyzed using next-generation sequencing (NGS), and compared with that of an age and sex matched control group generated from a pub ...[more]

PMID: 38420468

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Project description:BackgroundWe investigated the correlation between glucose metabolism patterns of different immune cells and the metabolic regulatory signaling pathways in myasthenia gravis (MG) and aimed to identify therapeutic targets for MG.MethodsWe isolated peripheral blood mononuclear cells (PBMCs) and sorted CD19+B cells, dendritic cells (DCs), CD4+ T cells, CD8+ T cells, CD4+CD25+ regulatory T cells (Tregs), CD4+CD25-T cells, and T helper (Th) cells such as Th1, Th2, and Th17 cells. Then, we detected the expression levels of PI3K/AKT/mTOR-HIF-1α, GLUT1, hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK) by RT-PCR, measured the oxygen consumption rate and extracellular acidification rate of ex vivo freshly sorted cells using the Seahorse XFe96 Analyzer. In addition, we compared the glycolysis levels using these cells from the same MG patients. By performing in vitro experiments, we measured, the mRNA expression levels of mTOR, HIF-1α, B cell activating factor receptor (BAFF-R), GLUT1, HK, PFK, and PK, in addition to ECAR profiles, frequency of CD80 and CD86, and IgG levels from the culture supernatant of B cells (isolated from MG patients) treated with rapamycin and PX-478 (selective mTOR and HIF-1α inhibitor, respectively) from.ResultsExcept PBMCs, Th2 and CD8+ T cells, the expression levels of the key enzymes involved in glycolysis and HIF-1α were significantly higher in B cells, DCs, Tregs, CD4+CD25-T cells, and Th1 and Th17 cells in MG patients, and the measurement of ECAR and OCR confirmed the metabolic status. In MG patients, B cells and DCs showed significantly higher levels of glycolysis and glycolytic capacity than CD8+ T cells, CD4+ T cells and its subsets. In vitro, except IgG levels, the increased glycolysis levels, expression of key glycolytic enzymes, BAFF-R and frequency of CD80 and CD86 of B cells, could be inhibited by rapamycin and PX-478.ConclusionsDifferent subtypes of immune cells in MG exhibit different glucose metabolism patterns. The mTOR-HIF-1α signaling pathway might be the immunometabolism reprogramming checkpoint of glycolysis-dependent activated B cells in MG.

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.

Dataset Information

Stereotypic T cell receptor clonotypes in the thymus and peripheral blood of Myasthenia gravis patients.

Publications

Stereotypic T cell receptor clonotypes in the thymus and peripheral blood of Myasthenia gravis patients.

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