Autoimmune and innate inflammation in the nervous system : neurotrophin production and impact on neuronal survival

Sammanfattning: The occurrence of a continuous immune surveillance in the central nervous system (CNS) is a fairly recent finding. For long the CNS was considered an immune privileged organ, with the blood-brain barrier constituting an effective barrier against blood-derived molecules and cells. Even though we today know that activated immune cells enter the CNS and interact with CNS resident cells there is limited knowledge about the functional consequences of the interaction between the nervous and immune systems. This thesis deals with the roles of both innate and adaptive immune responses in the CNS during neurodegenerative processes. A mechanical nerve injury paradigm, where ventral roots are avulsed, was used as a model for neurodegeneration. In the first two studies the characteristics of the innate inflammatory reaction in response to nerve root avulsion were determined. In addition, by studying the outcome in a panel of different rat strains, its genetic regulation could be explored. The results demonstrate that there is a clear genetic regulation of different inflammatory parameters, such as glial activation and major histocompatibility complex class II (MHC II) expression. Also the degree of nerve cell loss is subjected to genetic regulation. The genes regulating glial reactivity and neuronal death seem to reside outside the MHC complex, since MHC congenic rats display a differential response whereas rats with the same non-MHC genes do not. There was no indication of a regulatory influence of T cells, since depletion of [alpha][beta] T cell receptor (TCR) T cells did not affect the outcome. In the third study the effects of a concomitant adaptive immune response on neurodegeneration in the root avulsion model was explored. Rats were immunised with a myelin basic protein (MBP) peptide in complete Freund's adjuvant in order to induce experimental autoimmune encephalomyelitis. In rats immunised for EAE the number of surviving cells was increased up to 120% in comparison to solely avulsed controls. A likely explanation, at least in part, for this neuroprotective effect of EAE is that CNS infiltrating lymphocytes express high levels of neurotrophic factors. Sorting of infiltrating lymphocytes into encephalitogenic TCR BV8S2+ T cells, bystander recruited TCR BV8S2T cells and NK-RP1+ natural killer (NK) cells revealed high mRNA levels of the neurotrophic factors brain- derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and glial cell line-derived neurotrophic factor (GDNF) in all populations, but more so in bystander recruited lymphoid cells. In a cell culture assay using embryonic rat motoneurons, addition of neurotrophic factors attenuated the toxic effects of the pro-inflammatory cytokines interferon-[gamma] and tumor necrosis factor-[alpha]. In the final work a kinetic study of the expression of cytokines and neurotrophic factors in lymphocytes after EAE immunisation was performed- Expression of neurotrophic factors (BDNF, GDNF and NT-3) was highly upregulated during the peak of the disease and the highest levels were confined to the bystander recruited T cell population. These results are important for the understanding of how innate immune reactions are regulated in the CNS and the interaction between the nervous and immune systems. In addition, further exploration of the neuroprotective potential of autoimmunity may yield new therapeutic strategies for neurodegenerative diseases.