Single-cell mapping reveals dysregulation of immune cell populations and VISTA+ monocytes in myasthenia gravis

Rui, Fan; Que, Wenjun; Liu, Zhuoting; Wang, Zheng; Guo, Xulin; Liu, Linqi; Xiao, Fei

doi:10.1016/j.clim.2022.109184

Cited by 6 publications

(7 citation statements)

References 37 publications

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“…These cells have enhanced pro-inflammatory, pro-necrotic, and antigen-presenting capabilities compared to steady-state Ly6CHi monocytes [ [42] , [43] , [44] ]. A recent study reported an increase in the frequency of VISTA + CD14 + monocytes and HLA-DR expression in VISTA + CD14 + monocytes in patients with MG [ 17 ]. Additional studies have shown that VISTA expression can activate CD14 + monocytes and promote inflammatory responses [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

“…These gene expressions can impaired monocyte function and further reduced expression of genes associated with inflammatory regression, which may contribute to the chronicity of the disease [ 16 ]. A recent study showed a significant increase in the frequency of VISTA + CD14 + monocytes in patients with MG [ 17 ]. Therefore, the observed alterations in the number and function of monocytes in patients with MG are likely to be closely associated with the disease's development.…”

Section: Introductionmentioning

confidence: 99%

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Causal relationship between the immune phenotype of monocytes and myasthenia gravis: A Mendelian randomization study

Dong,

Duan,

Zhang

2024

Heliyon

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Causal relationship between the immune phenotype of monocytes and myasthenia gravis: A Mendelian randomization study

Dong,

Duan,

Zhang

2024

Heliyon

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“…These correspond to the pathogen-associated molecular pattern (PAMP) and damage-associated molecular pattern (DAMP), respectively, which are characteristics of monocyte toll-like receptor activation [ 54 ]. Previous studies have identified higher monocyte percentages in normal MG patients than controls using mass cytometry [ 55 , 56 ]. CD14 + monocytes also have been reported in MG patients and are known to exhibit high inflammatory activity [ 23 , 56 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

Peripheral immune landscape for hypercytokinemia in myasthenic crisis utilizing single-cell transcriptomics

Zhong,

Huan,

Zhao

et al. 2023

J Transl Med

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Background Myasthenia gravis (MG) is the most prevalent autoimmune disorder affecting the neuromuscular junction. A rapid deterioration in respiratory muscle can lead to a myasthenic crisis (MC), which represents a life-threatening condition with high mortality in MG. Multiple CD4+ T subsets and hypercytokinemia have been identified in the peripheral pro-inflammatory milieu during the crisis. However, the pathogenesis is complicated due to the many types of cells involved, leaving the underlying mechanism largely unexplored. Methods We conducted single-cell transcriptomic and immune repertoire sequencing on 33,577 peripheral blood mononuclear cells (PBMCs) from two acetylcholine receptor antibody-positive (AChR +) MG patients during MC and again three months post-MC. We followed the Scanpy workflow for quality control, dimension reduction, and clustering of the single-cell data. Subsequently, we annotated high-resolution cell types utilizing transfer-learning models derived from publicly available single-cell immune datasets. RNA velocity calculations from unspliced and spliced mRNAs were applied to infer cellular state progression. We analyzed cell communication and MG-relevant cytokines and chemokines to identify potential inflammation initiators. Results We identified a unique subset of monocytes, termed monocytes 3 (FCGR3B+ monocytes), which exhibited significant differential expression of pro-inflammatory signaling pathways during and after the crisis. In line with the activated innate immune state indicated by MC, a high neutrophil–lymphocyte ratio (NLR) was confirmed in an additional 22 AChR + MC patients in subsequent hemogram analysis and was associated with MG-relevant clinical scores. Furthermore, oligoclonal expansions were identified in age-associated B cells exhibiting high autoimmune activity, and in CD4+ and CD8+ T cells demonstrating persistent T exhaustion. Conclusions In summary, our integrated analysis of single-cell transcriptomics and TCR/BCR sequencing has underscored the role of innate immune activation which is associated with hypercytokinemia in MC. The identification of a specific monocyte cluster that dominates the peripheral immune profile may provide some hints into the etiology and pathology of MC. However, future functional studies are required to explore causality.

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“…Recently, a novel subset of CD8 T cells, CXCR5 + CD8 + T cells, were identified [ 141 – 143 ]. CXCR5 + CD8 + T cells have been found to infiltrate the B cell follicle in response to several diseases, including viral infection (simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV) [ 144 – 170 ], lymphocytic choriomeningitis virus (LCMV) [ 149 , 171 , 172 ], hepatitis B virus (HBV) [ 173 – 180 ], polycythemia-inducing FV [ 180 ], FluA [ 181 , 182 ], HSV [ 183 ], DENV2 [ 184 , 185 ], and SARS CoV-2 [ 186 – 190 ], EBV [ 191 ]); cancer (colorectal cancer [ 192 – 194 ], NCLC [ 195 ], hepatocellular carcinoma [ 175 , 196 ], hematologic malignancies [ 197 ], pancreatic tumors [ 198 ], gastric cancer [ 199 ], breast cancer [ 200 ], thyroid cancer [ 201 ], melanoma [ 202 ], and lymphoma [ 203 ]); bacterial infection ( Escherichia coli , Acinetobacter baumannii , Klebsiella pneumonia , Pseudomonas aeruginosa , and Staphylococcus aureus [ 204 ]); parasitic infection ( Leishmania mexicana [ 205 ]); immunodeficiency disease (CVID [ 206 ]); autoimmune diseases [ 4 , 131 , 207 – 210 ] (rheumatoid arthritis (RA) [ 131 , 207 ] [ 211 ], primary Sjögren syndrome (pSS) [ 208 ] [ 212 ], and multiple sclerosis (MS) [ 210 , 213 ]).…”

Section: Cxcr5 + Cd8 + T Cells ...mentioning

confidence: 99%

“…As the treatment of MG has remained a burden for patients, finding better treatments is necessary [ 6 ]. Abs in patients with MG are against the muscle nicotinic acetylcholine receptor (AChR), muscle-specific tyrosine kinase (MuSK), and lipoprotein-related protein 4 [ 1 , 3 , 5 , 7 ], and are secreted by B cells and plasma cells with assistance from CD4 + T cells [ 1 , 8 ], resulting in complement anti-AChR antibodies damaging the neuromuscular junctions and inducing MG symptoms such as ptosis, dysphagia, limb weakness, and even dyspnea [ 4 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

An angel or a devil? Current view on the role of CD8+ T cells in the pathogenesis of myasthenia gravis

Peng,

Yang,

Chen

et al. 2024

J Transl Med

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Background Myasthenia gravis (MG) and the experimental autoimmune MG (EAMG) animal model are characterized by T-cell-induced and B-cell-dominated autoimmune diseases that affect the neuromuscular junction. Several subtypes of CD4+ T cells, including T helper (Th) 17 cells, follicular Th cells, and regulatory T cells (Tregs), contribute to the pathogenesis of MG. However, increasing evidence suggests that CD8+ T cells also play a critical role in the pathogenesis and treatment of MG. Main body Herein, we review the literature on CD8+ T cells in MG, focusing on their potential effector and regulatory roles, as well as on relevant evidence (peripheral, in situ, cerebrospinal fluid, and under different treatments), T-cell receptor usage, cytokine and chemokine expression, cell marker expression, and Treg, Tc17, CD3+CD8+CD20+ T, and CXCR5+ CD8+ T cells. Conclusions Further studies on CD8+ T cells in MG are necessary to determine, among others, the real pattern of the Vβ gene usage of autoantigen-specific CD8+ cells in patients with MG, real images of the physiology and function of autoantigen-specific CD8+ cells from MG/EAMG, and the subset of autoantigen-specific CD8+ cells (Tc1, Tc17, and IL-17+IFN-γ+CD8+ T cells). There are many reports of CD20-expressing T (or CD20 + T) and CXCR5+ CD8 T cells on autoimmune diseases, especially on multiple sclerosis and rheumatoid arthritis. Unfortunately, up to now, there has been no report on these T cells on MG, which might be a good direction for future studies.

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Single-cell mapping reveals dysregulation of immune cell populations and VISTA+ monocytes in myasthenia gravis

Cited by 6 publications

References 37 publications

Causal relationship between the immune phenotype of monocytes and myasthenia gravis: A Mendelian randomization study

Causal relationship between the immune phenotype of monocytes and myasthenia gravis: A Mendelian randomization study

Peripheral immune landscape for hypercytokinemia in myasthenic crisis utilizing single-cell transcriptomics

An angel or a devil? Current view on the role of CD8+ T cells in the pathogenesis of myasthenia gravis

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