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Az antitest diverzifikációt meghatározó folyamatok, valamint egy autoantitestek által mediált neuromuszkuláris betegség, a myasthenia gravis immunológiai és genetikai hátterének vizsgálata
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Az antitest diverzifikációt meghatározó folyamatok, valamint egy autoantitestek által mediált neuromuszkuláris betegség, a myasthenia gravis immunológiai és genetikai hátterének vizsgálata
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Az antitest diverzifikációt meghatározó folyamatok, valamint egy autoantitestek által mediált neuromuszkuláris betegség, a myasthenia gravis immunológiai és genetikai hátterének vizsgálata
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Dissertation
Az antitest diverzifikációt meghatározó folyamatok, valamint egy autoantitestek által mediált neuromuszkuláris betegség, a myasthenia gravis immunológiai és genetikai hátterének vizsgálata
2011
Overview
In this thesis we focused on two major aspects of B-cell immunology. In the first part of the dissertation we investigated the role of a poorly defined transcription factor, homeobox C4 (Hox C4) in antibody diversification, a physiological characteristic of germinal centre B-cells. Using Hox C4 knock-out mice, we showed that Hox C4 plays a vital role in both somatic hypermutation and isotype switching via the regulation of activation induced cytidine deaminase, the key enzyme of antibody diversification. In the second part of the dissertation we focused on a pathological condition of antibody production, and examined two factors which could potentially influence the pathomechanism of autoimmune myasthenia gravis (MG). For this purpose we established a biobank consisting of 170 MG patients. First we examined the presence of natural autoantibodies reactive with carbohydrates and glucosaminoglycans found in skeletal muscle and thymus tissue in sera of patients with MG. We showed that the serum levels of chondroitin-sulphate A, C and heparane sulphate IgM as well as chondroitin-sulphate C IgG are significantly higher in patients with MG compared to age and gender matched healthy controls. We also found that in patients who harbour anti-AChR antibodies, there is a significant difference in the anti-carbohydrate antibody profile compared to healthy controls, the levels of anti-α-mannose IgG antibodies are higher. Secondly we investigated the genetic background of myasthenia by the investigation of association of various non-HLA genes. 1. We found that two intronic polymorphisms of the ERα gene previously shown to be associated with multiple autoimmune diseases, were not associated with MG in women. 2. We showed that from the examined three functional polymorphisms of the IL4Rα gene, the rare GG genotype of the I75V polymorphism, which influences signal transduction, is associated with MG. 3. We are the first to describe the association of a galectin-1 polymorphism with human disease. The haplotype of the rs4820293 galectin-1 polymorphism, and the rs743777 IL2Rβ polymorphism shows strong association with MG, and causes a 2,3 fold increase in the risk for developing the disease. 4. We are also the first to describe the disease association of a polymorphism of the galectin-8 gene. The described polymorphism is functional; it alters carbohydrate binding of galectin-8.
