Appearance of claudin-5+ leukocyte subtypes in the blood and CNS during progression of EAE

Abstract Background Tight junctions (TJs) are membrane specializations characteristic of barrier-forming membranes, which function to seal the aqueous pathway between endothelial cells or epithelial cells and, thereby, obstruct intercellular solute and cellular movement. However, previous work from our laboratory found that claudin-5 (CLN-5), a TJ protein prominent at the blood–brain barrier (BBB), was also detected, ectopically, on leukocytes (CLN-5+) in the blood and central nervous system (CNS) of mice with experimental autoimmune encephalomyelitis (EAE), a neuroinflammatory, demyelinating disease that is a model for multiple sclerosis. CLN-5 was further shown to be transferred from endothelial cells to circulating leukocytes during disease, prompting consideration this action is coupled to leukocyte transendothelial migration (TEM) into the CNS by fostering transient interactions between corresponding leukocyte and endothelial junctional proteins at the BBB. Methods To begin clarifying the significance of CLN-5+ leukocytes, flow cytometry was used to determine their appearance in the blood and CNS during EAE. Results Flow cytometric analysis revealed CLN-5+ populations among CD4 and CD8 T cells, B cells, monocytes and neutrophils, and these appeared with varying kinetics and to different extents in both blood and CNS. CLN-5 levels on circulating T cells further correlated highly with activation state. And, the percentage of CLN-5+ cells among each of the subtypes analyzed was considerably higher in CNS tissue than in blood, consistent with the interpretation that CLN-5+ leukocytes gain preferred access to the CNS. Conclusion Several leukocyte subtypes variably acquire CLN-5 in blood before they enter the CNS, an event that may represent a novel mechanism to guide leukocytes to sites for paracellular diapedesis across the BBB.

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Appearance of Claudin-5+ Leukocyte Subtypes in the Blood and CNS During Progression of EAE

10.21203/rs.3.rs-595470/v1 ◽

2021 ◽

Author(s):

Dylan Krajewski ◽

Debayon Paul ◽

Shujun Ge ◽

Evan Jellison ◽

Joel S. Pachter

Keyword(s):

T Cells ◽

Endothelial Cells ◽

Demyelinating Disease ◽

Flow Cytometric Analysis ◽

Autoimmune Encephalomyelitis ◽

Flow Cytometric ◽

Leukocyte Transendothelial Migration ◽

Transient Interactions ◽

Circulating T Cells ◽

Experimental Autoimmune

Abstract Background: Tight junctions (TJs) are membrane specializations characteristic of barrier-forming membranes, which function to seal the aqueous pathway between endothelial cells or epithelial cells and, thereby, obstruct intercellular solute and cellular movement. However, previous work from our laboratory found that claudin-5 (CLN-5), a TJ protein prominent at the blood-brain barrier (BBB), is also detected, ectopically, on leukocytes (CLN-5+) in the blood and central nervous system (CNS) of mice with experimental autoimmune encephalomyelitis (EAE), a neuroinflammatory, demyelinating disease that is a model for multiple sclerosis. CLN-5 was further shown to be transferred from endothelial cells to circulating leukocytes during disease, prompting consideration this action is coupled to leukocyte transendothelial migration (TEM) into the CNS by fostering transient interactions between corresponding leukocyte and endothelial junctional proteins at the BBB. Methods: To begin clarifying the significance of CLN-5+ leukocytes, flow cytometry was used to determine their appearance in the blood and CNS during EAE. Results: Flow cytometric analysis revealed CLN-5+ populations among CD4 and CD8 T cells, B cells, monocytes and neutrophils, and these appeared with varying kinetics and to different extents in both blood and CNS. CLN-5 levels on circulating T cells further correlated highly with activation state. And, percentage of CLN-5+ cells among each of the subtypes analyzed was considerably higher in CNS tissue than in blood, consistent with the interpretation that CLN-5+ leukocytes gain preferred access to the CNS. Conclusion: Several leukocyte subtypes variably acquire CLN-5 in blood before they enter the CNS, an event that may represent a novel mechanism to guide leukocytes to sites for paracellular diapedesis across the BBB.

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Mgat5 Deficiency in T Cells and Experimental Autoimmune Encephalomyelitis

ISRN Neurology ◽

10.5402/2011/374314 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 8

Author(s):

Ani Grigorian ◽

Michael Demetriou

Keyword(s):

T Cells ◽

T Cell ◽

Experimental Autoimmune Encephalomyelitis ◽

Demyelinating Disease ◽

Cell Receptor ◽

Protein Glycosylation ◽

Autoimmune Encephalomyelitis ◽

Glycosylation Pathway ◽

Experimental Autoimmune ◽

Surface Glycoproteins

Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease initiated by autoreactive T cells. Mgat5, a gene in the Asn (N-) linked protein glycosylation pathway, associates with MS severity and negatively regulates experimental autoimmune encephalomyelitis (EAE) and spontaneous inflammatory demyelination in mice. N-glycan branching by Mgat5 regulates interaction of surface glycoproteins with galectins, forming a molecular lattice that differentially controls the concentration of surface glycoproteins. T-cell receptor signaling, T-cell proliferation, TH1 differentiation, and CTLA-4 endocytosis are inhibited by Mgat5 branching. Non-T cells also contribute to MS pathogenesis and express abundant Mgat5 branched N-glycans. Here we explore whether Mgat5 deficiency in myelin-reactive T cells is sufficient to promote demyelinating disease. Adoptive transfer of myelin-reactive Mgat5−/− T cells into Mgat5+/+ versus Mgat5−/− recipients revealed more severe EAE in the latter, suggesting that Mgat5 branching deficiency in recipient naive T cells and/or non-T cells contribute to disease pathogenesis.

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Treatment of Experimental Autoimmune Encephalomyelitis with Genetically Modified Memory T Cells

Journal of Experimental Medicine ◽

10.1084/jem.186.1.159 ◽

1997 ◽

Vol 186 (1) ◽

pp. 159-164 ◽

Cited By ~ 130

Author(s):

Peter M. Mathisen ◽

Min Yu ◽

Justin M. Johnson ◽

Judith A. Drazba ◽

Vincent K. Tuohy

Keyword(s):

T Cells ◽

T Cell ◽

Experimental Autoimmune Encephalomyelitis ◽

Demyelinating Disease ◽

Memory T Cells ◽

Vector System ◽

Autoimmune Encephalomyelitis ◽

T Cell Clones ◽

Cell Clones ◽

Experimental Autoimmune

The migratory properties of memory T cells provide a model vector system for site-specific delivery of therapeutic transgene factors to autoimmune inflammatory lesions. Lymph node cells from (SWR×SJL)F1 mice immunized with the p139–151 determinant of myelin proteolipid protein (PLP) were transfected with a DNA construct that placed the anti-inflammatory cytokine interleukin-10 (IL-10) cDNA under control of an antigen-inducible IL-2 promoter region. Isolated T cell clones demonstrated antigen-inducible expression of transgene IL-10 and expressed cell surface markers consistent with the phenotype of normal memory T cells. Upon adoptive transfer, transfected T cell clones were able to inhibit onset of experimental autoimmune encephalomyelitis (EAE) and to treat EAE animals therapeutically after onset of neurologic signs. Semiquantitative immunocytochemistry showed a significant correlation between decreased demyelination and treatment with the transfected T cells. Taken together, these data indicate the autoreactive T cells can be genetically designed to produce therapeutic factors in an antigen-inducible manner resulting in a decreased severity of clinical and histological autoimmune demyelinating disease.

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IL-1β enables CNS access to CCR2hi monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1714948115 ◽

2018 ◽

Vol 115 (6) ◽

pp. E1194-E1203 ◽

Cited By ~ 36

Author(s):

Alexandre Paré ◽

Benoit Mailhot ◽

Sébastien A. Lévesque ◽

Camille Juzwik ◽

Prenitha Mercy Ignatius Arokia Doss ◽

...

Keyword(s):

Spinal Cord ◽

T Cells ◽

Endothelial Cells ◽

Myeloid Cells ◽

Autoimmune Encephalomyelitis ◽

Cns Inflammation ◽

Gm Csf ◽

Autoimmune Conditions ◽

Antigen Presenting ◽

Experimental Autoimmune

Molecular interventions that limit pathogenic CNS inflammation are used to treat autoimmune conditions such as multiple sclerosis (MS). Remarkably, IL-1β–knockout mice are highly resistant to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we show that interfering with the IL-1β/IL-1R1 axis severely impairs the transmigration of myeloid cells across central nervous system (CNS) endothelial cells (ECs). Notably, we report that IL-1β expression by inflammatory CCR2hi monocytes favors their entry into the spinal cord before EAE onset. Following activation with IL-1β, CNS ECs release GM-CSF, which in turn converts monocytes into antigen-presenting cells (APCs). Accordingly, spinal cord-infiltrated monocyte-derived APCs are associated with dividing CD4+ T cells. Factors released from the interaction between IL-1β–competent myeloid cells and CD4+ T cells are highly toxic to neurons. Together, our results suggest that IL-1β signaling is an entry point for targeting both the initiation and exacerbation of neuroinflammation.

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Flow Cytometric Analysis of Lymphocyte Infiltration in Central Nervous System during Experimental Autoimmune Encephalomyelitis

Journal of Visualized Experiments ◽

10.3791/61050 ◽

2020 ◽

Author(s):

Zhe Ji ◽

Chenghua Zhou ◽

Hongshen Niu ◽

Jinshen Wang ◽

Lei Shen

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Experimental Autoimmune Encephalomyelitis ◽

Flow Cytometric Analysis ◽

Lymphocyte Infiltration ◽

Autoimmune Encephalomyelitis ◽

Flow Cytometric ◽

Experimental Autoimmune

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Different Mechanisms of Inflammation Induced in Virus and Autoimmune-Mediated Models of Multiple Sclerosis in C57BL6 Mice

BioMed Research International ◽

10.1155/2013/589048 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 9

Author(s):

Abhinoy Kishore ◽

Anurag Kanaujia ◽

Soma Nag ◽

A. M. Rostami ◽

Lawrence C. Kenyon ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

White Matter ◽

Acute Inflammation ◽

Demyelinating Disease ◽

Small Population ◽

Demyelinating Diseases ◽

Autoimmune Encephalomyelitis ◽

Experimental Autoimmune

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system (CNS). Neurotropic demyelinating strain of MHV (MHV-A59 or its isogenic recombinant strain RSA59) induces MS-like disease in mice mediated by microglia, along with a small population of T cells. The mechanism of demyelination is at least in part due to microglia-mediated myelin stripping, with some direct axonal injury. Immunization with myelin oligodendrocyte glycoprotein (MOG) induces experimental autoimmune encephalomyelitis (EAE), a mainly CD4+T-cell-mediated disease, although CD8+T cells may play a significant role in demyelination. It is possible that both autoimmune and nonimmune mechanisms such as direct viral toxicity may induce MS. Our study directly compares CNS pathology in autoimmune and viral-induced MS models. Mice with viral-induced and EAE demyelinating diseases demonstrated similar patterns and distributions of demyelination that accumulated over the course of the disease. However, significant differences in acute inflammation were noted. Inflammation was restricted mainly to white matter at all times in EAE, whereas inflammation initially largely involved gray matter in acute MHV-induced disease and then is subsequently localized only in white matter in the chronic disease phase. The presence of dual mechanisms of demyelination may be responsible for the failure of immunosuppression to promote long-term remission in many MS patients.

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Analysis of the Runx3 expression during experiemental autoimmune encephalomyelitis

Revista dos Trabalhos de Iniciação Científica da UNICAMP ◽

10.20396/revpibic262018204 ◽

2018 ◽

Author(s):

Beatriz Souza Lopes ◽

Alessandro dos Santos Farias ◽

Ana Maria Marques

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

T Cells ◽

Nervous System ◽

Demyelinating Disease ◽

Autoimmune Encephalomyelitis ◽

The Central Nervous System ◽

Effector Activity ◽

Runx3 Gene ◽

Experimental Autoimmune

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS), which is attributed to a self-sustaining autoimmune mechanism. The majority of the knowledge regarding MS autoagressive mechanisms is resultant of studies performed in its experimental model (mice) the experimental autoimmune encephalomyelitis (EAE).Although, the literature reports that the EAE is mediated by proinflammatory CD4+ T cells , isn’t completely clear how these cells (known as helper cells) would be able of initiate the disease when adoptively transferred to healthy animals.We believe that the Runx3 gene presents a central role in the progression and regulation of the effector activity in CD4+ encephalitogenic lymphocytes.

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