scholarly journals B-cells expressing NgR1 and NgR3 are localized to EAE-induced inflammatory infiltrates and are stimulated by BAFF

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maha M. Bakhuraysah ◽  
Paschalis Theotokis ◽  
Jae Young Lee ◽  
Amani A. Alrehaili ◽  
Pei-Mun Aui ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Cell ◽  
Clinical Score ◽  
Axonal Dystrophy ◽  
Autoimmune Encephalomyelitis ◽  
Inflammatory Infiltrates ◽  
Neurological Progression ◽  
Experimental Autoimmune ◽  
Stimulation Of

AbstractWe have previously reported evidence that Nogo-A activation of Nogo-receptor 1 (NgR1) can drive axonal dystrophy during the neurological progression of experimental autoimmune encephalomyelitis (EAE). However, the B-cell activating factor (BAFF/BlyS) may also be an important ligand of NgR during neuroinflammation. In the current study we define that NgR1 and its homologs may contribute to immune cell signaling during EAE. Meningeal B-cells expressing NgR1 and NgR3 were identified within the lumbosacral spinal cords of ngr1+/+ EAE-induced mice at clinical score 1. Furthermore, increased secretion of immunoglobulins that bound to central nervous system myelin were shown to be generated from isolated NgR1- and NgR3-expressing B-cells of ngr1+/+ EAE-induced mice. In vitro BAFF stimulation of NgR1- and NgR3-expressing B cells, directed them into the cell cycle DNA synthesis phase. However, when we antagonized BAFF signaling by co-incubation with recombinant BAFF-R, NgR1-Fc, or NgR3 peptides, the B cells remained in the G0/G1 phase. The data suggest that B cells express NgR1 and NgR3 during EAE, being localized to infiltrates of the meninges and that their regulation is governed by BAFF signaling.

scholarly journals c-Jun N-Terminal Kinase as a Therapeutic Target in Experimental Autoimmune Encephalomyelitis

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2154
Author(s):  
Maud Bagnoud ◽  
Myriam Briner ◽  
Jana Remlinger ◽  
Ivo Meli ◽  
Sara Schuetz ◽  
...  
Keyword(s):  
Spinal Cord ◽  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cell ◽  
Disease Onset ◽  
Autoimmune Encephalomyelitis ◽  
Necrosis Factor Alpha ◽  
Experimental Autoimmune

c-Jun N-terminal kinase (JNK) is upregulated during multiple sclerosis relapses and at the peak of experimental autoimmune encephalomyelitis (EAE). We aim to investigate the effects of pharmacological pan-JNK inhibition on the course of myelin oligodendrocyte glycoprotein (MOG35-55) EAE disease using in vivo and in vitro experimental models. EAE was induced in female C57BL/6JRj wild type mice using MOG35-55. SP600125 (SP), a reversible adenosine triphosphate competitive pan-JNK inhibitor, was then given orally after disease onset. Positive correlation between SP plasma and brain concentration was observed. Nine, but not three, consecutive days of SP treatment led to a significant dose-dependent decrease of mean cumulative MOG35-55 EAE severity that was associated with increased mRNA expression of interferon gamma (INF-γ) and tumor necrosis factor alpha (TNF-α) in the spinal cord. On a histological level, reduced spinal cord immune cell-infiltration predominantly of CD3+ T cells as well as increased activity of Iba1+ cells were observed in treated animals. In addition, in vitro incubation of murine and human CD3+ T cells with SP resulted in reduced T cell apoptosis and proliferation. In conclusion, our study demonstrates that pharmacological pan-JNK inhibition might be a treatment strategy for autoimmune central nervous system demyelination.

scholarly journals B cell-mediated immunomodulation by S-nitrosoglutathione (GSNO) in experimental autoimmune encephalomyelitis

2020 ◽  
Author(s):  
Judong Kim ◽  
S.M. Touhidul Islam ◽  
Jeseong Won ◽  
Avtar K. Singh ◽  
Inderjit Singh
Keyword(s):  
B Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
B Cell ◽  
Cell Function ◽  
Autoimmune Encephalomyelitis ◽  
Immune Balance ◽  
Eae Model ◽  
Experimental Autoimmune

Abstract Background Experimental autoimmune encephalomyelitis (EAE) is the most commonly used animal model for human multiple sclerosis (MS), a demyelinating autoimmune disease mediated by T and B lymphocytes. The aim of the present study was to investigate the role of S-nitrosoglutathione (GSNO), a physiological nitric oxide carrier molecule, in regulation of effector or regulatory B cell function as IL-6 and IL-10 expressions and thus the potential role of GSNO in targeting B cell-mediated immunopathogenesis in MS using EAE model. Methods To this purpose, the in vivo EAE mouse model, generated by immunization with myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide, or in vitro model of cultured B cells stimulated with lipopolysaccharide or anti-IgM antibody were treated with exogenous GSNO or N6022, an inhibitor of GSNO reductase (GSNOR; GSNO degrading enzyme) to increase endogenous GSNO, and then analyzed for B cell specific IL-6 and IL-10 expression. Results In EAE model, administration of exogenous GSNO or inhibition of endogenous GSNO catabolism by N6022 treatment ameliorated the clinical disease with decreased CNS infiltration of B cells. In addition, GSNO/N6022 treatments increased the number of IL-10+ B cells but decreased the number of IL-6+ B cells in the CNS and spleen. Accordingly, GSNO/N6022 treatments increased the expression of IL-10 while reducing the IL-6 expression in the blood. Similar observations were also made in in vitro B cell culture model where GSNO treatment increased the IL-10+ B cells but decreased the IL-6+ B cells under BCR or TLR4 stimulatory conditions and under CD40 and BAFF co-stimulatory conditions. Accordingly, GSNO treatment increased the B cell production of IL-10 but reduced the IL-6 production under both stimulatory and co-stimulatory conditions. In vitro stimulation and co-stimulation of cultured naïve B cells increased two major distinct B cell populations; CD1dlow CD5high and CD1dhigh CD5high. In both populations, GSNO treatment increased the number of IL-10+ cells but decreased the IL-6+ cells. Conclusion These data document, for the first time, that cellular GSNO homeostasis is a critical target for the regulation of IL-10+ B cells vs. IL-6+ B cells mediated immune balance under auto-immune disease conditions.

scholarly journals The survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lihi Radomir ◽  
Matthias P. Kramer ◽  
Michal Perpinial ◽  
Nofar Schottlender ◽  
Stav Rabani ◽  
...  
Keyword(s):  
B Cells ◽  
Autoimmune Encephalomyelitis ◽  
Regulatory B Cell ◽  
The Central Nervous System ◽  
Factor C ◽  
And Function ◽  
Human And Mouse ◽  
Experimental Autoimmune

AbstractB cells have essential functions in multiple sclerosis and in its mouse model, experimental autoimmune encephalomyelitis, both as drivers and suppressors of the disease. The suppressive effects are driven by a regulatory B cell (Breg) population that functions, primarily but not exclusively, via the production of IL-10. However, the mechanisms modulating IL-10-producing Breg abundance are poorly understood. Here we identify SLAMF5 for controlling IL-10+ Breg maintenance and function. In EAE, the deficiency of SLAMF5 in B cells causes accumulation of IL10+ Bregs in the central nervous system and periphery. Blocking SLAMF5 in vitro induces both human and mouse IL-10-producing Breg cells and increases their survival with a concomitant increase of a transcription factor, c-Maf. Finally, in vivo SLAMF5 blocking in EAE elevates IL-10+ Breg levels and ameliorates disease severity. Our results suggest that SLAMF5 is a negative moderator of IL-10+ Breg cells, and may serve as a therapeutic target in MS and other autoimmune diseases.

Cytokines mediate protective stimulation of glucocorticoid output during autoimmunity: involvement of IL-1

1998 ◽  
Vol 275 (4) ◽  
pp. R1146-R1151 ◽  
Author(s):  
Adriana Del Rey ◽  
Isabel Klusman ◽  
Hugo O. Besedovsky
Keyword(s):  
Basic Protein ◽  
Interleukin 1 ◽  
Endocrine Response ◽  
Autoimmune Encephalomyelitis ◽  
Lewis Rats ◽  
Pituitary Adrenal Axis ◽  
Experimental Autoimmune ◽  
Stimulation Of

Endogenous glucocorticoid levels are increased during experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Although this endocrine response is essential for survival, the mechanism that triggers the stimulation of glucocorticoid output during the disease remains unknown. We report here that 1) after immunization with the encephalitogenic antigen myelin basic protein (MBP), increased blood glucocorticoid levels are not only observed in Lewis rats, but also in PVG rats, which do not develop EAE; 2) immune cells obtained from animals with EAE and stimulated in vitro with MBP produced mediators that increased glucocorticoid levels when administered to naive recipients; and 3) acute in vivo blockade of interleukin-1 (IL-1) receptors inhibited, to a large extent, the increase in corticosterone levels during EAE. These results show that the increase in corticosterone levels after immunization with MBP can be dissociated from the stress of the paralytic attack that characterizes EAE. Furthermore, they indicate that an endocrine response, which is decisive for the prevention or moderation of EAE, is mainly the result of the stimulation of the hypothalamic-pituitary-adrenal axis by cytokines produced during the immune response that induces the autoimmune disease.

scholarly journals TCDD Inhibition of IgG1 Production in Experimental Autoimmune Encephalomyelitis (EAE) and In Vitro

Antibodies ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 4
Author(s):  
Ashleigh J. Nicaise ◽  
Amye McDonald ◽  
Erin Rushing Sears ◽  
Trell Sturgis ◽  
Barbara L. F. Kaplan
Keyword(s):  
B Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Autoimmune Encephalomyelitis ◽  
Aryl Hydrocarbon ◽  
Eae Model ◽  
Igg1 Subclass ◽  
Experimental Autoimmune

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) is a ligand for the aryl hydrocarbon receptor (AhR). TCDD is well-characterized to produce immunotoxicity, including suppression of antibody production. Previously we showed that TCDD inhibited myelin oligodendrocyte glycoprotein (MOG) peptide-specific IgG and attenuated disease in experimental autoimmune encephalomyelitis (EAE) model in mice. Thus, the purpose of this study was to characterize the effects of TCDD on IgG subclasses in EAE and in vitro and assess effects in B cells derived from various tissues. TCDD modestly suppressed intracellular IgG expression in splenocytes (SPLC), but not bone marrow (BM) or lymph node (LN) cells. To further understand TCDD’s effects on IgG, we utilized LPS and LPS + IL-4 in vitro to stimulate IgG3 and IgG1 production, respectively. TCDD preferentially suppressed IgG1+ cell surface expression, especially in SPLC. However, TCDD was able to suppress IgG1 and IgG3 secretion from SPLC and B cells, but not BM cells. Lastly, we revisited the EAE model and determined that TCDD suppressed MOG-specific IgG1 production. Together these data show that the IgG1 subclass of IgG is a sensitive target of suppression by TCDD. Part of the pathophysiology of EAE involves production of pathogenic antibodies that can recruit cytolytic cells to destroy MOG-expressing cells that comprise myelin, so inhibition of IgG1 likely contributes to TCDD’s EAE disease attenuation.

scholarly journals Interleukin-26, preferentially produced by TH17 lymphocytes, regulates CNS barrier function

2020 ◽  
Vol 7 (6) ◽  
pp. e870 ◽  
Author(s):  
Bieke Broux ◽  
Stephanie Zandee ◽  
Elizabeth Gowing ◽  
Marc Charabati ◽  
Marc-André Lécuyer ◽  
...  
Keyword(s):  
Immune Cell ◽  
Postmortem Brain ◽  
Autoimmune Encephalomyelitis ◽  
Th17 Lymphocytes ◽  
Postmortem Brain Tissue ◽  
Human And Mouse ◽  
Experimental Autoimmune

ObjectiveTo investigate the involvement of interleukin (IL)-26 in neuroinflammatory processes in multiple sclerosis (MS), in particular in blood-brain barrier (BBB) integrity.MethodsExpression of IL-26 was measured in serum, CSF, in vitro differentiated T helper (TH) cell subsets, and postmortem brain tissue of patients with MS and controls by ELISA, quantitative PCR, and immunohistochemistry. Primary human and mouse BBB endothelial cells (ECs) were treated with IL-26 in vitro and assessed for BBB integrity. RNA sequencing was performed on IL-26–treated human BBB ECs. Myelin oligodendrocyte glycoprotein35–55 experimental autoimmune encephalomyelitis (EAE) mice were injected IP with IL-26. BBB leakage and immune cell infiltration were assessed in the CNS of these mice using immunohistochemistry and flow cytometry.ResultsIL-26 expression was induced in TH lymphocytes by TH17-inducing cytokines and was upregulated in the blood and CSF of patients with MS. CD4+IL-26+ T lymphocytes were found in perivascular infiltrates in MS brain lesions, and both receptor chains for IL-26 (IL-10R2 and IL-20R1) were detected on BBB ECs in vitro and in situ. In contrast to IL-17 and IL-22, IL-26 promoted integrity and reduced permeability of BBB ECs in vitro and in vivo. In EAE, IL-26 reduced disease severity and proinflammatory lymphocyte infiltration into the CNS, while increasing infiltration of Tregs.ConclusionsOur study demonstrates that although IL-26 is preferentially expressed by TH17 lymphocytes, it promotes BBB integrity in vitro and in vivo and is protective in chronic EAE, highlighting the functional diversity of cytokines produced by TH17 lymphocytes.

scholarly journals Toll-like receptor-9 stimulated plasmacytoid dendritic cell precursors suppress autoimmune neuroinflammation in a murine model of multiple sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hélène Letscher ◽  
Viviane A. Agbogan ◽  
Sarantis Korniotis ◽  
Pauline Gastineau ◽  
Emmanuel Tejerina ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Plasmacytoid Dendritic Cell ◽  
Toll Like Receptor ◽  
Hematopoietic Progenitors ◽  
Autoimmune Encephalomyelitis ◽  
Hematopoietic Precursor ◽  
Therapeutic Properties ◽  
Experimental Autoimmune

AbstractEarly innate education of hematopoietic progenitors within the bone marrow (BM) stably primes them for either trained immunity or instead immunoregulatory functions. We herein demonstrate that in vivo or in vitro activation within the BM via Toll-like receptor-9 generates a population of plasmacytoid dendritic cell (pDC) precursors (CpG-pre-pDCs) that, unlike pDC precursors isolated from PBS-incubated BM (PBS-pre-pDCs), are endowed with the capacity to halt progression of ongoing experimental autoimmune encephalomyelitis. CpG activation enhances the selective migration of pDC precursors to the inflamed spinal cord, induces their immediate production of TGF-β, and after migration, of enhanced levels of IL-27. CpG-pre-pDC derived TGF-β and IL-27 ensure protection at early and late phases of the disease, respectively. Spinal cords of CpG-pre-pDC-protected recipient mice display enhanced percentages of host-derived pDCs expressing TGF-β as well as an accumulation of IL-10 producing B cells and of CD11c+ CD11b+ dendritic cells. These results reveal that pDC precursors are conferred stable therapeutic properties by early innate activation within the BM. They further extend to the pDC lineage promising perspectives for cell therapy of autoimmune diseases with innate activated hematopoietic precursor cells.

scholarly journals Autologous stimulation of human lymphocyte subpopulation.

1975 ◽  
Vol 142 (5) ◽  
pp. 1327-1333 ◽  
Author(s):  
G Opelz ◽  
M Kiuchi ◽  
M Takasugi ◽  
P I Terasaki
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Lymphocytes ◽  
Human Lymphocyte ◽  
Lymphocyte Subpopulation ◽  
High Background ◽  
Background Stimulation ◽  
Most Probable Explanation ◽  
Stimulation Of

The background stimulation universally seen when lymphocytes are cultured in vitro has been shown to be markedly lowered by reducing the proportion of B lymphocytes. B-rich fractions of lymphocytes had extremely high background stimulation. It is concluded that stimulation of T cells, probably by autologous B cells, provides the most probable explanation for the findings described.

scholarly journals IL-9-triggered lncRNA Gm13568 regulates Notch1 in astrocytes through interaction with CBP/P300: contribute to the pathogenesis of experimental autoimmune encephalomyelitis

2021 ◽  
Author(s):  
Xiaomei Liu ◽  
Feng Zhou ◽  
Weixiao Wang ◽  
Guofang Chen ◽  
Qingxiu Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammatory Cytokines ◽  
Lentiviral Vector ◽  
Spinal Injury ◽  
Demyelinating Diseases ◽  
Autoimmune Encephalomyelitis ◽  
Aberrant Expression ◽  
Experimental Autoimmune

Abstract Background Interleukin 9 (IL-9), produced mainly by T helper 9 (Th9) cells, has been recognized as an important regulator in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Astrocytes respond to IL-9 and reactive astrocytes always associate with blood-brain barrier damage, immune cells infiltration and spinal injury in MS and EAE. Several long non-coding RNAs (lncRNAs) with aberrant expression have been identified in the pathogenesis of MS. Here, we examined the effects of lncRNA Gm13568 (a co-upregulated lncRNA both in EAE mice and in mouse primary astrocytes activated by IL-9) on the activation of astrocytes and the process of EAE. Methods In vitro, shRNA-recombinant lentivirus with Glial fibrillary acidic protein (GFAP) promoter were performed to determine the relative gene expression and proinflammatory cytokines production in IL-9 treated-astrocytes using Western blot, real-time PCR and Cytometric bead array, respectively. RIP and ChIP assays were analyzed for the mechanism of lncRNA Gm13568 regulating gene expression. Immunofluorescence assays was performed to measure the protein expression in astrocytes. In vivo, H&E staining and LFB staining were applied to detect the inflammatory cells infiltrations and the medullary sheath damage in spinal cords of EAE mice infected by the recombinant lentivirus. Results were analyzed by one-way ANOVA or student’s t-test, as appropriate. Results Knockdown of the endogenous lncRNA Gm13568 remarkably inhibits the Notch1 expression, astrocytosis and the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) as well as the production of inflammatory cytokines and chemokines (IL-6, TNF-α, IP-10) in IL-9 activated astrocytes. In which, Gm13568 associates with CBP/P300 is enriched in the promoter of Notch1 genes. More importantly, inhibiting Gm13568 with lentiviral vector in astrocytes ameliorates significantly inflammation and demyelination in EAE mice, therefore delaying the EAE process. Conclusions These findings uncover that Gm13568 regulates the production of inflammatory cytokines in active astrocytes and affects the pathogenesis of EAE through the Notch1/STAT3 pathway. LncRNA Gm13568 may be a promising target for treating MS and demyelinating diseases.

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