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MHC class I and MHC class II reporter mice enable analysis of immune oligodendroglia in mouse models of multiple sclerosis.

ABSTRACT: Oligodendrocytes and their progenitors upregulate MHC pathways in response to inflammation, but the frequency of this phenotypic change is unknown and the features of these immune oligodendroglia are poorly defined. We generated MHC class I and II transgenic reporter mice to define their dynamics in response to inflammatory demyelination, providing a means to monitor MHC activation in diverse cell types in living mice and define their roles in aging, injury, and disease.

SUBMITTER: Harrington EP

PROVIDER: S-EPMC10181822 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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MHC class I and MHC class II reporter mice enable analysis of immune oligodendroglia in mouse models of multiple sclerosis.

Harrington Em P EP Catenacci Riley B RB Smith Matthew D MD Heo Dongeun D Miller Cecilia E CE Meyers Keya R KR Glatzer Jenna J Bergles Dwight E DE Calabresi Peter A PA

eLife 20230414

Oligodendrocytes and their progenitors upregulate MHC pathways in response to inflammation, but the frequency of this phenotypic change is unknown and the features of these immune oligodendroglia are poorly defined. We generated MHC class I and II transgenic reporter mice to define their dynamics in response to inflammatory demyelination, providing a means to monitor MHC activation in diverse cell types in living mice and define their roles in aging, injury, and disease. ...[more]

PMID: 37057892

Similar Datasets

MHC class I and MHC class II reporter mice enable analysis of immune oligodendroglia in mouse models of multiple sclerosis

Project description:Oligodendrocytes and their progenitors upregulate MHC pathways in response to inflammation, but the frequency of this phenotypic change is unknown and the features of these immune oligodendroglia are poorly defined. We generated MHC class I and II transgenic reporter mice to define their dynamics in response to inflammatory demyelination, providing a means to monitor MHC activation in diverse cell types in living mice and define their roles in aging, injury and disease.

2022-09-23 | GSE213739 | GEO

MHC class I and MHC class II reporter mice enable analysis of immune oligodendroglia in mouse models of multiple sclerosis

Project description:MHC class I and MHC class II reporter mice enable analysis of immune oligodendroglia in mouse models of multiple sclerosis

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Increased frequencies of myelin oligodendrocyte glycoprotein/MHC class II-binding CD4 cells in patients with multiple sclerosis.

Project description:Multiple sclerosis (MS) is an autoimmune disease characterized by infiltration of pathogenic immune cells in the CNS resulting in destruction of the myelin sheath and surrounding axons. We and others have previously measured the frequency of human myelin-reactive T cells in peripheral blood. Using T cell cloning techniques, a modest increase in the frequency of myelin-reactive T cells in patients as compared with control subjects was observed. In this study, we investigated whether myelin oligodendrocyte glycoprotein (MOG)-specific T cells could be detected and their frequency was measured using DRB1*0401/MOG(97-109(107E-S)) tetramers in MS subjects and healthy controls expressing HLA class II DRB1*0401. We defined the optimal culture conditions for expansion of MOG-reactive T cells upon MOG peptide stimulation of PMBCs. MOG(97-109)-reactive CD4(+) T cells, isolated with DRB1*0401/MOG(97-109) tetramers, and after a short-term culture of PMBCs with MOG(97-109) peptides, were detected more frequently from patients with MS as compared with healthy controls. T cell clones from single cell cloning of DRB1*0401/MOG(97-109(107E-S)) tetramer(+) cells confirmed that these T cell clones were responsive to both the native and the substituted MOG peptide. These data indicate that autoantigen-specific T cells can be detected and enumerated from the blood of subjects using class II tetramers, and the frequency of MOG(97-109)-reactive T cells is greater in patients with MS as compared with healthy controls.

| S-EPMC3131477 | biostudies-literature

Cohesin regulates MHC class II genes through interactions with MHC class II insulators.

Project description:Cohesin is a multiprotein, ringed complex that is most well-known for its role in stabilizing the association of sister chromatids between S phase and M. More recently, cohesin was found to be associated with transcriptional insulators, elements that are associated with the organization of chromatin into regulatory domains. The human MHC class II (MHC-II) locus contains 10 intergenic elements, termed MHC-II insulators, which bind the transcriptional insulator protein CCCTC-binding factor. MHC-II insulators interact with each other, forming a base architecture of discrete loops and potential regulatory domains. When MHC-II genes are expressed, their proximal promoter regulatory regions reorganize to the foci established by the interacting MHC-II insulators. MHC-II insulators also bind cohesin, but the functional role of cohesin in regulating this system is not known. In this article, we show that the binding of cohesin to MHC-II insulators occurred irrespective of MHC-II expression but was required for optimal expression of the HLA-DR and HLA-DQ genes. In a DNA-dependent manner, cohesin subunits interacted with CCCTC-binding factor and the MHC-II-specific transcription factors regulatory factor X and CIITA. Intriguingly, cohesin subunits were important for DNA looping interactions between the HLA-DRA promoter region and a 5' MHC-II insulator but were not required for interactions between the MHC-II insulators themselves. This latter observation introduces cohesin as a regulator of MHC-II expression by initiating or stabilizing MHC-II promoter regulatory element interactions with the MHC-II insulator elements, events that are required for maximal MHC-II transcription.

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Present Yourself! By MHC Class I and MHC Class II Molecules.

Project description:Since the discovery of MHC molecules, it has taken 40 years to arrive at a coherent picture of how MHC class I and MHC class II molecules really work. This is a story of the proteases and MHC-like chaperones that support the MHC class I and II molecules in presenting peptides to the immune system. We now understand that the MHC system shapes both the repertoire of presented peptides and the subsequent T cell response, with important implications ranging from transplant rejection to tumor immunotherapies. Here we present an illustrated review of the ins and outs of MHC class I and MHC class II antigen presentation.

| S-EPMC5159193 | biostudies-literature

Equine MHC class II

Project description:Sequencing and annotation of equine MHC class II region

| PRJEB15527 | ENA

Ligation of MHC Class II Induces PKC-Dependent Clathrin-Mediated Endocytosis of MHC Class II.

Project description:In addition to antigen presentation to CD4+ T cells, aggregation of cell surface major histocompatibility complex class II (MHC-II) molecules induces signal transduction in antigen presenting cells that regulate cellular functions. We previously reported that crosslinking of MHC-II induced the endocytosis of MHC-II, which was associated with decreased surface expression levels in murine dendritic cells (DCs) and resulted in impaired activation of CD4+ T cells. However, the downstream signal that induces MHC-II endocytosis remains to be elucidated. In this study, we found that the crosslinking of MHC-II induced intracellular Ca2+ mobilization, which was necessary for crosslinking-induced MHC-II endocytosis. We also found that these events were suppressed by inhibitors of Syk and phospholipase C (PLC). Treatments with a phorbol ester promoted MHC-II endocytosis, whereas inhibitors of protein kinase C (PKC) suppressed crosslinking-induced endocytosis of MHC-II. These results suggest that PKC could be involved in this process. Furthermore, crosslinking-induced MHC-II endocytosis was suppressed by inhibitors of clathrin-dependent endocytosis. Our results indicate that the crosslinking of MHC-II could stimulate Ca2+ mobilization and induce the clathrin-dependent endocytosis of MHC-II in murine DCs.

| S-EPMC7465434 | biostudies-literature

Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility.

Project description:Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG) and myelin by immune cells, which are thought to be the main drivers of MS susceptibility. We found that immune genes exhibit a primed chromatin state in single mouse and human OLG in a non-disease context, compatible with transitions to immune-competent states in MS. We identified BACH1 and STAT1 as transcription factors involved in immune gene regulation in oligodendrocyte precursor cells (OPCs). A subset of immune genes presents bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon gamma (IFN-γ) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse and human OLG. Treatment of mouse OPCs with IFN-γ leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Thus, the susceptibility for MS may involve OLG, which therefore constitutes novel targets for immunological-based therapies for MS.

| S-EPMC9810341 | biostudies-literature

HLA-class II genes association with multiple sclerosis: An immunogenetic prediction among multiple sclerosis Jordanian patients.

Project description:Multiple sclerosis (MS) is an inflammatory autoimmune disease affecting the central nervous system (CNS). The pathogenesis of MS is characterized by neuronal axonal degeneration and demyelination. Among the genes that raises MS risk are the HLA-class II genes. The goals of this study were to investigate the role of the HLA-DRB1 and HLA-DQB1 genes (for the first time) in Jordanian MS patients and their association with MS disease. The association of these genes with other clinical features, such as optic neuritis, sensory impairment, and brainstem symptoms in MS patients was investigated as well using PCR-SSP techniques. Our findings indicated an association between HLA-DRB1 * 03:01 (Pc = 0.01) and HLA-DRB1 * 04:01 (Pc = 0.004) alleles with Jordanian MS patients. In addition, a significant linkage between HLA-DRB1 * 15:01 and HLA-DQB1 * 06:01 alleles (Pc ≤ 0.001 and Pc = 0.012, respectively) were presented among Jordanian MS patients with optic neuritis compared to Jordanian MS patients without optic neuritis. Moreover, HLA-DQB1 * 05:01 and HLA-DQB1 * 06:02 alleles (Pc ≤ 0.001 and Pc = 0.006, respectively) was found to be related with sensory impairment in MS patients. Additionally, HLA-DRB1 * 07:01 allele indicates a positive correlation in MS patients with brainstem symptoms (Pc < 0.001). Moreover, our results indicated that there is no association on the HLA-DRB1 ~ HLA-DQB1 haplotype level and MS disease. Knowing the genes that are linked to MS, they may facilitate MS diagnosis, prevention, and treatment at earlier stage. Also, these results may serve in the development of more potent therapeutic regimens for MS and its related complications, such as optic neuritis, sensory impairment, and brainstem symptoms.

| S-EPMC11856260 | biostudies-literature

Class II HLA interactions modulate genetic risk for multiple sclerosis.

Project description:Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01-HLA-DRB1*15:01 and HLA-DQB1*03:01-HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles.

| S-EPMC4874245 | biostudies-literature

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