Faculty Opinions recommendation of Brain leukocyte infiltration initiated by peripheral inflammation or experimental autoimmune encephalomyelitis occurs through pathways connected to the CSF-filled compartments of the forebrain and midbrain.

Experimental autoimmune encephalomyelitis (EAE) is considered a useful animal model for preclinical development of drugs to treat human multiple sclerosis. The relationship between clinical disease signs and leukocyte infiltration into the lower spinal cord was studied in EAE in order to assess analytical and statistical methods for evaluating drug candidates. As expected, the degree of clinical disease was correlated with the amount of leukocyte infiltration into the lower spinal cord. Additionally, we were able to distinguish patterns of clinical signs and leukocyte infiltration for classes of recurring-remitting and progressive forms of the disease. The distributions of leukocyte infiltration sites correspond to negative binomial distributions, and the parameters calculated from the respective distributions differ significantly among disease classes. We determined the sensitivity of histological measures of the leukocyte infiltration and calculated the magnitude of differences required in order to observe statistically significant changes in leukocyte infiltration. Using immunohistochemistry to assess cell surface markers of leukocytes in the lower spinal cord, we measured the infiltration of CD4+ and CD8+ lymphocytes and cells of the macrophage/microglial lineage stained with the monoclonal antibody, F4/80. Treatment with an anti-4 integrin monoclonal antibody, PS/2, served as an indicator of how we may expect to measure the effects of new pharmaceutical agents tested using our particular model of EAE. PS/2 treatment affected clinical signs of disease only when administered very early in the time course of the disease, despite a marked statistically significant decline in CD4+ cells regardless of when the PS/2 was administered. The analytical and statistical techniques applied here may be used to design efficient and sensitive assays for the evaluation of new drugs that may prove useful in the treatment of multiple sclerosis.

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Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis

Journal of Experimental Medicine ◽

10.1084/jem.20051342 ◽

2006 ◽

Vol 203 (4) ◽

pp. 1007-1019 ◽

Cited By ~ 354

Author(s):

Smriti Agrawal ◽

Per Anderson ◽

Madeleine Durbeej ◽

Nico van Rooijen ◽

Fredrik Ivars ◽

...

Keyword(s):

Endothelial Cell ◽

Basement Membrane ◽

Experimental Autoimmune Encephalomyelitis ◽

Cell Monolayer ◽

Cerebral Vessels ◽

Leukocyte Infiltration ◽

Endothelial Cell Monolayer ◽

Autoimmune Encephalomyelitis ◽

Astrocyte Endfeet ◽

Experimental Autoimmune

The endothelial cell monolayer of cerebral vessels and its basement membrane (BM) are ensheathed by the astrocyte endfeet, the leptomeningeal cells, and their associated parenchymal BM, all of which contribute to establishment of the blood–brain barrier (BBB). As a consequence of this unique structure, leukocyte penetration of cerebral vessels is a multistep event. In mouse experimental autoimmune encephalomyelitis (EAE), a widely used central nervous system inflammatory model, leukocytes first penetrate the endothelial cell monolayer and underlying BM using integrin β1-mediated processes, but mechanisms used to penetrate the second barrier defined by the parenchymal BM and glia limitans remain uninvestigated. We show here that macrophage-derived gelatinase (matrix metalloproteinase [MMP]-2 and MMP-9) activity is crucial for leukocyte penetration of the parenchymal BM. Dystroglycan, a transmembrane receptor that anchors astrocyte endfeet to the parenchymal BM via high affinity interactions with laminins 1 and 2, perlecan and agrin, is identified as a specific substrate of MMP-2 and MMP-9. Ablation of both MMP-2 and MMP-9 in double knockout mice confers resistance to EAE by inhibiting dystroglycan cleavage and preventing leukocyte infiltration. This is the first description of selective in situ proteolytic damage of a BBB-specific molecule at sites of leukocyte infiltration.

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Anti-MOG autoantibodies pathogenicity in children and macaques demyelinating diseases

Journal of Neuroinflammation ◽

10.1186/s12974-019-1637-7 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 3

Author(s):

Che Serguera ◽

Lev Stimmer ◽

Claire-Maelle Fovet ◽

Philippe Horellou ◽

Vanessa Contreras ◽

...

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

Targeted Therapies ◽

Myelin Oligodendrocyte Glycoprotein ◽

Brain Lesions ◽

Demyelinating Diseases ◽

Leukocyte Infiltration ◽

Phagocytic Cells ◽

Autoimmune Encephalomyelitis ◽

Cynomolgus Macaques ◽

Experimental Autoimmune

Abstract Background Autoantibodies against myelin oligodendrocyte glycoprotein (anti-MOG-Abs) occur in a majority of children with acquired demyelinating syndromes (ADS) and physiopathology is still under investigation. As cynomolgus macaques immunized with rhMOG, all develop an experimental autoimmune encephalomyelitis (EAE), we assessed relatedness between anti-MOG-Abs associated diseases in both species. Methods The study includes 27 children followed for ADS and nine macaques with rhMOG-induced EAE. MRI lesions, cytokines in blood, and CSF at onset of ADS or EAE, as well as histopathological features of brain lesions were compared. Results Twelve children with anti-MOG-Abs ADS (ADS MOG+) and nine macaques with EAE, presented increased IL-6 and G-CSF in the CSF, whereas no such signature was found in 15 ADS MOG−. Furthermore, IgG and C1q were associated to myelin and phagocytic cells in brains with EAE (n = 8) and in biopsies of ADS MOG+ (n = 2) but not ADS MOG− children (n = 1). Macaque brains also revealed prephagocytic lesions with IgG and C1q depositions but no leukocyte infiltration. Conclusions Children with ADS MOG+ and macaques with EAE induced with rhMOG, present a similar cytokine signature in the CSF and a comparable aspect of brain lesions indicating analogous pathophysiological processes. In EAE, prephagocytic lesions points at IgG as an initial effector of myelin attack. These results support the pertinence of modeling ADS MOG+ in non-human primates to apprehend the natural development of anti-MOG-associated disease, find markers of evolution, and above all explore the efficacy of targeted therapies to test primate-restricted molecules.

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