Systemic lupus erythematosus (SLE) is complex autoimmune disease in which autoantibodies form against double stranded DNA (dsDNA) and nuclear antigens. Autoantigen immune complexes form, deposit in the vasculature, and cause multisystem organ damage. Both genetic and environmental factors contribute to the development of SLE. This thesis will explore three major themes found in the study of SLE: 1) Bacterial infection as an environmental trigger, 2) cytokine dysregulation in immune cells, and 3) the treatment of end organ damage in the form of lupus nephritis. Viral infections have long been associated with the development of systemic autoimmune disease, but the mechanisms by which chronic bacterial infections may promote autoimmunity remain unclear. In chapter three we show that a component of bacterial biofilms, the amyloid-like protein “curli”, irreversibly forms fibers with bacterial or eukaryotic DNA during biofilm formation. This interaction accelerates amyloid polymerization and creates potent immunogenic complexes that activate immune cells, including dendritic cells, to produce cytokines such as type I interferons, which are pathogenic in SLE. When given systemically, curli/DNA composites trigger immune activation and production of autoantibodies in lupus-prone and wild type mice. We also found that infection with curli-producing bacteria triggered higher autoantibody titers in lupus-prone mice compared to curli-deficient bacteria. These data provide a mechanism by which the microbiome and biofilm-producing enteric infections may contribute to the progression of SLE and point to a potential molecular target for treatment of autoimmunity. Cytokine dysregulation is also common in SLE patients. Serum cytokines are often elevated during active disease, including type I IFNs and IL-10. In chapter four we demonstrate that Il10 is a type I IFN response gene and has increased basal expression in dendritic cells (DCs) derived from pre-disease lupus-prone Sle1,2,3 mice. We show that Sle1,2,3-derived DCs overproduce IL-10 in response to TLR ligands and that this is the result of autocrine signaling though the type I IFN receptor (IFNAR). These results suggest that dysregulation of cytokine signaling in the myeloid compartment may contribute to IL-10 dysregulation in SLE. Renal disease remains a major cause of morbidity and mortality in SLE. A number of mouse models of chronic kidney disease have implicated the EGFR-family receptors in the progression of renal fibrosis and dysfunction. In chapter five we show that renal expression of ErbB2 is increased in murine lupus. We therefore asked if EGFR-family inhibition could prevent murine lupus nephritis. To test this possibility we used lapatinib, an EGFR-ErbB2 dual kinase inhibitor, in an IFN-accelerated model of murine lupus. We found that lapatinib administration lowered autoantibody levels but worsened renal disease. Lapatinib failure to treat murine lupus nephritis despite lowered autoantibody levels suggests EGFR-family signaling is required for tissue repair in the acute phase of kidney injury. Together this thesis clearly demonstrates the complexity of systemic autoimmune disease – bringing us to the crossroads of immunity and tolerance. The combination of both environmental triggers (e.g. bacterial infection) and genetic susceptibility (e.g. intrinsic cytokine dysregulation) leads to end organ damage (e.g. lupus nephritis). Here we sought to explore each aspect of disease progression in the hopes to develop better interventions for systemic autoimmune disease. / Microbiology and Immunology

Wigging Out, a memoir, chronicles my first chemotherapy treatment which began in 2008 for the autoimmune disease Lupus. The primary focus is on how identity is affected by disability. Each symptom of my disease and side effect from my medications prompted a reevaluation of my identity as I felt a change both in myself and in the way others perceived me. In order to maintain a sense of control, I tried several techniques to pass and cover my disabled status, including the use of prosthetic hair pieces. Ultimately, the use of prosthetics made accepting my situation more difficult as it encouraged holding onto a former identity rather than creating a new one. It was not until I stopped using prosthetics as a form of denial and instead adopted them as part of a new identity that I was finally able to achieve the confidence necessary to fight for my life. / by Jeanette Moffa. / Thesis (M.F.A.)--Florida Atlantic University, 201?. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.

published_or_final_version / Medicine / Master / Master of Research in Medicine

 Neuropsychiatric systemic erythematosus (NPSLE) is a complicated complication of systemic erythematosus (SLE). Asian patients are associated with high prevalence of systemic disease and mortality It increases patients’ morbidity and mortality (Samanta et al., 1991). But the detailed pathology and pathogenesis are still remained unclear. Our study’s purpose is to use advanced functional imaging method, including diffusion tensor imaging (DTI) and magnetic resonance spectroscopy imaging (MRSI) to detect intracranial volumetry, functional and other metabolite changes in NPSLE patients. We recruited 3 age-matched female groups, one patient group with NPSLE (20 patients), one patient group with SLE (20 patients) and one control group (15 normal controls). Each patient was applied to structural 3D-T1 and axial T2, DTI and MRSI. Whole brain volumetry and hippocampus volumetry were analyzed by FSL and MARINA software from T1 images. White matter hyperintensity was calculated manually. Whole brain FA and other indices were collected. Regional FA was also collected and was collected with MRS over corpus callosum slice. The result showed no significant whole brain atrophy in NPSLE patients and SLE patients compared with controls. But with segmentation of grey matter, white matter and CSF, NPSLE patients showed significant decrease volume from SLE patients in white matter. Left hippocampus showed significant decreased volume in white matter and grey matter compared with control, while right hippocampus showed significant decreased volume in white matter. No other significant difference was found between NPSLE vs SLE and SLE vs controls. Whole brain FA was significantly decreased in NPSLE compared to SLE and controls, but not significantly different between SLE and controls. MD, λ∥ and λ⊥ were significantly increased in NPSLE and SLE compared with controls, but not significantly different between SLE and controls. White matter hyperintensity score was consistent with MD, λ∥ and λ⊥ results, showed significantly higher scores in two patients groups compared to controls. Regional FA, involving frontal lobes and corpus callosum, periventricular regions adjacent to centrum semiovale and posterior lateral temporal lobe, confirmed the regional FA decrease showed in whole brain FA statistical color map and NPSLE patients’ regional FA decrease correlated with MRS metabolic changes. N-acetyl aspartate (NAA)/ Creatine (Cr), the marker of neurons, decreased significantly in NPSLE patients compared with SLE and controls. Choline (Cho)/Cr showed significant increase of tendency of significant increase in NPSLE and SLE patients in some ROIs compared with controls. Our finding suggested that, although the whole brain atrophy is not obvious in NPSLE, the hippocampus and white matter suffered atrophy in NPSLE patients. These atrophy in white matter of whole brain and hippocampus combined with functional imaging results of DTI and MRS, indicated that NPSLE endured more severe axonal damage than SLE, which might be due to a variety of lesions, such as demyelination, microangiopathy, large vessel thrombosis, cytokine, etc. Varying ratio of NAA/Cr and Cho/Cr may be associated with the severity of axonal damage, probably due to demyelination in the background of inflammatory/ischemic/vasculitic changes. / published_or_final_version / Diagnostic Radiology / Master / Master of Philosophy

published_or_final_version / Medicine / Master / Doctor of Medicine

Thesis (Ph. D.)--University of Virginia, 2008. / Includes bibliographical references. Also available online through Digital Dissertations.

Thesis (M.S.W.)--University of Hong Kong, 1994. / Includes bibliographical references (leaves 81-88).

The purpose of the study was to determine the point prevalence of cognitive dysfunction in patients with systemic lupus erythematosus (SLE) and to investigate its association with corticosteroids and depression. The severity of dysfunction and the pattern of cognitive changes were examined. This study hypothesized that cognitive dysfunction is common in SLE and many previous studies have underestimated its prevalence, partially due to using limited neuropsychological batteries and insensitive test instruments. It was further hypothesized that the pattern of cognitive changes in SLE patients will resemble that observed in subcortical dementias.

published_or_final_version / abstract / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

published_or_final_version / Medicine / Master / Master of Philosophy