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    Melissa Chng Hui Yen.
    Type 2 diabetes mellitus (T2DM) has reached epidemic proportions, afflicting 8% of the world's adult population, and represents a huge public health problem. It is strongly associated with obesity and is often preceded by obesity-associated insulin resistance (IR). While multiple factors have been shown to contribute to IR, chronic inflammation in adipose tissue is widely viewed as one of the major contributors. Extensive studies have elucidated the key roles of the cells of the innate immune system in promoting adipose tissue inflammation. Recently cells of the adaptive immune system, B and T lymphocytes, have also emerged as important regulators of glucose homeostasis. B and T cells are particularly interesting to study, not only for the different functions of their respective subpopulations, but because they bear antigen-specific receptors and are capable of memory responses, raising the intriguing possibility of antigen-specific autoimmune processes in the pathology of this disease. I approached this topic from two angles (introduced in Chapter 1). Because of the lack of information on how different B cell subpopulations affect insulin resistance, I began by studying the follicular B-2 cells and the innate-like B-1a subset that is most prominent in the peritoneal cavity (in Chapter 2). I found that the B-2 cell subset was pathogenic while the B-1a cells were novel regulators that ameliorated insulin resistance via secretion of IL-10 and IgM. Depleting BAFF to selectively deplete B-2 cells while leaving the B-1a compartment intact helped to improve glucose tolerance, suggesting a novel avenue of therapy for the future. Next, using next generation sequencing techniques, I studied the changes of the B cell immune repertoire to high fat diet (HFD) exposure (in Chapter 3) and found systematic changes in the antibody repertoire, particularly for the IgA isotype and particularly in the intestines. HFD led to increased proportions of IgA-expressing B cells with short and hydrophobic complementarity-determining region-3 sequences, and increased proportions of sequences lacking somatic mutation. Highly stereotyped or "convergent" antibody gene rearrangements expressed by the B cells in the visceral adipose tissue (VAT) and, to a lesser degree, intestinal tissues, could also be detected across numerous individual mice. These convergent antibody gene rearrangements in the adipose tissues of HFD mice were notable for having higher mutation levels, indicating that they have undergone somatic mutation. Taken together, these results demonstrate that HFD can cause significant changes in the systematic immunoglobulin repertoire in mice. To determine whether the repertoire changes seen above and in other studies might be due to an autoimmune response to obesity-related antigens, I tried a series of proof-of-principle experiments in animals with transgenic receptors against model antigens (in Chapter 4). While I could confirm enrichment of CD8 memory T cells in the VAT, experiments with obese mice bearing different MHCs, skewed B cell receptor and T cell receptor specificities showed no significant changes in glucose intolerance compared to wild type. I also immunized mice against a putative antigen in IR, glial fibrillary acidic protein (GFAP), and found no significant changes in glucose intolerance. While these results do not support the hypothesis that IR is caused or worsened by autoimmunity, the limited nature of studying a few model antigens means that autoantigens specific to the obese state, if they existed, could easily be missed by my experiments. The results also do not preclude the involvement of exogenous antigens, like bacterial antigens, and this will be the subject of future investigation.
    Digital Access   2016