Genetics and inflammation in nerve injury-induced neurodegeneration

Abstract: Neurodegeneration and inflammation are characteristic of many diseases of the central nervous system (CNS) and understanding the molecular networks that regulate these processes is of central importance for the development of effective therapies. Although the CNS has traditionally been regarded as an immuno privileged organ, immune reactions, including components of both local innate and systemic immunity, do occur in this tissue. Animal models can provide powerful tools for mimicking and dissecting certain aspects of human pathology. Accordingly, responses to nerve lesions have been investigated in various such animal models and certain key regulators identified. However, our knowledge of how these processes are regulated on a more global genomic level is extremely limited. In the present thesis models of nerve lesion and experimental autoimmune encephalomyelitis have been employed to probe certain fundamental questions regarding neuroinflammation. The three-fold findings can be summarized as follows: First, the pattern of expression and functional role of MHC class I in the changes in CNS neurons induced by axotomy were examined. Pronounced expression of non-classical MHC class I, RT1-U, was observed in several different neuronal populations in the CNS. Furthermore, lack of functional MHC class I was found to enhance synaptic detachment from axotomized motoneurons, as well as the astroglial reaction. This novel finding which indicates that MHC class I plays an important role in the synaptic plasticity in the adult animal. Secondly, genetic influences on experimentally induced neurodegeneration and CNS inflammation were examined. Using different rat strains (i.e., DA(RT1av1), PVG.1AV1, LEW.1AV1, LEW1.N, BN(RT1n), and E3(RT1u)) significant strain differences were observed in the responses to a standardized nerve trauma, ventral root avulsion (VRA), including glial activation, motoneuronal degeneration, and expression of MHC class II on microglia. There were also substantial strain differences in the glial response to facial nerve lesion in mice. Subsequently, utilizing a microsatellitebased genome scan in an F2 population established by crossing DA(RT1av1) and PVG(RT1c), several discrete QTLs involved in the regulation of VRA-induced phenotypes were identified. These QTLs are Vra1, located on rat chromosome 8 and significantly linked to neurodegeneration; Vra2, located on rat chromosome 5 and significantly linked to T cell infiltration and with suggestive linkage to neurodegeneration as well; Vra3, also located on rat chromosome 5 and suggestively linked to T cell infiltration; and, finally, Vra4, located on rat chromosome 10 and significantly linked to expression of MHC class II on microglia. Employing an advanced intercross line, the QTL regulating MHC class 11 expression by microglia was further mapped more precisely to a 3.7-megabase DNA fragment that contains the mhc2ta gene encoding the class II transactivator (CIITA). Expression studies and gene sequencing identify this gene as a strong candidate regulator of nerve lesion-induced MHC class II expression in the CNS. Finally, the potential neuroprotective roles of CNS-directed autoimmunity and the expression of neurotrophic factors by leukocyte populations infiltrating this tissue were explored. A combination of VRA and active induction of EAE resulted in increased survival of axotomized motoneurons, compared to rats subjected to VRA alone, suggesting that an autoantigen-specific immune response in the CNS plays a protective role. This survival was associated with increased expression of several neurotrophic factors in the CNS of EAE animals, as well as increased of infiltration of T and NK cells into the CNS. These findings shed new light on highly interesting aspects of the association between neurodegeneration and CNS inflammation. These new insights have implications for the understanding of chronic and acute human neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke and traumatic brain injury.