Type 1 diabetes (T1D) is a chronic autoimmune disease in which the insulin producing β-cells in the pancreatic islets of Langerhans are selectively attacked by the immune system. The β-cells are destroyed resulting in a reduced or eliminated insulin production, which in turn lead to a high blood glucose level. The non-obese diabetic (NOD) mouse is the most commonly used animal model for human T1D. NOD mice develop diabetes spontaneously through a process that closely resembles the human pathogenesis. In both humans and the NOD mouse, disease is caused by a combination of genetic and environmental factors. In the NOD mouse, more than 30 insulin-dependent diabetes (Idd) loci on 15 chromosomes have been linked to disease susceptibility, however, most of the Idd-regions lack identification of a disease associated gene. B cells are required for T1D development, although the underlying mechanisms are not fully revealed. The aim of this thesis was to dissect B cell-related immune deviations in the NOD mouse, including the underlying genetics of these traits. The TACI receptor binds two ligands, i.e. the cytokines BAFF and APRIL.TACI ligation by APRIL mediates class switch, drives plasma cell differentiation and increases immunoglobulin production. In Paper I, a novel NOD-specific B cell-related trait was identified, i.e. the increased percentage of TACIhigh-expressing splenic B cells, by comparing NOD mice with non-autoimmune disease prone C57BL/6 mice. To investigate if the described TACI trait was controlled by genes linked to any Idd-region, an Idd-focused linkage analysis was performed. The TACI-trait mapped to regions on chromosome 1 and 8, more specifically to the vicinity of the Idd5.4 and Idd22. Interestingly, the linkage to Idd22 was explained by mice ≥61 days of age, suggesting a temporal genetic regulation of TACI expression possibly influenced by the ongoing autoimmune process. In Paper II, the linkage of the TACI trait to chromosome 1 and 8 was confirmed by analyzing the percentage of TACIhigh-expressing B cells in congenic NOD.C1/Idd22 mice. Moreover, the functional consequence of TACI upregulation was investigated, with the focus on plasma cell development and immunoglobulin production. NOD splenic B cells stimulated with APRIL displayed increased numbers of plasma cells and produced higher amounts of IgG and IgA compared to B cells from C57BL/6 mice. Thus, the TACI upregulation on NOD B cells possibly contribute to a B cell compartment which is more disposed to plasma cell differentiation and isotype switch. NOD mice display enhanced and prolonged immune response towards several antigens, including non-self immunoglobulins. In Paper III, the genetic factor(s) controlling the altered immune response against a BALB/c derived monoclonal antibody were dissected. Significant linkage to the Idd1/Idd24, Idd12, and Idd18.1 regions as well as to a proximal region on chromosome 2 (33.5 Mb) was detected. The linkage to Idd1/24 was verified by analyzing a set of H2-congenic NOD and C57BL/6 mice, and the linked region was narrowed down to ~8 Mb. Candidate gene analysis revealed a significant difference in the transcription of the H2-O/DO molecule. This suggests that multiple mechanisms contribute to the loss of immune response control, including an altered MHC class II peptide loading on NOD B cells. In Paper IV, a novel B cell intrinsic receptor for IgM and IgG was revealed. The receptor appeared to be more abundant in NOD mice compared to C57BL/6 mice, as the level of extramembranous IgG monomers and IgM pentamers on peripheral blood B cells from NOD mice was significantly higher compared to C57BL/6 mice. In addition, analysis of immune complex binding using IgG- or IgM-opsonized bacterial particles revealed a higher degree of binding in NOD mice compared with C57BL/6 mice. The enhanced capture of immunoglobulins and immune complexes could thus contribute to the development of T1D by altering normal B cell functions such as activation and immune complex transportation.
| Identifer | oai:union.ndltd.org:UPSALLA1/oai:DiVA.org:umu-51509 |
| Date | January 2012 |
| Creators | Sundström, Mia |
| Publisher | Umeå universitet, Immunologi/immunkemi, Umeå : Umeå Universitet |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, info:eu-repo/semantics/doctoralThesis, text |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | Umeå University medical dissertations, 0346-6612 ; 1476 |
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