Stiftung Tierärztliche Hochschule Hannover (TiHo)

Bedeutung der akuten Neuroinflammation bei Erkrankungen des zentralen Nervensystems für die Initiation und Progression von Entmarkungsprozessen

Beineke, Andreas Alfons

Canine distemper leukoencephalomyelitis and Theiler’s murine encephalomyelitis (TME) represent spontaneous and experimental viral animal models for demyelinating disorders of the central nervous system (CNS). While autoimmunity leads to demyelination in the chronic progressive phase of human multiple sclerosis (MS), immunological and neurodegenerative processes during the initial disease phase are largely undetermined. Therefore, the aims of the present studies were a detailed characterization of neuropathological findings during the acute phase of virus-induced CNS disorders and identification of factors, which induce immune mediated tissue damage and myelin loss, respectively. During the early phase of canine distemper leukoencephalitis a dominating expression of proinflammatory cytokines, such as interleukin (IL)-6, IL-8, IL-12 and tumor necrosis factor (TNF)-a by resident cells of the cerebrum was detected. The lack of immune regulatory cytokines is supposed to induce a derailment of the immune response, which triggers neuroinflammation during the progressive disease stage. In order to detect equivalent reaction patterns of resident glial cells in other morbillivirus infections, cellular immune responses were phenotyped in the brain of harbor seals suffering from phocine distemper. In a pilot study a series of leukocyte markers were tested for cross reactivity with lymphoid cells of harbor seals. Similar to canine distemper infected seals exhibited a predominant infection of neurons and early activation of resident cells in the cerebral cortex. To investigate microglial function in more detail, immunological parameters have been determined in traumatized spinal cord tissue of dogs and canine organotypic spinal cord slice cultures. As observed in canine distemper, a dominating expression of proinflammatory cytokines and a lack (IL-10) or delayed (transforming growth factor-β) upregulation of neuroprotective cytokines have been observed. Based on the hypothesis, that a dysregulated immune homeostasis during early virus infection contributes to immunopathology, neuropathological lesions and immune responses have been investigated in TME, as a translational mouse model. Lesion development in infected mice was similar to that observed in MS as well as in canine and phocine distemper. Comparison of susceptible and resistant mouse strains revealed that the switch of cell tropism from neurons to microglia and oligodendrocytes represents an essential prerequisite for persistence of the TME virus and demyelination in SJL mice. To characterize the impact of the peripheral immune system upon the initiation of neuroinflammation in the TME model, global gene expression analyses have been performed. Here, associated with virus induced polioencephalitis a transient gene expression was detected in the brain draining cervical lymph node during the early acute infection phase. Functional annotation analyses revealed differential expression of genes involved in B cell immunity, antigen presentation and complement activation. Early gene expression is indicative of virus triggered immune responses in the brain-draining lymph node, which might initiate antibody mediated myelin damage and a compartimentalization of CNS-inflammation during the chronic TME phase. For further classification of local immune responses in the brain during acute infection, phenotyping of infiltrating immune cells and cytokine expression analyses have been performed. Comparison of mice with different mouse strains, revealed a prominent infiltration of Foxp3+ regulatory T cells and CD45R+ B cells associated with the mRNA expression of IL-10 in the brain of susceptible SJL mice. In contrast, an early increase of TNF-a mRNA transcription was associated with accelerated TME virus elimination in resistant C57BL/6 mice. Accordingly, IL-10 represents a potential candidate molecule for the impaired antiviral immunity and virus persistence in mice with a susceptible genetic background. Furthermore, results substantiate the hypothesis that an imbalanced cytokine milieu during the early infection phase contributes to immune mediated demyelination in the chronic phase. This raised the question about the impact of neurodegenerative changes upon immunmodulatory mechanisms in infectious MS models. In a subsequent experiment, the effect of the neurotoxin cuprizone upon the clinical course and spinal demyelination was tested in TME virus infected mice. Cuprizone induces oligodendroglial alterations with apoptosis induction and reduced myelin basic protein expression, but without overt spinal demyelination, which substantiates the concept of major morphological and functional regional differences between brain and spinal cord. In TME virus infected mice cuprizone causes a temporary improvement of clinical signs and reduced demyelinating leukomyelitis despite toxic myelin damage in the corpus callosum. This process was associated with reduced infiltration of leukocytes and decreased expression of pro- and anti-inflammatory cytokines in the spinal cord. This phenomenon is supposed to be a consequence of selective inhibition of detrimental inflammatory responses with maintained protective immunity against the virus. In summary, the present studies highlight the importance of early inflammatoty responses for the pathogeneses of progressive demyelination. However, disease phase and species specific properties, such as differences of modulatory effects of microglial cells and the peripheral immune system, have to be taken into consideration for future immunoregulatory strategies and cell transplantation approaches for the treatment of chronic CNS disorders.

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Beineke, Andreas Alfons: Bedeutung der akuten Neuroinflammation bei Erkrankungen des zentralen Nervensystems für die Initiation und Progression von Entmarkungsprozessen. Hannover 2012. Tierärztliche Hochschule.

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