Anti-inflammatory genes associated with multiple sclerosis: A gene expression study

Perga, Simona; Montarolo, Francesca; Martire, Serena; Berchialla, Paola; Malucchi, S.; Bertolotto, Antonio

doi:10.1016/j.jneuroim.2015.01.004

Cited by 18 publications

(18 citation statements)

References 23 publications

(27 reference statements)

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“…18 Conversely, BACH2, a critical transcriptional factor regulating the balance between tolerance and immunity by repressing CD4 + T-cell differentiation, 19 is downregulated in pathogenic T cells in EAE mice 18 and in the blood of RR-MS subjects. 20 Our study confirms this observation and extends it to the other MS stages. Very limited information is present in the literature about the expression of other GWAS genes in MS blood cells.…”

Section: Discussionsupporting

confidence: 87%

Dysregulation of MS risk genes and pathways at distinct stages of disease

Srinivasan

Dario

Russo

et al. 2017

Neurol Neuroimmunol Neuroinflamm

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Objective:To perform systematic transcriptomic analysis of multiple sclerosis (MS) risk genes in peripheral blood mononuclear cells (PBMCs) of subjects with distinct MS stages and describe the pathways characterized by dysregulated gene expressions.Methods:We monitored gene expression levels in PBMCs from 3 independent cohorts for a total of 297 cases (including clinically isolated syndromes (CIS), relapsing-remitting MS, primary and secondary progressive MS) and 96 healthy controls by distinct microarray platforms and quantitative PCR. Differential expression and pathway analyses for distinct MS stages were defined and validated by literature mining.Results:Genes located in the vicinity of MS risk variants displayed altered expression in peripheral blood at distinct stages of MS compared with the healthy population. The frequency of dysregulation was significantly higher than expected in CIS and progressive forms of MS. Pathway analysis for each MS stage–specific gene list showed that dysregulated genes contributed to pathogenic processes with scientific evidence in MS.Conclusions:Systematic gene expression analysis in PBMCs highlighted selective dysregulation of MS susceptibility genes playing a role in novel and well-known pathogenic pathways.

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Section: Discussionsupporting

confidence: 87%

Dysregulation of MS risk genes and pathways at distinct stages of disease

Srinivasan

Dario

Russo

et al. 2017

Neurol Neuroimmunol Neuroinflamm

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“…Inflammation is another characteristic of these diseases, which involves a group of cytokines, chemokines, and interactions between CD4 + T helper cells (e.g., Th1, Th2, Th9, Th17, and Tfh) and regulatory T cells (Tregs). Gene polymorphisms of the single gene locus encoding Bach2 are also correlated with a variety of immune-mediated diseases including multiple sclerosis (MS) [41], RA [42], CP [20], type 2 chronic airway inflammation [18], inflammatory bowel disease (IBD) [43], and type 1 diabetes [44]. Significantly, both proinflammatory and anti-inflammatory molecular mechanisms are involved in the variant expression of Bach2 and these diseases.…”

Section: The Connection Between Bach2 and Immune-mediated Diseasesmentioning

confidence: 99%

The Critical Role of Bach2 in Shaping the Balance between CD4⁺ T Cell Subsets in Immune-Mediated Diseases

Yang

Chen

Zhao

et al. 2019

Mediators of Inflammation

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The transcription factor Bach2 which is predominantly expressed in B and T lymphocytes represses the expression of genes by forming heterodimers with small Maf and Batf proteins and binding to the corresponding sequence on the DNA. In this way, Bach2 serves as a highly conserved repressor which controls the terminal differentiation and maturation of both B and T lymphocytes. It is required for class switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes in activated B cells, and its function in B cell differentiation has been well-described. Furthermore, emerging data show that Bach2 regulates transcriptional activity in T cells at super enhancers or regions of high transcriptional activity, thus stabilizing immunoregulatory capacity and maintaining T cell homeostasis. Bach2 is also critical for the formation and function of CD4+ T cell lineages (Th1, Th2, Th9, Th17, T follicular helper (Tfh), and regulatory T (Treg) cells). Genetic variations within Bach2 locus are associated with numerous immune-mediated diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), chronic pancreatitis (CP), type 2 chronic airway inflammation, inflammatory bowel disease (IBD), and type 1 diabetes. Here, we reveal a critical role of Bach2 in regulating T cell biology and the correlation with these immune-mediated diseases.

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“…TNFAIP3 has been genetically associated with different inflammatory autoimmune diseases (4-7), among which MS (8). We previously demonstrated a significant down-regulation of the TNFAIP3 transcript level in peripheral blood obtained from treatment-naïve MS patients in comparison to HC (9)(10)(11)(12)22). Further researches revealed that the unbalanced expression of TNFAIP3 in MS was mainly due to the monocyte cell population (13).…”

Section: Discussionmentioning

confidence: 97%

TNFAIP3 in circulating and parenchymal myeloid lineage critically controls monocytes, monocytes-derived cells and microglia

Montarolo¹,

Perga²,

Tessarolo³

et al. 2019

Preprint

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Background. The intracellular ubiquitin-ending enzyme TNFAIP3 is one of the most potent inhibitor of the pro-inflammatory NF-kB pathway. Single nucleotide polymorphisms in the TNFAIP3 locus have been associated to autoimmune inflammatory disorders, including Multiple Sclerosis (MS). Previously, we reported a TNFAIP3 down-regulated gene expression level in blood and specifically in CD14+ monocytes obtained from treatment naïve MS patients in comparison to healthy controls (HC). Notably, myeloid cells which include monocytes, exert a key role in the neuro-inflammatory pathogenic process of MS.Methods. Here, we evaluated the effect of the specific TNFAIP3 deficiency in myeloid cells including monocytes, monocyte-derived cells (M-MDC) and microglia analyzing the lymphoid organs and central nervous system (CNS) of experimental mice. The TNFAIP3 deletion is induced using conditional knock-out mice for the myeloid lineage. Flow cytometry and histological procedures were applied to evaluate the immune cell population of spleen, lymph nodes and bone marrow and the microglial cell density in CNS, respectively.Results. Here, we found that the deletion of TNFAIP3 in myeloid cells induces a reduced body weight, a decrease in the percentage number of M-MDC and of common monocyte and granulocyte precursor cells. We also reported that the deletion of TNFAIP3 in myeloid cells reports an increased microglial cell density in brain.Conclusions. Collectively, the results suggest that the presence of TNFAIP3 in myeloid cells critically controls the development of M-MDC in lymphoid organ and of microglia in brain.

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Anti-inflammatory genes associated with multiple sclerosis: A gene expression study

Cited by 18 publications

References 23 publications

Dysregulation of MS risk genes and pathways at distinct stages of disease

Dysregulation of MS risk genes and pathways at distinct stages of disease

The Critical Role of Bach2 in Shaping the Balance between CD4⁺ T Cell Subsets in Immune-Mediated Diseases

TNFAIP3 in circulating and parenchymal myeloid lineage critically controls monocytes, monocytes-derived cells and microglia

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Anti-inflammatory genes associated with multiple sclerosis: A gene expression study

Cited by 18 publications

References 23 publications

Dysregulation of MS risk genes and pathways at distinct stages of disease

Dysregulation of MS risk genes and pathways at distinct stages of disease

The Critical Role of Bach2 in Shaping the Balance between CD4+ T Cell Subsets in Immune-Mediated Diseases

TNFAIP3 in circulating and parenchymal myeloid lineage critically controls monocytes, monocytes-derived cells and microglia

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The Critical Role of Bach2 in Shaping the Balance between CD4⁺ T Cell Subsets in Immune-Mediated Diseases