Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL

Here, we provide evidence for a detrimental role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in neural death in T cell-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Clinical severity and neuronal apoptosis in brainstem motor areas were substantially reduced upon brain-specific blockade of TRAIL after induction of EAE through adoptive transfer of encephalitogenic T cells. Furthermore, TRAIL-deficient myelin-specific lymphocytes showed reduced encephalitogenicity when transferred to wild-type mice. Conversely, intracerebral delivery of TRAIL to animals with EAE increased clinical deficits, while naive mice were not susceptible to TRAIL. Using organotypic slice cultures as a model for living brain tissue, we found that neurons were susceptible to TRAIL-mediated injury induced by encephalitogenic T cells. Thus, in addition to its known immunoregulatory effects, the death ligand TRAIL contributes to neural damage in the inflamed brain

Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action

In the present study, upon showing sexual dimorphism in dimethyl fumarate (DMF) efficacy to moderate the clinical severity of experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats, cellular and molecular substrate of this dimorphism was explored. In rats of both sexes, DMF administration from the day of immunization attenuated EAE severity, but this effect was more prominent in males leading to loss of the sexual dimorphism observed in vehicle-administered controls. Consistently, in male rats, DMF was more efficient in diminishing the number of CD4+ T lymphocytes infiltrating spinal cord (SC) and their reactivation, the number of IL-17+ T lymphocytes and particularly cellularity of their highly pathogenic IFN-gamma+GM-CSF+IL-17+ subset. This was linked with changes in SC CD11b+CD45+TCR alpha beta- microglia/proinflammatory monocyte progeny, substantiated in a more prominent increase in the frequency of anti-inflammatory phygocyting CD163+ cells and the cells expressing high surface levels of immunoregulatory CD83 molecule (associated with apoptotic cells phagocytosis and implicated in downregulation of CD4+ T lymphocyte reactivation) among CD11b+CD45+TCR alpha beta- cells in male rat SC. These changes were associated with greater increase in the nuclear factor (erythroid-derived 2)-like 2 expression in male rats administered with DMF. In accordance with the previous findings, DMF diminished reactive nitrogen and oxygen species generation and consistently, SC level of advanced oxidation protein products, to the greater extent in male rats. Overall, our study indicates sex-specificity in the sensitivity of DMF cellular and molecular targets and encourages sex-based clinical research to define significance of sex for action of therapeutic agents moderating autoimmune neuroinflammation-/oxidative stress-related nervous tissue damage

The role of TRAIL/TRAIL receptors in central nervous system pathology

Initially, the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) aroused major interest due to its preferential toxic effect against malignant cells. However, subsequent studies revealed that the TRAIL system, comprising the family of signal-mediating and decoy TRAIL receptors, (i) can also induce death of non-transformed cells, (ii) has potent immunoregulatory functions, and (iii) exhibits a unique expression pattern in the central nervous system (CNS). Indeed, TRAIL is not expressed within the human brain, while apoptosis-inducing TRAIL receptors are found differently distributed on neurons, oligodendrocytes, and astrocytes. These findings rule out a major contribution of TRAIL to the so-called "immune privilege" of the brain, in which local inflammation is limited, although such a role has previously been suggested for the CD95 (Fas) ligand belonging to the same TNF/nerve growth factor (NGF) family. If, under pathologic circumstances, the CNS is inflamed, immune cells such as macrophages and T cells upregulate TRAIL upon activation and use this death ligand as a weapon, not only against tumor cells but also against neurons and oligodendrocytes within the inflamed CNS. In parallel, a profound immunoregulatory impact of TRAIL on activation and proliferation of encephalitogenic T cells outside the brain has also been shown. Thus, these studies have uncovered a complex action of TRAIL on CNS pathology, indicating the possible value of targeted manipulation of the TRAIL system for the treatment of inflammatory neurodegenerative diseases such as multiple sclerosis

Roles of the kallikrein/kinin system in the adaptive immune system

This review deals with the effects of kinins, a family of octa- to decapeptides structurally related to bradykinin (BK), in adaptive immune responses. Herein, we discuss the experimental evidence that kinins may exert influence on multiple players of the immune system (i.e. macrophages, dendritic cells, T and B lymphocytes), and modulate the activation, proliferation, migration and effector functions of these cells. We also give an overview of the possible impact of kinins in human autoimmune diseases and corresponding animal models, with special emphasis on autoimmune neuroinflammation and arthritis. These studies indicate a possible immunomodulatory capacity of kinins beyond our current knowledge of kinin actions regarding the vascular system, and thus the way towards future therapeutic approaches

Differential immune cell dynamics in the CNS cause CD4+ T cell compartmentalization

In the course of autoimmune CNS inflammation, inflammatory infiltrates form characteristic perivascular lymphocyte cuffs by mechanisms that are not yet well understood. Here, intravital two-photon imaging of the brain in anesthetized mice, with experimental autoimmune encephalomyelitis, revealed the highly dynamic nature of perivascular immune cells, refuting suggestions that vessel cuffs are the result of limited lymphocyte motility in the CNS. On the contrary, vessel-associated lymphocyte motility is an actively promoted mechanism which can be blocked by CXCR4 antagonism. In vivo interference with CXCR4 in experimental autoimmune encephalomyelitis disrupted dynamic vessel cuffs and resulted in tissue-invasive migration. CXCR4-mediated perivascular lymphocyte movement along CNS vessels was a key feature of CD4(+) T cell subsets in contrast to random motility of CD8(+) T cells, indicating a dominant role of the perivascular area primarily for CD4(+) T cells. Our results visualize dynamic T cell motility in the CNS and demonstrate differential CXCR4-mediated compartmentalization of CD4(+) T-cell motility within the healthy and diseased CNS

MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies

Whether B cells serve as antigen-presenting cells (APCs) for activation of pathogenic T cells in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE) is unclear. To evaluate their role as APCs, we engineered mice selectively defici