Interakcija Th-17 imunskog odgovora i glutamatske ekscitotoksičnosti u patogenezi multiple skleroze : klinička i eksperimentalna studija

Introduction: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) characterized by episodic neurological defects, disseminated in time and neuroanatomical localization. The central role in the development of inflammatory mediated lesions in MS is now attributed to autoreactive, myelin-specific CD4+ T lymphocytes, which are thought to regulate all immune mechanisms that lead to the myelin sheath damage. It was originally thought that these cells belong to the subpopulation of Th-1 cells, however, a number of nowadays studies indicate the importance Th-17 cells in the pathogenesis of the disease. In addition to demyelination, which is still considered to be the main pathological feature of the disease, in the last few years special attention in MS research has been given to neurodegenerative processes, considering that it has been shown that the clinical symptoms of the disease are directly related to the degree of axonal damage and loss. Recently, glutamate excitotoxicity is considered as a possible mechanism of neurodegeneration in MS. This is a phenomenon that occurs when the excessive amount of excitatory neurotransmitter glutamate, overactivates its receptors on the membranes of neurons and oligodendrocytes, which leads to the intracellular accumulation of Ca2+ ions and the consequent cell death. Aims of the Thesis: To examine the association of Th-17 mediated inflammation and glutamate excitotoxicity in the development of MS. To determine the potential molecular mechanisms by which inflammation stimulates glutamate excitotoxicity and the consequent neurodegeneration with special emphasis on the role of astrocytes. Materials and Methods: The study had two integral parts: a clinical part conducted on the human material and experimental part conducted on the primary cultures of rat astrocytes. The clinical study enrolled 79 patients, divided into two groups: a control group and a group of MS patients. The presence of a Th