Determinant Spreading Associated with Demyelination in a Nonhuman Primate Model of Multiple Sclerosis

McFarland, H. F.; Lobito, Adrian A.; Johnson, Martin L.; Nyswaner, Jeffrey T.; Frank, Joseph A.; Palardy, Gregory R.; Tresser, Nancy; Genain, Claude P.; Mueller, John P.; Matis, Louis A.; Lenardo, Michael J.

doi:10.4049/jimmunol.162.4.2384

Cited by 72 publications

(2 citation statements)

References 46 publications

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“…However, individual peptides selected from these proteins have shown only limited success in treating patients with EAE and MS ( 70 ). Nevertheless, our approach enables an individual set of antigens to be selected by the host system during initial disease and in response to potential epitope spreading in more advanced disease ( 37 , 41 , 71 , 72 ).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of antigen-induced reversal of CNS inflammation in experimental demyelinating disease

Binder

et al. 2023

Sci. Adv.

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Autoimmune central nervous system (CNS) demyelinating diseases are a major public health burden and poorly controlled by current immunosuppressants. More precise immunotherapies with higher efficacy and fewer side effects are sought. We investigated the effectiveness and mechanism of an injectable myelin-based antigenic polyprotein MMPt (myelin oligodendrocyte glycoprotein, myelin basic protein and proteolipid protein, truncated). We find that it suppresses mouse experimental autoimmune encephalomyelitis without major side effects. MMPt induces rapid apoptosis of the encephalitogenic T cells and suppresses inflammation in the affected CNS. Intravital microscopy shows that MMPt is taken up by perivascular F4/80 + cells but not conventional antigen-presenting dendritic cells, B cells, or microglia. MMPt-stimulated F4/80 + cells induce reactive T cell immobilization and apoptosis in situ, resulting in reduced infiltration of inflammatory cells and chemokine production. Our study reveals alternative mechanisms that explain how cognate antigen suppresses CNS inflammation and may be applicable for effectively and safely treating demyelinating diseases.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of antigen-induced reversal of CNS inflammation in experimental demyelinating disease

Binder

et al. 2023

Sci. Adv.

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“…A highly immunogenic myelin protein is myelin oligodendrocyte glycoprotein (MOG), which can cause chronic EAE in susceptible animals by eliciting humoral and cellular immune responses. 4 In comparison to other rodent EAE models, MOG-induced EAE is considered to be more like MS. [5][6][7] MOG is a promising candidate autoantigen in MS, 8,9 as it reveals various autoantigens-like properties, including (a) molecular mimicry, such as sharing of epitope with common infectious agents, 10 (b) determinant spreading, 11 (c) complement binding. 12 Therefore, MOG-induced EAE is a useful model for studying pathogenetic mechanisms and treatment strategies related to MS. For this reason it has been chosen for the gene expression profiling studies of EAE.…”

Section: Introductionmentioning

confidence: 99%

mRNA expression profile reveals differentially expressed genes in splenocytes of experimental autoimmune encephalomyelitis model

Mehmood

Song

et al. 2023

Int J Experimental Path

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Experimental autoimmune encephalomyelitis (EAE) is a mouse model that can be used to investigate aetiology, pathogenesis, and treatment approaches for multiple sclerosis (MS). A novel integrated bioinformatics approach was used to understand the involvement of differentially expressed genes (DEGs) in the spleen of EAE mice through data mining of existing microarray and RNA‐seq datasets. We screened differentially expressed mRNAs using mRNA expression profile data of EAE spleens taken from Gene Expression Omnibus (GEO). Functional and pathway enrichment analyses of DEGs were performed by Database for Annotation, Visualization, and Integrated Discovery (DAVID). Subsequently, the DEGs‐encoded protein–protein interaction (PPI) network was constructed. The 784 DEGs in GSE99300 A.SW PP‐EAE mice spleen mRNA profiles, 859 DEGs in GSE151701 EAE mice spleen mRNA profiles, and 646 DEGs in GSE99300 SJL/J PP‐EAE mice spleen mRNA profiles were explored. Functional enrichment of 55 common DEGs among 3 sub‐datasets revealed several immune‐related terms, such as neutrophil extravasation, leucocyte migration, antimicrobial humoral immune response mediated by an antimicrobial peptide, toll‐like receptor 4 bindings, IL‐17 signalling pathway, and TGF‐beta signalling pathway. In the screening of 10 hub genes, including MPO, ELANE, CTSG, LTF, LCN2, SELP, CAMP, S100A9, ITGA2B, and PRTN3, and in choosing and validating the 5 DEGs, including ANK1, MBOAT2, SLC25A21, SLC43A1, and SOX6, the results showed that SLC43A1 and SOX6 were significantly decreased in EAE mice spleen. Thus this study offers a list of genes expressed in the spleen that might play a key role in the pathogenesis of EAE.

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Frequency, heterogeneity and encephalitogenicity of T cells specific for myelin oligodendrocyte glycoprotein in naive outbred primates

et al. 2001

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Auto‐reactive T cells present in healthy subjects remain in a state of unresponsiveness, but may trigger autoimmunity under various situations. Although myelin oligodendrocyte glycoprotein (MOG) is a potential target antigen in multiple sclerosis (MS), MOG‐reactive T cell responses are present in the blood of both healthy subjects and MS‐affected individuals. To investigate the disease‐inducing potential and regulation of these autoreactive T cells in healthy outbred populations, we have characterized MOG‐reactive T cell clones obtained by limiting dilution from peripheral blood ofunimmunized C. jacchus marmosets. We report an extraordinarily high prevalence of circulating MOG‐reactive T cells in these naive animals (2.6 ± 1.4 / 105 PBMC), and a broadly diverse repertoire of epitope recognition encompassing at least three regions within the extracellular domain of MOG. Adoptive transfer of a MOG21 – 40‐specific T cell clone resulted in mild clinical experimental allergic encephalomyelitis, characterized pathologically by rare foci of inflammation and minimal demyelination. We conclude that MOG‐reactive T cells are present in healthy primates at a highly prevalent frequency, and are potentially capable of triggering central nervous system autoimmunity. Expansion of these autoreactive T cells must be tightly controlled to maintain immune homeostasis in healthy individuals.

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Determinant Spreading Associated with Demyelination in a Nonhuman Primate Model of Multiple Sclerosis

Cited by 72 publications

References 46 publications

Mechanisms of antigen-induced reversal of CNS inflammation in experimental demyelinating disease

Mechanisms of antigen-induced reversal of CNS inflammation in experimental demyelinating disease

mRNA expression profile reveals differentially expressed genes in splenocytes of experimental autoimmune encephalomyelitis model

Frequency, heterogeneity and encephalitogenicity of T cells specific for myelin oligodendrocyte glycoprotein in naive outbred primates

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