In multiple sclerosis (MS), the immune cell attack leads to axonal injury as a major cause for neurological disability. Here, we report a novel role of the cell adhesion molecule L1 in the crosstalk ...between the immune and nervous systems. L1 was found to be expressed by CNS axons of MS patients and human T cells. In MOG
35–55
-induced murine experimental neuroinflammation, CD4
+
T cells were associated with degenerating axons in the spinal cord, both expressing L1. However, neuronal L1 expression in the spinal cord was reduced, while levels of the transcriptional repressor REST (RE1-Silencing Transcription Factor) were up-regulated. In PLP
139–151
-induced relapsing–remitting neuroinflammation, L1 expression was low at the peak stage of disease, reached almost normal levels in the remission stage, but decreased again during disease relapse indicating adaptive expression regulation of L1. In vitro, activated CD4
+
T cells caused contact-dependent down-regulation of L1, up-regulation of its repressor REST and axonal injury in co-cultured neurons. T cell adhesion to neurons and axonal injury were prevented by an antibody blocking L1 suggesting that down-regulation of L1 ameliorates neuroinflammation. In support of this hypothesis, antibody-mediated blocking of L1 in C57BL/6 mice as well as neuron-specific depletion of L1 in synapsin
Cre
× L1
fl/fl
mice reduces disease severity and axonal pathology despite unchanged immune cell infiltration of the CNS. Our data suggest that down-regulation of neuronal L1 expression is an adaptive process of neuronal self-defense in response to pro-inflammatory T cells, thereby alleviating immune-mediated axonal injury.
Multiple sclerosis (MS) is an inflammatory disease of the CNS thought to be driven by CNS-specific T lymphocytes. Although CD8(+) T cells are frequently found in multiple sclerosis lesions, their ...distinct role remains controversial because direct signs of cytotoxicity have not been confirmed in vivo. In the present work, we determined that murine ovalbumin-transgenic (OT-1) CD8(+) T cells recognize the myelin peptide myelin oligodendrocyte glycoprotein 40-54 (MOG40-54) both in vitro and in vivo. The aim of this study was to investigate whether such cross-recognizing CD8(+) T cells are capable of inducing CNS damage in vivo. Using intravital two-photon microscopy in the mouse model of multiple sclerosis, we detected antigen recognition motility of the OT-1 CD8(+) T cells within the CNS leading to a selective enrichment in inflammatory lesions. However, this cross-reactivity of OT-1 CD8(+) T cells with MOG peptide in the CNS did not result in clinically or subclinically significant damage, which is different from myelin-specific CD4(+) Th17-mediated autoimmune pathology. Therefore, intravital imaging demonstrates that local myelin recognition by autoreactive CD8(+) T cells in inflammatory CNS lesions alone is not sufficient to induce disability or increase axonal injury.
Cladribine is a purine nucleoside analog developed to treat lymphoid malignancies. Reported therapeutic benefits for the autoimmune disease multiple sclerosis indicate additional immunomodulatory ...effects beyond the well-characterized cytotoxic activity causing lymphopenia. Here, we demonstrate that cladribine reduces the secretion of inflammatory cytokines and chemokines by murine and human dendritic cells, the most potent antigen-presenting cells. This compound also modulates the expression of the activation markers CD86 and MHC II. Furthermore, cladribine affects the T cell priming capacity of dendritic cells, resulting in reduced induction of interferon-γ- and tumor necrosis factor-α-producing T cells and increased induction of interleukin-10-producing T cells. These effects, observed at cladribine concentrations in the therapeutically relevant range of serum steady-state concentrations for leukemia and multiple sclerosis, confirm the immunomodulatory activity of cladribine.
•Cladribine reduces chemokine production by DC.•Cladribine modulates T cell polarizing capacity of DC.•Cladribine alters DC to a semi-mature differentiation-locked tolerogenic phenotype.•Cladribine shows immunomodulatory effects at therapeutic doses.
Multiple sclerosis (MS) is an inflammatory disease of the CNS thought to be driven by CNS-specific T lymphocytes. Although CD8 super(+) T cells are frequently found in multiple sclerosis lesions, ...their distinct role remains controversial because direct signs of cytotoxicity have not been confirmed in vivo. In the present work, we determined that murine ovalbumin-transgenic (OT-1) CD8 super(+) T cells recognize the myelin peptide myelin oligodendrocyte glycoprotein 40-54 (MOG sub(40-54)) both in vitro and in vivo. The aim of this study was to investigate whether such cross-recognizing CD8 super(+) T cells are capable of inducing CNS damage in vivo. Using intravital two-photon microscopy in the mouse model of multiple sclerosis, we detected antigen recognition motility of the OT-1 CD8 super(+) T cells within the CNS leading to a selective enrichment in inflammatory lesions. However, this cross-reactivity of OT-1 CD8 super(+) T cells with MOG peptide in the CNS did not result in clinically or subclinically significant damage, which is different from myelin-specific CD4 super(+) Th17-mediated autoimmune pathology. Therefore, intravital imaging demonstrates that local myelin recognition by autoreactive CD8 super(+) T cells in inflammatory CNS lesions alone is not sufficient to induce disability or increase axonal injury.
T cells have an essential role in the induction of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Although for CD4(+) T cells it is well established that ...they contribute to the disease, less is known about the role of CD8(+) T cells. Our aim was to determine the individual contribution of CD4(+) and CD8(+) T cells in myelin oligodendrocyte glycoprotein (MOG)35-55-induced EAE. We investigated MOG35-55-activated CD8(+) T cells to clarify their potential to induce or attenuate EAE. We monitored the behavior of CD8(+) T cells and their interaction with CD4(+) T cells directly at the site of inflammation in the CNS using intravital imaging of the brainstem of EAE-affected living anesthetized mice. We found that mice without CD4(+) T cells did not develop relevant clinical signs of disease, although CD8(+) T cells were present in the CNS of these mice. These CD8(+) T cells displayed reduced motility compared with those in the presence of CD4(+) T cells. In mice that harbored CD4(+) and CD8(+) T cells, we saw a similar extent of clinical signs of EAE as in mice with only CD4(+) T cells. Furthermore, the dynamic motility and viability of CD4(+) T cells were not disturbed by CD8(+) T cells in the lesions of these mice. Therefore, we conclude that in MOG35-55-induced EAE, CD8(+) T cell accumulation in the CNS represents instead an epiphenomenon with no impact on clinical disease or on the effects of CD4(+) T cells, the latter being the true inducers of the disease.
Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a ...key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System x
or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration.
Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system x
, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT
) mice and irradiated mice reconstituted in xCT
bone marrow (BM), to their proper wild type (xCT
) controls.
xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT
mice, xCT
mice were equally susceptible to EAE, whereas mice transplanted with xCT
BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected.
Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system x
on immune cells invading the CNS participates to EAE. Since a total loss of system x
had no net beneficial effects, these results have important implications for targeting system x
for treatment of MS.
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