Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

Dimethyl fumarate (DMF) (BG-12, Tecfidera) is a fumaric acid ester (FAE) that was advanced as a multiple sclerosis (MS) therapy largely for potential neuroprotection as it was recognized that FAEs are capable of activating the antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, DMF treatment in randomized controlled MS trials was associated with marked reductions in relapse rate and development of active brain MRI lesions, measures considered to reflect CNS inflammation. Here, we investigated the antiinflammatory contribution of Nrf2 in DMF treatment of the MS model, experimental autoimmune encephalomyelitis (EAE). C57BL/6 wild-type (WT) and Nrf2-deficient (Nrf2−/−) mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35–55 (p35–55) for EAE induction and treated with oral DMF or vehicle daily. DMF protected WT and Nrf2−/− mice equally well from development of clinical and histologic EAE. The beneficial effect of DMF treatment in Nrf2−/− and WT mice was accompanied by reduced frequencies of IFN-γ and IL-17–producing CD4+ cells and induction of antiinflammatory M2 (type II) monocytes. DMF also modulated B-cell MHC II expression and reduced the incidence of clinical disease in a B-cell–dependent model of spontaneous CNS autoimmunity. Our observations that oral DMF treatment promoted immune modulation and provided equal clinical benefit in acute EAE in Nrf2−/− and WT mice, suggest that the antiinflammatory activity of DMF in treatment of MS patients may occur through alternative pathways, independent of Nrf2.

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MHC class II–dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies

Journal of Experimental Medicine ◽

10.1084/jem.20130699 ◽

2013 ◽

Vol 210 (13) ◽

pp. 2921-2937 ◽

Cited By ~ 195

Author(s):

Nicolas Molnarfi ◽

Ulf Schulze-Topphoff ◽

Martin S. Weber ◽

Juan C. Patarroyo ◽

Thomas Prod’homme ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Mhc Class Ii ◽

Cell Receptor ◽

Autoimmune Encephalomyelitis ◽

Specific Antibodies ◽

Mhc Ii ◽

Cns Autoimmunity ◽

Antigen Presenting ◽

Experimental Autoimmune

Whether B cells serve as antigen-presenting cells (APCs) for activation of pathogenic T cells in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE) is unclear. To evaluate their role as APCs, we engineered mice selectively deficient in MHC II on B cells (B–MHC II−/−), and to distinguish this function from antibody production, we created transgenic (Tg) mice that express the myelin oligodendrocyte glycoprotein (MOG)–specific B cell receptor (BCR; IgHMOG-mem) but cannot secrete antibodies. B–MHC II−/− mice were resistant to EAE induced by recombinant human MOG (rhMOG), a T cell– and B cell–dependent autoantigen, and exhibited diminished Th1 and Th17 responses, suggesting a role for B cell APC function. In comparison, selective B cell IL-6 deficiency reduced EAE susceptibility and Th17 responses alone. Administration of MOG-specific antibodies only partially restored EAE susceptibility in B–MHC II−/− mice. In the absence of antibodies, IgHMOG-mem mice, but not mice expressing a BCR of irrelevant specificity, were fully susceptible to acute rhMOG-induced EAE, also demonstrating the importance of BCR specificity. Spontaneous opticospinal EAE and meningeal follicle–like structures were observed in IgHMOG-mem mice crossed with MOG-specific TCR Tg mice. Thus, B cells provide a critical cellular function in pathogenesis of central nervous system autoimmunity independent of their humoral involvement, findings which may be relevant to B cell–targeted therapies.

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Experimental Autoimmune Encephalomyelitis Induction in Genetically B Cell–deficient Mice

Journal of Experimental Medicine ◽

10.1084/jem.184.6.2271 ◽

1996 ◽

Vol 184 (6) ◽

pp. 2271-2278 ◽

Cited By ~ 435

Author(s):

Susan D. Wolf ◽

Bonnie N. Dittel ◽

Fridrika Hardardottir ◽

Charles A. Janeway

Keyword(s):

T Cells ◽

B Cells ◽

Experimental Autoimmune Encephalomyelitis ◽

B Cell ◽

Immune Modulation ◽

Disease Onset ◽

Central Nervous System Disease ◽

Autoimmune Encephalomyelitis ◽

Deficient Mice ◽

Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is an animal model for autoimmune central nervous system disease mediated by CD4 T cells. To examine the role of B cells in the induction of EAE, we used B10.PL (I-Au) mice rendered deficient in B cells by deletion of their μ chain transmembrane region (B10.PLμMT). By immunizing B10.PL and B10.PLμMT mice with the NH-terminal myelin basic protein encephalitogenic peptide Ac1-11, we observed no difference in the onset or severity of disease in the absence of mature B cells. There was, however, a greater variation in disease onset, severity, and especially of recovery in the B cell–deficient mice compared to controls. B10.PLμMT mice rarely returned to normal in the absence of B cells. Taken together, our data suggest that B cells do not play a role in the activation of encephalitogenic T cells, but may contribute to the immune modulation of acute EAE. The mechanisms to explain these effects are discussed.

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Selected Clostridia Strains from The Human Microbiota and their Metabolite, Butyrate, Improve Experimental Autoimmune Encephalomyelitis

Neurotherapeutics ◽

10.1007/s13311-021-01016-7 ◽

2021 ◽

Author(s):

Laura Calvo-Barreiro ◽

Herena Eixarch ◽

Thais Cornejo ◽

Carme Costa ◽

Mireia Castillo ◽

...

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

Therapeutic Effect ◽

Clinical Effect ◽

Short Chain Fatty Acid ◽

Human Gut ◽

Autoimmune Encephalomyelitis ◽

Gut Dysbiosis ◽

Cns Autoimmunity ◽

The Central Nervous System ◽

Experimental Autoimmune

SummaryGut microbiome studies in multiple sclerosis (MS) patients are unravelling some consistent but modest patterns of gut dysbiosis. Among these, a significant decrease of Clostridia cluster IV and XIVa has been reported. In the present study, we investigated the therapeutic effect of a previously selected mixture of human gut-derived 17 Clostridia strains, which belong to Clostridia clusters IV, XIVa, and XVIII, on the clinical outcome of experimental autoimmune encephalomyelitis (EAE). The observed clinical improvement was related to lower demyelination and astrocyte reactivity as well as a tendency to lower microglia reactivity/infiltrating macrophages and axonal damage in the central nervous system (CNS), and to an enhanced immunoregulatory response of regulatory T cells in the periphery. Transcriptome studies also highlighted increased antiinflammatory responses related to interferon beta in the periphery and lower immune responses in the CNS. Since Clostridia-treated mice were found to present higher levels of the immunomodulatory short-chain fatty acid (SCFA) butyrate in the serum, we studied if this clinical effect could be reproduced by butyrate administration alone. Further EAE experiments proved its preventive but slight therapeutic impact on CNS autoimmunity. Thus, this smaller therapeutic effect highlighted that the Clostridia-induced clinical effect was not exclusively related to the SCFA and could not be reproduced by butyrate administration alone. Although it is still unknown if these Clostridia strains will have the same effect on MS patients, gut dysbiosis in MS patients could be partially rebalanced by these commensal bacteria and their immunoregulatory properties could have a beneficial effect on MS clinical course.

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The complement system contributes to the pathology of experimental autoimmune encephalomyelitis by triggering demyelination and modifying the antigen-specific T and B cell response

Clinical Immunology ◽

10.1016/j.clim.2012.12.007 ◽

2013 ◽

Vol 146 (3) ◽

pp. 155-164 ◽

Cited By ~ 17

Author(s):

Lorenz C. Hundgeburth ◽

Marie Wunsch ◽

Damiano Rovituso ◽

Mascha S. Recks ◽

Klaus Addicks ◽

...

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

B Cell ◽

Complement System ◽

Cell Response ◽

Autoimmune Encephalomyelitis ◽

The Complement System ◽

Experimental Autoimmune ◽

B Cell Response

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Inhibitory Effect of Matrine on Blood-Brain Barrier Disruption for the Treatment of Experimental Autoimmune Encephalomyelitis

Mediators of Inflammation ◽

10.1155/2013/736085 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 20

Author(s):

Su Zhang ◽

Quan-Cheng Kan ◽

Yuming Xu ◽

Guang-Xian Zhang ◽

Lin Zhu

Keyword(s):

Basement Membrane ◽

Experimental Autoimmune Encephalomyelitis ◽

Blood Brain Barrier ◽

Adaptor Protein ◽

Brain Barrier ◽

Autoimmune Encephalomyelitis ◽

Novel Therapy ◽

Cns Inflammation ◽

Blood Brain ◽

Experimental Autoimmune

Dysfunction of the blood-brain barrier (BBB) is a primary characteristic of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to suppress clinical EAE and CNS inflammation. However, whether this effect of MAT is through protecting the integrity and function of the BBB is not known. In the present study, we show that MAT treatment had a therapeutic effect comparable to dexamethasone (DEX) in EAE rats, with reduced Evans Blue extravasation, increased expression of collagen IV, the major component of the basement membrane, and the structure of tight junction (TJ) adaptor protein Zonula occludens-1 (ZO-1). Furthermore, MAT treatment attenuated expression of matrix metalloproteinase-9 and -2 (MMP-9/-2), while it increased the expression of tissue inhibitors of metalloproteinase-1 and -2 (TIMP-1/-2). Our findings demonstrate that MAT reduces BBB leakage by strengthening basement membrane, inhibiting activities of MMP-2 and -9, and upregulating their inhibitors. Taken together, our results identify a novel mechanism underlying the effect of MAT, a natural compound that could be a novel therapy for MS.

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Primary diffuse large B cell lymphoma of the optic chiasm in an immunocompetent patient

BMJ Case Reports ◽

10.1136/bcr-2021-243307 ◽

2021 ◽

Vol 14 (7) ◽

pp. e243307

Author(s):

Orlando De Jesus ◽

Christian Rios-Vicil ◽

Frances M Gómez-González ◽

Román Vélez

Keyword(s):

B Cell ◽

Clinical Course ◽

Cell Lymphoma ◽

Brain Mri ◽

B Cell Lymphoma ◽

Optic Chiasm ◽

Immunocompetent Patient ◽

Primary Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

Primary lymphoma of the visual pathway is rare, especially at the chiasm. Very few cases have been reported. The lesion is frequently confused with an optic–hypothalamic glioma. A 55-year-old man was found disoriented at his home by a friend and evaluated with a brain MRI which demonstrated an expansile mass located at the optic chiasm and hypothalamus level. The principal differential was a high-grade hypothalamic glioma due to the contrast enhancement. A biopsy of the chiasmal lesion was performed. Histological diagnosis of the lesion was compatible with a diffuse large B cell lymphoma. He was started on methotrexate and rituximab; however, his clinical course kept deteriorating, and he died 64 days after his presentation. All prior cases of primary lymphoma of the chiasm are reviewed.

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Modulation of experimental autoimmune encephalomyelitis through colonisation of the gut with Escherichia coli

Beneficial Microbes ◽

10.3920/bm2020.0012 ◽

2020 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

J.E. Libbey ◽

J.M.S. Sanchez ◽

B.A. Fleming ◽

D.J. Doty ◽

A.B. DePaula-Silva ◽

...

Keyword(s):

Escherichia Coli ◽

Experimental Autoimmune Encephalomyelitis ◽

Gut Microbiota ◽

Disease Onset ◽

Probiotic Bacterium ◽

Coli Strain ◽

Preclinical Model ◽

Autoimmune Encephalomyelitis ◽

Cns Inflammation ◽

Experimental Autoimmune

Multiple sclerosis (MS) is a neuro-inflammatory autoimmune disease of the central nervous system (CNS) that affects young adults. It is characterised by the development of demyelinating lesions and inflammation within the CNS. Although the causes of MS are still elusive, recent work using patient samples and experimental animal models has demonstrated a strong relationship between the gut microbiota and its contribution to CNS inflammation and MS. While there is no cure for MS, alteration of the gut microbiota composition through the use of probiotics is a very promising treatment. However, while most recent works have focused on the use of probiotics to modify pre-existing disease, little is known about its role in protecting from the establishment of MS. In this study, we determined whether colonisation with the probiotic bacterium Escherichia coli strain Nissle 1917 (EcN) could be used as a prophylactic strategy to prevent or alter the development of experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS. We found that double gavage (two doses) of EcN before induction of EAE delayed disease onset and decreased disease severity. We also found that EcN-treated mice had decreased amounts of perivascular cuffing, CD4+ T cell infiltration into the CNS, together with significantly decreased absolute numbers of Th1 cells, and reduced activation of microglia. Although further studies are necessary to comprehend the exact protective mechanisms induced, our study supports a promising use of EcN as a probiotic for the prevention of MS.

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Dimethyl fumarate as a first- vs second-line therapy in MS

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000508 ◽

2018 ◽

Vol 5 (6) ◽

pp. e508 ◽

Cited By ~ 8

Author(s):

Elsebeth Staun-Ram ◽

Eiman Najjar ◽

Anat Volkowich ◽

Ariel Miller

Keyword(s):

B Cells ◽

B Cell ◽

Cell Activation ◽

Plasma Cells ◽

Dimethyl Fumarate ◽

Functional Markers ◽

Immunomodulatory Effects ◽

Immune Profile ◽

Line Therapy ◽

B Cell Subsets

ObjectiveTo elucidate the immunomodulatory effects of dimethyl fumarate (DMF) on B cells in patients with relapsing MS receiving DMF as a “1st-line” vs “2nd-line” therapy.MethodsB cells were isolated from 43 patients with MS at baseline and after 15-week DMF therapy. Phenotype and functional markers and cytokine profile were assessed by flow cytometry. Analysis included clinical and MRI parameters recorded during a 1-year follow-up.Results1st-line and 2nd-line patients presented several differences in their baseline immune profile, which corresponded with differences in their immunologic response to DMF treatment. DMF reduced the proportions of B cells and CD8 T cells whereas increased monocytes. DMF reduced memory B cells, including plasma cells in 2nd-line patients only, whereas strongly increased transitional B cells. Several IL10+ B-cell subsets and TGFβ+ B cells were increased. Proinflammatory LTα+ and TNFα+ B cells were reduced, while IL4+ B cells elevated, whereas IFNγ+ B cells showed opposite effects in 1st-line and 2nd-line patients. HLA and ICAM-1 expression was increased, but % CD86+ B cells reduced. The expression of B-cell activating factor receptor and the proportion of activated CD69 B cells were increased.ConclusionsDMF is associated with increased transitional and IL10+ and TGFβ+ regulatory B cells and a shift toward a more anti-inflammatory immune profile. Cell activation with reduced costimulatory capacity may induce immune hyporesponsiveness. Carryover effects of preceding therapies in 2nd-line patients and the stage of disease influence the immune profile of the patients and the immunomodulatory effects of DMF.

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