Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pertussis Toxin Inhibits Encephalitogenic T-Cell Infiltration and Promotes a B-Cell-Driven Disease during Th17-EAE.

ABSTRACT: Pertussis toxin (PTX) is a required co-adjuvant for experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin antigen. However, PTX's effects on EAE induced by the transfer of myelin-specific T helper cells is not known. Therefore, we investigated how PTX affects the Th17 transfer EAE model (Th17-EAE). We found that PTX significantly reduced Th17-EAE by inhibiting chemokine-receptor-dependent trafficking of Th17 cells. Strikingly, PTX also promoted the accumulation of B cells in the CNS, suggesting that PTX alters the disease toward a B-cell-dependent pathology. To determine the role of B cells, we compared the effects of PTX on Th17-EAE in wild-type (WT) and B-cell-deficient (µMT) mice. Without PTX treatment, disease severity was equivalent between WT and µMT mice. In contrast, with PTX treatment, the µMT mice had significantly less disease and a reduction in pathogenic Th17 cells in the CNS compared to the WT mice. In conclusion, this study shows that PTX inhibits the migration of pathogenic Th17 cells, while promoting the accumulation of pathogenic B cells in the CNS during Th17-EAE. These data provide useful methodological information for adoptive-transfer Th17-EAE and, furthermore, describe another important experimental system to study the pathogenic mechanisms of B cells in multiple sclerosis.

SUBMITTER: Maria Z

PROVIDER: S-EPMC7998427 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Experimental priming of encephalitogenic Th1/Th17 cells requires pertussis toxin-driven IL-1β production by myeloid cells.

Project description:CD4(+) Th17 are heterogeneous in terms of cytokine production and capacity to initiate autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE). Here we demonstrate that experimental priming of encephalitogenic Th cells expressing RORγt and T-bet and producing IL-17A, IFN-γ and GM-CSF but not IL-10 (Th1/Th17), is dependent on the presence of pertussis toxin (PTX) at the time of immunization. PTX induces early production of IL-1β by CD11b(+)CCR2(+)Gr1(+) myeloid cells, which are rapidly recruited to antigen-draining lymph nodes. PTX-induced generation of Th1/Th17 cells is impaired in IL-1β- and ASC-deficient mice and in mice in which myeloid cells are depleted or fail to migrate to lymph nodes and requires expression of IL-1R1 and MyD88 on both T cells and non-T cells. Collectively, these data shed light on the enigmatic function of PTX in EAE induction and suggest that inflammatory monocytes and microbial infection can influence differentiation of pathogenic Th1/Th17 cells in autoimmune diseases through production of IL-1β.

| S-EPMC4873938 | biostudies-literature

Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenic Th1 responses in EAE.

Project description:When exposed to a pathogen, a naive CD4(+) T cell is forced to make a cell fate decision that leads to a polarized population of Th1 IFN-gamma- or Th2 IL-4- producing cells. Although IL-4 has traditionally been considered a factor that promotes Th2 cell differentiation, recent evidence has demonstrated that the site and timing of IL-4 expression in an immune response determines its ultimate effects on CD4(+) T cell fate. Using a mast cell (MC) reconstitution model, we demonstrate that MC-derived IL-4 promoted Th1 responses in vivo. Furthermore, MCs from genetically disparate mouse strains varied in their potential for IL-4 expression. Independent of the activation mode, MCs from Th1-prone C57BL/6 mice exhibited a more robust Il4 response than did the Th2-prone strain Balb/c. The hierarchy of IL-4 expression potential was directly associated with the degree of basal chromatin accessibility at cis-regulatory elements conserved noncoding sequence-1 and V(A) enhancer within the Th2 locus. GATA1/2 and Ikaros, factors with opposing roles in chromatin remodeling, acted at these sites. We propose that GATA and Ikaros proteins coordinately fine-tune accessibility at the Il4 locus during development to variably regulate IL-4 expression. These events likely contribute to the genetically determined heterogeneity in Th1 responses that underlie susceptibility to many diseases.

| S-EPMC1440706 | biostudies-literature

Domperidone Inhibits <i>Clostridium botulinum</i> C2 Toxin and <i>Bordetella pertussis</i> Toxin.

Project description:Bordetella pertussis toxin (PT) and Clostridium botulinum C2 toxin are ADP-ribosylating toxins causing severe diseases in humans and animals. They share a common translocation mechanism requiring the cellular chaperones Hsp90 and Hsp70, cyclophilins, and FK506-binding proteins to transport the toxins' enzyme subunits into the cytosol. Inhibitors of chaperone activities have been shown to reduce the amount of transported enzyme subunits into the cytosol of cells, thus protecting cells from intoxication by these toxins. Recently, domperidone, an approved dopamine receptor antagonist drug, was found to inhibit Hsp70 activity. Since Hsp70 is required for cellular toxin uptake, we hypothesized that domperidone also protects cells from intoxication with PT and C2. The inhibition of intoxication by domperidone was demonstrated by analyzing the ADP-ribosylation status of the toxins' specific substrates. Domperidone had no inhibitory effect on the receptor-binding or enzyme activity of the toxins, but it inhibited the pH-driven membrane translocation of the enzyme subunit of the C2 toxin and reduced the amount of PTS1 in cells. Taken together, our results indicate that domperidone is a potent inhibitor of PT and C2 toxins in cells and therefore might have therapeutic potential by repurposing domperidone to treat diseases caused by bacterial toxins that require Hsp70 for their cellular uptake.

| S-EPMC10467066 | biostudies-literature

HMGB1 from Astrocytes Promotes EAE by Influencing the Immune Cell Infiltration-Associated Functions of BMECs in Mice.

Project description:High mobility group box 1 (HMGB1) has been reported to play an important role in experimental autoimmune encephalomyelitis (EAE). Astrocytes are important components of neurovascular units and tightly appose the endothelial cells of microvessels by their perivascular endfeet and directly regulate the functions of the blood-brain barrier. Astrocytes express more HMGB1 during EAE while the exact roles of astrocytic HMGB1 in EAE have not been well elucidated. Here, using conditional-knockout mice, we found that astrocytic HMGB1 depletion decreased morbidity, delayed the onset time, and reduced the disease score and demyelination of EAE. Meanwhile, there were fewer immune cells, especially pathogenic T cells infiltration in the central nervous system of astrocytic HMGB1 conditional-knockout EAE mice, accompanied by up-regulated expression of the tight-junction protein Claudin5 and down-regulated expression of the cell adhesion molecules ICAM1 and VCAM1 in vivo. In vitro, HMGB1 released from astrocytes decreased Claudin5 while increased ICAM1 and VCAM1 expressed by brain microvascular endothelial cells (BMECs) through TLR4 or RAGE. Taken together, our results demonstrate that HMGB1 derived from astrocytes aggravates EAE by directly influencing the immune cell infiltration-associated functions of BMECs.

| S-EPMC9672173 | biostudies-literature

Regulation of Th17 cell differentiation and EAE induction by MAP3K NIK.

Project description:Th17 cells play an important role in mediating autoimmune diseases, but the molecular mechanism underlying Th17 differentiation is incompletely understood. We show here that NF-kappaB-inducing kinase (NIK), which is known to regulate B-cell maturation and lymphoid organogenesis, is important for the induction of Th17 cells. NIK-deficient naive CD4 T cells are attenuated in the differentiation to Th17 cells, although they are competent in committing to the other effector lineages. Consistently, NIK knockout mice are resistant to experimental autoimmune encephalomyelitis, a disease model that involves the function of Th17 cells. This phenotype was also detected in Rag2 knockout mice reconstituted with NIK-deficient T cells, confirming a T-cell intrinsic defect. We further show that NIK mediates synergistic activation of STAT3 by T-cell receptor and IL-6 receptor signals. NIK deficiency attenuates activation of STAT3 and induction of STAT3 target genes involved in Th17-commitment program. These findings establish NIK as an important signaling factor that regulates Th17 differentiation and experimental autoimmune encephalitis induction.

| S-EPMC2710918 | biostudies-literature

Obesity Promotes EAE Through IL-6 and CCL-2-Mediated T Cells Infiltration.

Project description:Growing evidence suggests that obesity is associated with the susceptibility and disease severity of multiple sclerosis. The chronic inflammation induced by obesity is believed to contribute to this process. However, the immune mechanisms connecting obesity to the prevalence and pathogenesis of MS are poorly defined. In this study, we show that high fat diet (HFD)-induced obese mice developed an exacerbated EAE as indicated by higher clinical scores and more severe pathological changes in spinal cord than the control mice fed with normal diet (ND), following immunization with myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide. The exacerbation of EAE in HFD mice was associated with enhanced microglial activation and increased expansion of Th1 and Th17 cells. The HFD mice also showed aggravated disease in an adoptive T cell transfer EAE model. Mechanistically, HFD augmented the expression level of IL-6 and CCL-2 both in serum and brain, and blockade of IL-6 and CCL-2 signal ameliorated EAE with reduced T cells infiltration in CNS. Taken together, our results suggest that obesity promotes CNS inflammation in EAE through IL-6 and CCL-2 mediated the inflammatory cells infiltration.

| S-EPMC6718738 | biostudies-literature

Protein kinase CK2 governs the molecular decision between encephalitogenic TH17 cell and Treg cell development.

Project description:T helper 17 (TH17) cells represent a discrete TH cell subset instrumental in the immune response to extracellular bacteria and fungi. However, TH17 cells are considered to be detrimentally involved in autoimmune diseases like multiple sclerosis (MS). In contrast to TH17 cells, regulatory T (Treg) cells were shown to be pivotal in the maintenance of peripheral tolerance. Thus, the balance between Treg cells and TH17 cells determines the severity of a TH17 cell-driven disease and therefore is a promising target for treating autoimmune diseases. However, the molecular mechanisms controlling this balance are still unclear. Here, we report that pharmacological inhibition as well as genetic ablation of the protein kinase CK2 (CK2) ameliorates experimental autoimmune encephalomyelitis (EAE) severity and relapse incidence. Furthermore, CK2 inhibition or genetic ablation prevents TH17 cell development and promotes the generation of Treg cells. Molecularly, inhibition of CK2 leads to reduced STAT3 phosphorylation and strongly attenuated expression of the IL-23 receptor, IL-17, and GM-CSF. Thus, these results identify CK2 as a nodal point in TH17 cell development and suggest this kinase as a potential therapeutic target to treat TH17 cell-driven autoimmune responses.

| S-EPMC5018788 | biostudies-other

Mapping the accumulation of co-infiltrating CNS dendritic cells and encephalitogenic T cells during EAE.

Project description:Evidence from experimental autoimmune encephalomyelitis (EAE) suggests that CNS-infiltrating dendritic cells (DCs) are crucial for restimulation of coinfiltrating T cells. Here we systematically quantified and visualized the distribution and interaction of CNS DCs and T cells during EAE. We report marked periventricular accumulation of DCs and myelin-specific T cells during EAE disease onset prior to accumulation in the spinal cord, indicating that the choroid plexus-CSF axis is a CNS entry portal. Moreover, despite emphasis on spinal cord inflammation in EAE and in correspondence with MS pathology, inflammatory lesions containing interacting DCs and T cells are present in specific brain regions.

| S-EPMC4250311 | biostudies-literature

Neurons promote encephalitogenic CD4+ lymphocyte infiltration in experimental autoimmune encephalomyelitis.

Project description:Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by neuroinflammation, leading to demyelination and axonal degeneration. Neuronal excitotoxity mediated by Ca2+/calmodulin-dependent protein kinase II? (CaMKII?) results in neuronal damage in experimental autoimmune encephalitis (EAE), an animal model of MS. Here, we define a critical role of excitatory neurons in the pathogenesis of CD4+ lymphocyte accumulation in EAE. We silenced the activity of excitatory neurons in a mouse model of targeted EAE using inhibitory designer receptors exclusively activated by designer drugs (DREADD) under a CaMKII? promoter. Neuronal silencing mitigated clinical disease scores in EAE, reduced the expression of c-fos, Tnf?, Ccl2, and Ccr2 mRNAs in targeted EAE lesions, and prevented the migration of CD4+ lymphocytes towards neurons. Ccl2 shRNA treatment of targeted EAE suppressed the migration of CD4+ lymphocytes and alleviated the motor deficits of EAE. Our findings indicate that neuronal activation in EAE promotes the migration of CCR2+ CD4+ lymphocytes and that neuronal silencing with an inhibitory DREADD alleviates clinical and molecular markers of disease. Neuronal CCL2 is thought to be involved in promoting lymphocytes migration.

| S-EPMC7192891 | biostudies-literature

Bordetella pertussis Strain Lacking Pertactin and Pertussis Toxin.

Project description:A Bordetella pertussis strain lacking 2 acellular vaccine immunogens, pertussis toxin and pertactin, was isolated from an unvaccinated infant in New York State in 2013. Comparison with a French strain that was pertussis toxin-deficient, pertactin wild-type showed that the strains carry the same 28-kb deletion in similar genomes.

| S-EPMC4734536 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data