Comparative analysis of B-cell receptor repertoires in severe and mild myasthenia gravis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE308514 | GEO | 2025/09/22
REPOSITORIES: GEO
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Project description:Myasthenia gravis (MG) is an autoantibody-mediated autoimmune disorder of the neuromuscular junction. Some patients with MG have pathogenic mAbs that recognize muscle-specific tyrosine kinase (MuSK). Patients respond well to CD20-mediated B-cell depletion therapy (BCDT); most achieve complete stable remission. However, relapse often occurs. To further understand the immunomechanisms underlying relapse we sought to study autoantibody-producing B-cells over the course of BCDT. We developed a monomeric fluorescently labelled antigen to enrich for MuSK-specific B-cells, which was validated with a novel Nalm6 cell line engineered to express a human MuSK autoantibody as B-cell receptor. We found that MuSK-specific B-cells are rare within the circulation (<3 per 10 million cells). From two MuSK-specific B-cells isolated from two distinct patients, we generated human recombinant MuSK mAbs. The autoantibodies originated from plasmablasts, used the IgG4 subclass, recognized the Ig1-like domain of MuSK and showed pathogenic capacity using an in vitro AChR clustering assay. Persistent clones of the mAbs were identified through B-cell repertoire tracing. Clonal variants of 2E6 were detected at several timepoints spanning more than five years months and reemerged after BCDT-mediated remission, appearing several months prior to relapse. These results indicate that a reservoir of rare pathogenic MuSK autoantibody-expressing B cell clones survive BCDT, then reemerge prior to manifestation of clinical relapse. This study provides both a mechanistic understanding of MuSK MG relapse and a valuable candidate biomarker for relapse prediction.
2022-11-07 | GSE215237 | GEO
Project description:Comparative analysis of B-cell receptor repertoires in severe and mild myasthenia gravis
| PRJNA1330802 | ENA
Project description:Protective immunity against COVID-19 likely depends on the production of SARS-CoV-2 binding plasma cells and memory B cells after infection or vaccination. Previous work has shown evidence that germinal center reactions, a critical component of the B cell response, are disrupted in severe COVID-19. This may adversely affect protective immunity from re-infection. Consistent with an extrafollicular B cell response, severe COVID-19 patients have large scale changes in B cell populations such as elevated frequencies of clonally expanded, class switched, unmutated plasmablasts. However, it is not clear whether mild or asymptomatically infected individuals show similar differences in B cell repertoires. Here, we use single cell RNA sequencing of B cells to show that, in contrast to hospitalized COVID-19 patients, mildly symptomatic COVID-19 subjects have B cell repertoires skewed towards clonally diverse, somatically hypermutated memory B cells approximately 30 days after the onset of symptoms. This provides evidence that B cell responses are less disrupted in mild COVID-19, and that the infection resolves with the production of memory B cells.
2021-04-26 | GSE164379 | GEO
Project description:Protective immunity against COVID-19 likely depends on the production of SARS-CoV-2 binding plasma cells and memory B cells after infection or vaccination. Previous work has shown evidence that germinal center reactions, a critical component of the B cell response, are disrupted in severe COVID-19. This may adversely affect protective immunity from re-infection. Consistent with an extrafollicular B cell response, severe COVID-19 patients have large scale changes in B cell populations such as elevated frequencies of clonally expanded, class switched, unmutated plasmablasts. However, it is not clear whether mild or asymptomatically infected individuals show similar differences in B cell repertoires. Here, we use single cell RNA sequencing of B cells to show that, in contrast to hospitalized COVID-19 patients, mildly symptomatic COVID-19 subjects have B cell repertoires skewed towards clonally diverse, somatically hypermutated memory B cells approximately 30 days after the onset of symptoms. This provides evidence that B cell responses are less disrupted in mild COVID-19, and that the infection resolves with the production of memory B cells.
2021-04-26 | GSE164380 | GEO
Project description:Distinct B cell repertoires characterize patients with mild and severe COVID-19
| PRJNA690249 | ENA
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.
2016-05-01 | E-MTAB-4489 | biostudies-arrayexpress
Project description:Identification of deregulated genes in the thymus of myasthenia gravis patients' subgroup.
2006-11-09 | E-MEXP-518 | biostudies-arrayexpress
Project description:Distinct B cell repertoires characterize patients with mild and severe COVID-19 [GEX]
| PRJNA690255 | ENA
Project description:Distinct B cell repertoires characterize patients with mild and severe COVID-19 [VDJ]
| PRJNA690256 | ENA
Project description:Background Myasthenia gravis (MG) is an autoimmune disorder with fluctuating muscle weakness, divided into generalized and localized (ocular) forms. Maternal antibodies to acetylcholine receptors cross the placenta and may cause transient neonatal myasthenia gravis (TNMG). We present a case of seronegative maternal ocular MG and delayed TNMG. Case A 29-year-old G3P1011 underwent cesarean birth of a male infant who developed oxygen desaturation requiring supplemental oxygen on day of life (DOL) 3. Based on the clinical course and after exclusion of other diagnoses, the infant was diagnosed with TNMG. Infant's condition improved spontaneously and he was weaned off supplemental oxygen and discharged home on DOL 12. Conclusion Infants born to mothers with seronegative localized (ocular) MG are also susceptible to TNMG which may be late in onset.
| S-EPMC4794443 | biostudies-other