IMMUNOLOGICAL BASIS OF EPILEPSY

点击翻译按钮获取中文摘要

The overall goal of this project is to elucidate the role of the immune response in the mechanisms underlying epilepsy. In some epileptic disorders, inflammation with significant leukocytic infiltration has been observed in the patient's central nervous system. Our basic hypothesis is that T cells which have entered the brain play an important role in the initiation and/or progression of diesease by secreting a large number of pro-inflammatory and neurotoxic mediators into the brain microenvironment, and by regulating the function of B cells and macrophages. To examine our hypothesis we will study in detail the contribution of activated lymphocytes to chronic focal encephalitis (CFE or Rasmussen's syndrome), a progressive and intractable form of epilepsy characterized pathologically by focal brain inflammation. CFE is associated with progressive neurologic deficits and intellectual impairment. Surgical removal of the affected brain tissue is the only therapy clearly shown to positively influence seizure frequency and disesase progression. The experiments proposed in the present application will test the specificity and function of T and B lymphocytes in CFE. In the first aim, T cell receptor usage, antigen specificity, and characteristics of T cells in human brain foci and peripheral blood of CFE patients will be studied. We will also genotype polymorphic genes in the MHC region in chromosome 6, including HLA class II determinants. In the second aim, we will analyze the spectrum of soluble messengers secreted by brain infiltrating T cells to asses their function during diesease. In the third aim, we will use family- specific leader-region primers for PCR amplification of the human Ig heavy chain variable-region gene repertoire in the CFE brain. In addition, single antigen (GluR3)-specific Ig+B cells will be selected from patient's peripheral blood using antigen-coated magnetic beads in order to analyze immunoglobulins V region usage. These experiments may shed considerable light on the role of the immune response in epilepsy. Extensive collaborative ties with skillful teams, access to relevant clinical samples, a superb research environment and suggestive preliminary results, all indicate that this project has a high chance of success.