MicroRNA-directed pathway discovery elucidates an miR-221/222–mediated regulatory circuit in class switch recombination

Wigton, Eric J.; Mikami, Yohei; McMonigle, Ryan J.; Castellanos, Carlos A.; Wade-Vallance, Adam K.; Zhou, Simon; Kageyama, Robin; Litterman, Adam J.; Roy, Suparna; Kitamura, Daisuke; Dykhuizen, Emily C.; Allen, Christopher D.C.; Hu, Hui; O’Shea, John J.; Ansel, K. Mark

doi:10.1084/jem.20201422

Cited by 13 publications

(9 citation statements)

References 84 publications

(130 reference statements)

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“…A recent study proved evidence that it’s also critical in JIA-associated autoimmune uveitis ( 53 ). It is worth noting that ARID1A was also found playing important role in T-cell development ( 54 , 55 ), while its expression in B cells was found to regulate levels of IgE and IgG ( 56 ). Moreover, ARID1A has been found to induce antiviral IFN-I production in macrophages as well ( 57 ).…”

Section: Discussionmentioning

confidence: 99%

Study of the shared gene signatures of polyarticular juvenile idiopathic arthritis and autoimmune uveitis

Zheng

Wang

2023

Front. Immunol.

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ObjectiveTo explore the shared gene signatures and potential molecular mechanisms of polyarticular juvenile idiopathic arthritis (pJIA) and autoimmune uveitis (AU).MethodThe microarray data of pJIA and AU from the Gene Expression Omnibus (GEO) database were downloaded and analyzed. The GEO2R tool was used to identify the shared differentially expressed genes (DEGs) and genes of extracellular proteins were identified among them. Then, weighted gene co-expression network analysis (WGCNA) was used to identify the shared immune-related genes (IRGs) related to pJIA and AU. Moreover, the shared transcription factors (TFs) and microRNAs (miRNAs) in pJIA and AU were acquired by comparing data from HumanTFDB, hTFtarget, GTRD, HMDD, and miRTarBase. Finally, Metascape and g: Profiler were used to carry out function enrichment analyses of previously identified gene sets.ResultsWe found 40 up-regulated and 15 down-regulated shared DEGs via GEO2R. Then 24 shared IRGs in positivity-related modules, and 18 shared IRGs in negatively-related modules were found after WGCNA. After that, 3 shared TFs (ARID1A, SMARCC2, SON) were screened. And the constructed TFs-shared DEGs network indicates a central role of ARID1A. Furthermore, hsa-miR-146 was found important in both diseases. The gene sets enrichment analyses suggested up-regulated shared DEGs, TFs targeted shared DEGs, and IRGs positivity-correlated with both diseases mainly enriched in neutrophil degranulation process, IL-4, IL-13, and cytokine signaling pathways. The IRGs negatively correlated with pJIA and AU mainly influence functions of the natural killer cell, cytotoxicity, and glomerular mesangial cell proliferation. The down-regulated shared DEGs and TFs targeted shared DEGs did not show particular functional enrichment.ConclusionOur study fully demonstrated the flexibility and complexity of the immune system disorders involved in pJIA and AU. Neutrophil degranulation may be considered the shared pathogenic mechanism, and the roles of ARID1A and MiR-146a are worthy of further in-depth study. Other than that, the importance of periodic inspection of kidney function is also noteworthy.

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Section: Discussionmentioning

confidence: 99%

Study of the shared gene signatures of polyarticular juvenile idiopathic arthritis and autoimmune uveitis

Zheng

Wang

2023

Front. Immunol.

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“…We found that the risk allele for rheumatoid arthritis was correlated with high expression levels of AFF3 and frequent utilization of IgG2 and IgA2 in B cells. In patients with rheumatoid arthritis, rheumatoid factor IgG and anticyclic citrullinated peptide IgG antibodies are detected even before the onset of the disease and are related to disease severity, suggesting that specific classes of autoantibodies are related to the pathogenesis (60)(61)(62)(63). Moreover, islet-specific autoantibodies (anti-insulin, glutamate decarboxylase, islet antigen 2, and islet-specific zinc transporter antibodies) have been detected in patients with T1D (64)(65)(66) and are considered to be the best available markers for predicting the disease.…”

Section: Discussionmentioning

confidence: 99%

“…Gene expression data of immune cells in the ImmuNexUT database ( 61 ) were used for the analysis. AFF3 gene expression was compared among immune cells using healthy control samples.…”

Section: Methodsmentioning

confidence: 99%

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AFF3, a susceptibility factor for autoimmune diseases, is a molecular facilitator of immunoglobulin class switch recombination

et al. 2022

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Immunoglobulin class switch recombination (CSR) plays critical roles in controlling infections and inflammatory tissue injuries. Here, we show that AFF3 , a candidate gene for both rheumatoid arthritis and type 1 diabetes, is a molecular facilitator of CSR with an isotype preference. Aff3 -deficient mice exhibit low serum levels of immunoglobulins, predominantly immunoglobulin G2c (IgG2c) followed by IgG1 and IgG3 but not IgM. Furthermore, Aff3 -deficient mice show weak resistance to Plasmodium yoelii infection, confirming that Aff3 modulates immunity to this pathogen. Mechanistically, the AFF3 protein binds to the IgM and IgG1 switch regions via a C-terminal domain, and Aff3 deficiency reduces the binding of AID to the switch regions less efficiently. One AFF3 risk allele for rheumatoid arthritis is associated with high mRNA expression of AFF3 , IGHG2 , and IGHA2 in human B cells. These findings demonstrate that AFF3 directly regulates CSR by facilitating the recruitment of AID to the switch regions.

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“…As in all cells, microRNAs are important determinants of B-cell function and patterned responses [83]. As many miRNAs are ROS-regulated, alterations in mitochondrial function and mitochondrial ROS production will drive variations in miRNAs, thereby shaping patterned gene expressions in B-cells.…”

Section: B-cells Antibodies and Mitochondriamentioning

confidence: 99%

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders

Anderson¹,

Almulla

Reíter

et al. 2023

Cells

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Although previously restricted to a limited number of medical conditions, there is a growing appreciation that ‘autoimmune’ (or immune-mediated) processes are important aspects of a wide array of diverse medical conditions, including cancers, neurodegenerative diseases and psychiatric disorders. All of these classes of medical conditions are associated with alterations in mitochondrial function across an array of diverse cell types. Accumulating data indicate the presence of the mitochondrial melatonergic pathway in possibly all body cells, with important consequences for pathways crucial in driving CD8+ T cell and B-cell ‘autoimmune’-linked processes. Melatonin suppression coupled with the upregulation of oxidative stress suppress PTEN-induced kinase 1 (PINK1)/parkin-driven mitophagy, raising the levels of the major histocompatibility complex (MHC)-1, which underpins the chemoattraction of CD8+ T cells and the activation of antibody-producing B-cells. Many factors and processes closely associated with autoimmunity, including gut microbiome/permeability, circadian rhythms, aging, the aryl hydrocarbon receptor, brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) all interact with the mitochondrial melatonergic pathway. A number of future research directions and novel treatment implications are indicated for this wide collection of poorly conceptualized and treated medical presentations. It is proposed that the etiology of many ‘autoimmune’/‘immune-mediated’ disorders should be conceptualized as significantly determined by mitochondrial dysregulation, with alterations in the mitochondrial melatonergic pathway being an important aspect of these pathoetiologies.

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MicroRNA-directed pathway discovery elucidates an miR-221/222–mediated regulatory circuit in class switch recombination

Cited by 13 publications

References 84 publications

Study of the shared gene signatures of polyarticular juvenile idiopathic arthritis and autoimmune uveitis

Study of the shared gene signatures of polyarticular juvenile idiopathic arthritis and autoimmune uveitis

AFF3, a susceptibility factor for autoimmune diseases, is a molecular facilitator of immunoglobulin class switch recombination

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders

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