Multiplex immunoassays reveal increased serum cytokines and chemokines associated with the subtypes of achalasia

Chen, Wei‐Feng; Liu, Zu‐Qiang; Pu, Zhening; Xu, Jiaqi; Yao, Lu; Wu, Xing‐Yue; Xu, Xiaoyue; Xu, Jiaxin; Zhu, Yan; Wang, Yun; Cheng, Jing; Zhu, Liang; Zhou, Ping‐Hong; Li, Quan‐Lin

doi:10.1111/nmo.13832

Cited by 9 publications

(15 citation statements)

References 36 publications

(58 reference statements)

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“…Recently, our team collected serological information from 47 patients with achalasia and 47 matched healthy controls 15 . Using a Luminex xMAP immunoassay (Merck Milipore) of 51 cytokines and chemokines, we found that patients with achalasia had significantly increased TGF‐β1, TGF‐β2, TGF‐β3, IL‐1Ra, IL‐17, IL‐18, IFN‐γ, monokine induced by gamma (MIG), platelet‐derived growth factor (PDGF)‐BB, IFN‐γ‐induced protein‐10 (IP‐10), and stem cell growth factor (SCGF)‐B compared with the controls.…”

Section: Immunologymentioning

confidence: 99%

“…IL‐23 and IL‐6 promote the proliferation of Th17 cells 39,40 . PDGF‐BB, SCGF‐B, and TRAIL are also common proinflammatory cytokines; among them, SCGF‐B is key to the self‐renewal and maturation of hematopoietic stem cells 15 . High levels of these proinflammatory cytokines reflect the active immune process in achalasia, and some cytokines also promote fibroplasia, which can further accelerate inflammation (Figure 1).…”

Section: Immunologymentioning

confidence: 99%

“…40 PDGF-BB, SCGF-B, and TRAIL are also common proinflammatory cytokines; among them, SCGF-B is key to the selfrenewal and maturation of hematopoietic stem cells 15. High levels of these proinflammatory cytokines reflect the active immune process in achalasia, and some cytokines also promote fibroplasia, which can further accelerate inflammation(Figure 1) 15. Chemokines such as MIG, MCP-1, Eotaxin, SDF-1a, and IP-10 are secreted by various immune cells and participate in the proliferation, migration, and activation of immune cells during the inflammation.Increased levels of these chemokines are also related to immune response activity 15.…”

mentioning

confidence: 99%

“…High levels of these proinflammatory cytokines reflect the active immune process in achalasia, and some cytokines also promote fibroplasia, which can further accelerate inflammation(Figure 1) 15. Chemokines such as MIG, MCP-1, Eotaxin, SDF-1a, and IP-10 are secreted by various immune cells and participate in the proliferation, migration, and activation of immune cells during the inflammation.Increased levels of these chemokines are also related to immune response activity 15. While among the abovementioned anti-inflammatory cytokines, TGF-β negatively regulates inflammation, differentiation, collagen synthesis, cellular growth, proliferation and apoptosis.…”

mentioning

confidence: 99%

“…However, they failed to find a difference in the patterns of these cytokines among different subtypes of achalasia 14. Recently, our team collected serological information from 47 patients with achalasia and 47 matched healthy controls 15. Using a Another important report used microarray technology and achieved the first genome-wide expression profiling of mRNA in tissue samples of achalasia patients 22.…”

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The etiology of achalasia: An immune‐dominant disease

Liu

Wang

et al. 2021

J of Digest Diseases

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There is accumulating evidence suggesting that an autoimmune component is involved in esophageal achalasia. An increase in immune cells, cytokines, chemokines, and autoimmune antibodies in serum and infiltration of immune cells in tissues support the view that immune-mediated inflammation is a crucial pathogenesis of inhibitory neuron degeneration in the lower esophageal sphincter. Infection of viruses such as the herpes virus family has been suspected of provoking the autoimmune reaction. Meanwhile, previous reports on immunogenetics have proposed that specific risk alleles on the human leukocyte antigen complex define the susceptible population to achalasia. In this study we reviewed current knowledge regarding the immune-related factors of achalasia, including immunology, viral infection and immunogenetic variations. K E Y W O R D S autoimmune diseases, esophageal achalasia, histocompatibility antigens class II, immunology, viruses 1 | INTRODUCTION Esophageal achalasia is a motility disorder that presents with symptoms including dysphagia, regurgitation, chest pain, and weight loss. It is clinically subclassified into three types based on different manifestations in high-resolution manometry: type I achalasia is the classical achalasia with no pressurization; in type II achalasia there is compression of over 30 mmHg in the distal esophagus; while type III achalasia can be diagnosed when two or more spastic contractions are observed. 1 The pathophysiology of this disease is a loss of peristalsis and inadequate relaxation of the lower esophageal sphincter (LES), which results from gradual disappearance of the myenteric neurons. Previous histological studies have found the loss of inhibitory enteric neurons in the esophageal tissues of patients with achalasia. 2 In the nervous system, these types of neurons contain nitric oxide and vasoactive intestinal polypeptide, which are responsible for this process. 7 Achalasia was recognized as a degenerative disease of the myenteric plexus. 8 About three decades ago studies on achalasia revealed inflammatory cell infiltration in the myenteric ganglia. 9 Later reports have demonstrated that the pathogenesis of achalasia is associated with immunology, viral infection, and host genetics. It turns out that immunology is potentially the crucial factor, and viral infection may trigger the disordered immune reaction in specific patients with an immunogenetic variation. In this review, we focused on all the *These three authors contributed equally to this work.

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Section: Immunologymentioning

confidence: 99%

Section: Immunologymentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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The etiology of achalasia: An immune‐dominant disease

Liu

Wang

et al. 2021

J of Digest Diseases

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The molecular pathogenesis of achalasia: a paired lower esophageal sphincter muscle and serum 4D label-free proteomic study

Chen

Xing

et al. 2022

Gastroenterology Report

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Background Achalasia is a primary esophageal motility disorder with potential molecular pathogenesis remaining uncertain. This study aimed to identify the differentially expressed proteins and potential pathways among achalasia subtypes and controls to further reveal the molecular pathogenesis of achalasia. Methods Paired lower esophageal sphincter (LES) muscle and serum samples from 24 achalasia patients were collected. We also collected 10 normal serum samples from healthy controls and 10 normal LES muscle samples from esophageal cancer patients. The 4D label-free proteomic analysis was performed to identify the potential proteins and pathways involved in achalasia. Results Analysis of Similarities showed distinct proteomic patterns of serum and muscle samples between achalasia patients and controls (both P < 0.05). Functional enrichment analysis suggested that these differentially expressed proteins were immunity-, infection-, inflammation-, and neurodegeneration-associated. The mfuzz analysis in LES specimens showed that proteins involved in the extracellular matrix–receptor interaction increased sequentially between the control group, type III, type II, and type I achalasia. Only 26 proteins altered in the same directions in serum and muscle samples. Conclusions This first 4D label-free proteomic study of achalasia indicated that there were specific protein alterations in both the serum and muscle of achalasia, involving immunity, inflammation, infection, and neurodegeneration pathways. Distinct protein clusters between types I, II, and III revealed the potential molecular pathways associated with different disease stages. Analysis of proteins changed in both muscle and serum samples highlighted the importance of further studies on LES muscle and revealed potential autoantibodies.

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A cross‐sectional study reveals a chronic low‐grade inflammation in achalasia

Liu

Chen

et al. 2023

J of Gastro and Hepatol

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Background and Aim: Immune-mediated neuroinflammation has been proposed to underlie the loss of lower esophageal sphincter (LES) myenteric neurons in achalasia. However, the immune status and key pathogenic immune subpopulations remain unclear. This study aims to evaluate the inflammatory status of patients with achalasia and their correlation with clinical characteristics, and further explore the key pathogenic subpopulations. Methods: We investigated the complete blood cell count and inflammatory markers in a large population of patients with achalasia (n = 341) and healthy controls (n = 80). The subpopulations of lymphocytes were analyzed by flow cytometry. Immunofluorescence was used to determine immune cell infiltration in the LES. Transcriptome changes of the key subpopulation were determined by RNA sequencing analysis. Results: NLR, MLR, CRP, globulin, IL-6 and IL-10 were significantly elevated in patients with achalasia. MLR and globulin were positively correlated with disease duration. The absolute count and percentage of CD8+ T cells in peripheral blood and its infiltration around ganglion in the LES were significantly increased in achalasia. Transcriptome analysis indicated that CD8+ T cells were activated and proliferative. In addition to multiple inflammatory pathways, regulation of neuroinflammatory response pathway was also significantly up-regulated in achalasia. GSEA analysis revealed a close association with autoimmune diseases. Conclusions: Patients with achalasia suffered from chronic low-grade inflammation with dysregulated immune cells and mediators associated with disease duration. CD8+ T cells might be the key pathogenic subpopulation of achalasia. Our results provide an important immune cell signature of the pathogenesis of achalasia.

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Multiplex immunoassays reveal increased serum cytokines and chemokines associated with the subtypes of achalasia

Cited by 9 publications

References 36 publications

The etiology of achalasia: An immune‐dominant disease

The etiology of achalasia: An immune‐dominant disease

The molecular pathogenesis of achalasia: a paired lower esophageal sphincter muscle and serum 4D label-free proteomic study

A cross‐sectional study reveals a chronic low‐grade inflammation in achalasia

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