2,806 research outputs found
The Ambivalent Role of Apoptosis in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis
No full textApoptosis is synonymous to programmed cell death, which occurs in response to a plethora of stimuli and employs a series of highly conserved mediators and pathways. Its ambivalent role in immunology is illustrated by the fact that this process not only serves homeostatic functions but also exerts harmful effects including tissue damage. This is particularly true for neuroinflammatory diseases such as multiple sclerosis (MS), the most frequent neurological disease to afflict adolescents in the western world. Considerable insight into the role of apoptosis in MS has been obtained by using its animal model experimental autoimmune encephalomyelitis (EAE). Experiments using the EAE model have revealed that cell death affects both infiltrating lymphocytes and CNS resident cells, and that it contributes to axonal injury as well as the resolution of inflammation. Furthermore, it was discovered that the molecules involved in inducing and regulating this process are the Fas-FasL system, pro- and anti-apoptotic Bcl-2 family members, 'initiator' and 'effector' caspases, glucocorticoid hormones and various modulatory proteins. The variety of apoptotic mechanisms in combination with their often opposing effects on the disease course highlights the need for a detailed understanding of apoptosis in this context. In the future, this may pave the way to novel approaches aiming at interfering with the apoptotic process to prevent tissue damage or at intentionally inducing cell death in order to ameliorate the disease by deleting autoreactive lymphocytes
Function of Neurotrophic Factors Beyond the Nervous System: Inflammation and Autoimmune Demyelination
No full textIn the nervous system, neurotrophic factors play a role during development, especially for the differentiation of neuronal and glial cells. Moreover, they promote cell survival of neurons, axons, and oligodendrocytes, as well as their precursors, in vitro and in lesional paradigms. In recent years, several functions of neurotrophic factors outside the nervous system have been described, with a special focus on the immune system as well as on models of autoimmune demyelination, such as experimental autoimmune encephalomyelitis (EAE). In the family of neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were investigated. NGF may influence B-cell as well as T-cell function and particularly plays a role in macrophage migration into inflamed lesions. BDNF is produced by several immune-cell subtypes in vitro and also in multiple sclerosis (MS) plaques. This observation gave rise to the concept of neuroprotective autoimmunity, implying that immune-cell infiltration in the nervous system may not only be detrimental but may also play a beneficial role, for example, through the production of neurotrophic factors. In the family of neurotrophic cytokines, ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) share some common protective roles in axons and oligodendrocytes. In EAE, endogenous CNTF targets myelin, oligodendroglial cells, and axons. In contrast, LIF exerts protective functions on oligodendrocytes in some models but is also able to interact with the immune response and may modulate T-cell, monocyte and neutrophil functions. In summary, neurotrophic factors have distinct roles in the immune system during autoimmunity and may modulate immune responses as well as the susceptibility of the target tissue
Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration
No full textFumaric acid esters (FAE) have proven their therapeutic efficacy in psoriasis, a Th1 mediated skin disease. More recently, preliminary data have suggested an activity in multiple sclerosis (MS) as well. To investigate further possible mechanisms of action of these compounds in inflammatory diseases, we studied the FAE methyl hydrogen fumarate (MHF) and dimethyl fumarate (DMF) in chronic experimental autoimmune encephalomyelitis (EAE) induced by immunization of C57BL/6 mice with MOG peptide aa 35-55. Preventive treatment with these FAE was delivered twice a day by oral gavage. Both esters had a significant therapeutic effect on the disease course and histology showed a strongly reduced macrophage inflammation in the spinal cord. Multiparameter cytokine analysis from blood detected an increase of IL-10 in the treated animals. We conclude that the underlying biological activity of FAE in EAE is complex and, to elucidate the molecular mechanisms, further investigation is needed
Autoimmune disease in the brain - how to spot the culprits and how to keep them in check
No full textCurrent concepts attribute an early and central role for auto-aggressive, myelin-specific T-lymphocytes in the pathogenesis of multiple sclerosis. This view emerged from immunological and pathological findings in experimental autoimmune encephalitis, an animal model characterised by pathological lesions closely resembling the ones found in multiple sclerosis. Furthermore, therapeutic strategies targeting the functions of these encephalitogenic T cells which attenuate their pathogenicity such as glatiramer acetate or anti-VLA4 antibody treatments represent proven approaches in multiple sclerosis. Nonetheless, all therapies evaluated to date either insufficiently dampen down inflammation or completely block immune processes. For this reason, there is a need to identify new therapeutic targets. We have employed live intravital two-photon microscopy to learn more about the behaviour of T cells during the preclinical phase of EAE, when T cells acquire the properties required to invade their target organ. Furthermore, we were able to identify an unexpected locomotive behaviour of T cells at the blood-brain barrier, which occurs immediately before diapedesis and the induction of paralytic disease. Such studies might open new avenues for the treatment of CNS autoimmune diseases. Multiple sclerosis is considered to be an autoimmune disease in which self-reactive T cells enter the central nervous system (CNS) and create an inflammatory milieu that destroys myelin and neurons. Immunomodulatory strategies for the treatment of multiple sclerosis target this process by attempting to inactivate these auto-aggressive T cells. However, so far, these strategies have failed to extinguish disease activity completely. For this reason, there is a need to understand in more detail the mechanisms by which T cells become encephalitogenic, how they enter the nervous system, and what the signals are that guide them along this path. If these processes could be better understood, it may be possible to design more effective and specific therapies for multiple sclerosis. This article will give a brief overview about our recent findings obtained using intravital imaging of autoaggressive effector T cells in an experimental model of multiple sclerosis. This new technological approach might help to fill some gaps in the understanding of autoimmune pathogenesis of multiple sclerosis. (C) 2011 Elsevier B.V. All rights reserved
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