The primate autoimmune encephalomyelitis model; a bridge between mouse and man

Hart, Bert A. ’t; Kooyk, Yvette van; Geurts, Jeroen J. G.; Gran, Bruno

doi:10.1002/acn3.194

Cited by 48 publications

(62 citation statements)

References 92 publications

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“…12, 45) show that LCV-infected B cells have a central pathogenic role in the activation of highly pathogenic MHC-E-restricted effector memory cytotoxic T cells that, upon activation with the MOG34-56 peptide (core epitope [40][41][42][43][44][45][46][47][48], can elicit MS-like pathology and disease. Notably, similar autoaggressive CTLs were found in MS lesions, where they seemed to be engaged in cytotoxic interactions with HLA-E + oligodendrocytes (5).…”

Section: Discussionmentioning

confidence: 99%

“…Although CatG of marmosets has a mouse-like narrow specificity for aromatic (chymotryptic) cleavage sites (Trp, Phe, Tyr), a double mutation in the specificity-determining residues (Ala-189-Ser and Glu-226-Ala) broadens the activity of rhesus monkey and human CatG to basic (tryptic) cleavage sites (e.g., Arg and Lys) (42). To test the proteolytic degradation of the pathogenically dominant Mm-MOG34-56 peptide we used the shorter peptide MOG35-51 to avoid interference of the Arg residue at position 52, which is outside the epitope of interest (residues [40][41][42][43][44][45][46][47][48]. The reported in vitro data show that native Mm-MOG35-51 peptide is rapidly degraded in cellfree lysates of noninfected and LCV infected B cells of rhesus monkeys as well as in LCV-infected B cells of marmosets.…”

Section: Prolongation Of the Half-life Of The Ctl Epitopementioning

confidence: 99%

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Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

Jagessar

Holtman

Hofman

et al. 2016

The Journal of Immunology

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EBV is the major infectious environmental risk factor for multiple sclerosis (MS), but the underlying mechanisms remain obscure. Patient studies do not allow manipulation in vivo. We used the experimental autoimmune encephalomyelitis (EAE) models in the common marmoset and rhesus monkey to model the association of EBV and MS. We report that B cells infected with EBV-related lymphocryptovirus (LCV) are requisite APCs for MHC-E–restricted autoaggressive effector memory CTLs specific for the immunodominant epitope 40-48 of myelin oligodendrocyte glycoprotein (MOG). These T cells drive the EAE pathogenesis to irreversible neurologic deficit. The aim of this study was to determine why LCV infection is important for this pathogenic role of B cells. Transcriptome comparison of LCV-infected B cells and CD20+ spleen cells from rhesus monkeys shows increased expression of genes encoding elements of the Ag cross-presentation machinery (i.e., of proteasome maturation protein and immunoproteasome subunits) and enhanced expression of MHC-E and of costimulatory molecules (CD70 and CD80, but not CD86). It was also shown that altered expression of endolysosomal proteases (cathepsins) mitigates the fast endolysosomal degradation of the MOG40–48 core epitope. Finally, LCV infection also induced expression of LC3-II+ cytosolic structures resembling autophagosomes, which seem to form an intracellular compartment where the MOG40–48 epitope is protected against proteolytic degradation by the endolysosomal serine protease cathepsin G. In conclusion, LCV infection induces a variety of changes in B cells that underlies the conversion of destructive processing of the immunodominant MOG40–48 epitope into productive processing and cross-presentation to strongly autoaggressive CTLs.

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Section: Discussionmentioning

confidence: 99%

Section: Prolongation Of the Half-life Of The Ctl Epitopementioning

confidence: 99%

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

Jagessar

Holtman

Hofman

et al. 2016

The Journal of Immunology

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“…The second model, induced with recombinant human myelin oligodendrocite glycoprotein (rhMOG) gives generally fewer but larger demyelinated lesions. Although the rhMOG model recapitulates many of the pathological and immunological aspects of human MS (tHart et al, 2015), in our experience the disease in this model appears more aggressive, sometimes hemorrhagic, and therefore less close to MS than the former one ).…”

Section: Eae In the Common Marmosetmentioning

confidence: 99%

“…As it happens in humans, the development of the marmoset's immune system is influenced by environmental pathogens and chronic latent infections (tHart et al, 2015;Leibovitch et al, 2013). It has been hypothesized that through a mechanism of brain-pathogen antigen cross-recognition and/or direct cellular infection, these environmental pathogens play an important role in the development of autoimmunity both in MS and in EAE (Berer et al, 2011).…”

Section: Eae In the Common Marmosetmentioning

confidence: 99%

“…Both in MS and marmoset EAE (Jordan et al, 1999) new inflammatory lesions detected from Gd based MRI, are mainly associated to extensive demyelination with relative sparing of the axons, whereas older lesions are characterized by markedly reduced inflammatory activity associated to various degree of axonal damage (Hauser, 2015;Jordan et al, 1999;Hart et al, 1998). Both in MS and marmoset EAE inflammatory lesions not only T lymphocytes but also B cells are found (tHart et al, 2015;Maggi et al, 2014a). In the animal model Genain et al showed that antibodies and presumably B cells are required for the development of demyelination Genain et al, 1995).…”

Section: Comparison Of Mri Findings With Histopathologymentioning

confidence: 99%

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Magnetic resonance imaging of experimental autoimmune encephalomyelitis in the common marmoset

Maggi

Sati

Massacesi

2017

Journal of Neuroimmunology

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Magnetic resonance imaging (MRI) is an invaluable tool for the diagnosis and monitoring of patients with multiple sclerosis (MS) as well as for the study of the disease pathophysiology. Because of its strong clinical, radiological and histopathological similarities with the human disease, experimental autoimmune encephalomyelitis (EAE) in the common marmoset has been studied more intensively over the past several years. Here, we review the current knowledge on MRI in the marmoset EAE, and we outline the physiopathological significance and translational values of these studies with respect to MS. Accumulating evidences suggest that the application of conventional, as well as non-conventional, MRI techniques in the marmoset EAE is a promising approach to elucidate the pathological processes underlying the development of inflammatory demyelinated lesions in the central nervous system, potentially improving the identification and development of new therapeutics.

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Mechanistic underpinning of an inside–out concept for autoimmunity in multiple sclerosis

Hart

Luchicchi

Schenk

et al. 2021

Ann Clin Transl Neurol

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The neuroinflammatory disease multiple sclerosis is driven by autoimmune pathology in the central nervous system. However, the trigger of the autoimmune pathogenic process is unknown. MS models in immunologically naïve, specific‐pathogen‐free bred rodents support an exogenous trigger, such as an infection. The validity of this outside–in pathogenic concept for MS has been frequently challenged by the difficulty to translate pathogenic concepts developed in these models into effective therapies for the MS patient. Studies in well‐validated non‐human primate multiple sclerosis models where, just like in humans, the autoimmune pathogenic process develops from an experienced immune system trained by prior infections, rather support an endogenous trigger. Data reviewed here corroborate the validity of this inside–out pathogenic concept for multiple sclerosis. They also provide a plausible sequence of events reminiscent of Wilkin’s primary lesion theory: (i) that autoimmunity is a physiological response of the immune system against excess antigen turnover in diseased tissue (the primary lesion) and (ii) that individuals developing autoimmune disease are (genetically predisposed) high responders against critical antigens. Data obtained in multiple sclerosis brains reveal the presence in normally appearing white matter of myelinated axons where myelin sheaths have locally dissociated from their enwrapped axon (i.e., blistering). The ensuing disintegration of axon–myelin units potentially causes the excess systemic release of post‐translationally modified myelin. Data obtained in a unique primate multiple sclerosis model revealed a core pathogenic role of T cells present in the normal repertoire, which hyper‐react to post‐translationally modified (citrullinated) myelin–oligodendrocyte glycoprotein and evoke clinical and pathological aspects of multiple sclerosis.

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The primate autoimmune encephalomyelitis model; a bridge between mouse and man

Cited by 48 publications

References 92 publications

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

Magnetic resonance imaging of experimental autoimmune encephalomyelitis in the common marmoset

Mechanistic underpinning of an inside–out concept for autoimmunity in multiple sclerosis

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