Introduction: SLE is associated with pro-atherogenic metabolic derangement and an elevated cardiovascular risk. The vascular endothelium may be a key interface between active SLE and premature atherosclerosis. Improved understanding of the contribution of inflammation and its management to cardiovascular risk in SLE will inform personalised treatment decisions in SLE patients. Methods: Data from an international inception cohort was used to investigate the relationship between inflammatory disease activity, lupus phenotype and corticosteroid exposure and the metabolic syndrome (MetS) over 2 years in SLE patients. The relationship between disease activity (BILAG-2004) and markers of endothelial function (flow-mediated dilatation (FMD) of the brachial artery) and endothelial damage (endothelial microparticles (EMPs)) following a change in anti-inflammatory therapy was investigated in a longitudinal cohort of patients with active SLE. Results: MetS was common in young SLE patients (12.6-16.0%) over the initial 2 years of disease. Factors independently associated with developing MetS over the 2-year study period were (odds ratio (95% CI)) Hispanic ethnicity (3.47 (1.76, 6.86)), higher initial peak corticosteroid dose (1.02 (1.01,1.03)), and elevated anti-dsDNA antibodies at study entry (1.86(1.19,2.81)). MetS was often persistent and preceding MetS strongly predicted future MetS (4.83 (2.93, 7.87)). Patients with active SLE had reduced FMD (median (IQR) FMD 1.63% (-1.22, 5.32) vs. 5.40% (3.02, 8.57); p = 0.05) and elevated EMPs (157,548/ml (59,906, 272,643) vs. 41,025 (30,179, 98,082); p = 0.003) compared to age-matched controls. Both improved following a change in anti-inflammatory therapy, and correlated moderately with change in disease activity over time. Conclusions: Inflammatory disease activity and higher doses of corticosteroids in very early disease influence the development of MetS in SLE, which can become persistent. Endothelial dysfunction is common in patients with active SLE but can be improved with better disease control. Therefore even from disease onset, therapeutic regimes should be individually tailored to achieve good disease control whilst minimising corticosteroid doses, to improve cardiovascular risk surrogates in SLE.

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Gain-of-function polymorphisms in the gene encoding human interferon regulatory factor-5 (IRF5) are associated with an increase in risk for the development of the autoimmune disease Systemic Lupus Erythematosus (SLE). IRF5 is a transcription factor that participates in the activation of the immune system through its role in both innate and adaptive immune cells. To determine the role of IRF5 in lupus pathogenesis in vivo, we evaluated the effect of Irf5-deficiency in the MRL/lpr mouse lupus model. We find that Irf5-deficient (Irf5-/-) MRL/lpr mice develop much less severe disease than their Irf5-sufficient (Irf5+/+) littermates, demonstrating an important role for IRF5 in disease pathogenesis in vivo. Patients with SLE are at increased risk for the development of atherosclerosis due in large part to poorly-defined lupus-specific risk factors. One such lupus-specific risk factor is thought to be chronic inflammation associated with the autoimmune process. As IRF5 is involved in pro-inflammatory responses we hypothesized that Irf5-deficiency would ameliorate atherosclerosis development in the context of autoimmunity. We therefore examined the role of IRF5 in the gld.apoE-/- mouse model of lupus and lupus-associated atherosclerosis. Irf5-deficiency led to a decrease in splenomegaly, lymphadenopathy, anti-nuclear autoantibody production and the severity of kidney disease. Surprisingly, despite the reduction in systemic autoimmunity, Irf5-deficiency led to a marked increase in the severity of atherosclerosis and to metabolic dysregulation characterized by hyperlipidemia, increased adiposity and insulin-resistance. Bone marrow chimera studies revealed that the pathogenic role of IRF5 in lupus was solely due to its expression in hematopoietic cells. The atheroprotective effect of Irf5 and the suppression of adiposity were found to be due to Irf5 expression in both hematopoietic and non-hematopoietic cells, whereas protection from hyperlipidemia was solely due to the expression of Irf5 in non-hematopoietic cells. Together, our results reveal a role for IRF5 in metabolic homeostasis, as well as in protection against atherosclerosis even in the setting of reduced lupus severity.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19365号 / 医博第4042号 / 新制||医||1011(附属図書館) / 32379 / 新制||医||1011 / 京都大学大学院医学研究科医学専攻 / (主査)教授 椛島 健治, 教授 佐藤 俊哉, 教授 山田 泰広 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression via inhibiting mRNA translation or degrading mRNA. Since the discovery of miRNAs, dysregulated miRNAs have been identified in human patients with various diseases. Moreover, the role of miRNAs in biological processes, including immune homeostasis and autoimmunity pathogenesis, has been widely investigated. Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that causes systemic damage to multiple organs and is characterized by the production of pathogenic autoimmune antibodies. In previous work in my lab, a set of commonly upregulated miRNAs in splenic lymphocytes of three lupus-prone mouse models was identified, including the miR-183-96-182 cluster (miR-183C) and miRNAs located at DLK1-DIO3 region. The work presented in this dissertation focuses on comparing the dysregulation pattern of miRNAs from different cell sources of lupus-prone mice and investigating the potential role of miR-183C in the pathogenesis of SLE and inflammation. The first goal was to test whether dysregulated miRNAs initially identified in the spleen of MRL/lpr mice, a standard model for SLE, is also reflected in the peripheral blood mononuclear cells (PBMCs) as PBMC is the primary source of lymphocytes in human patients. In MRL/lpr mice, we found that dysregulated miRNAs in PBMCs were overall comparable to those identified in the splenic lymphocytes. Further, comparing dysregulated miRNAs between mice and humans showed a similarity in the dysregulation of miRNAs in PBMCs of murine and human lupus. Among the upregulated miRNAs, the expression of three miRNAs of miR-183C was found to be commonly upregulated. To investigate the role of miR-183C, we developed miR-183C in CD2+ cells of C57BL/6 Faslpr/lpr (miR-183C-/-B6/lpr) mice. In miR-183C-/-B6/lpr mice, we observed a significantly reduced level of anti-dsDNA in the serum and IgG immunocomplex deposition in the kidney. Importantly, in vitro inhibition of miR-183C in activated splenic lymphocytes led to reduced production of the proinflammatory cytokine, IFN, and Foxo1, a transcription factor that is a target of miR-183C miRNAs. I also tested for miRNA changes in C57BL/6 Faslpr/lpr mice with conditional deletion of Early Growth Response-2 (EGR2) (Egr2-/- B6/lpr), another knockout mouse developed in our laboratory. Egr2 has recently been shown to regulate immunity and autoimmunity and play a role in lupus. An unexpected observation is that Egr2-/-B6/lpr mice had significantly reduced expression of a group of lupus-related miRNAs that are located at the genomic imprinted DLK1-DIO3 locus. Given that the upregulation of DLK1-DIO3 miRNAs in lupus is subjected to DNA methylation regulation and that the epigenetic regulatory role of EGR2 is emerging in recent studies, reduced representative bisulfite sequencing (RRBS) was performed to evaluate the methylation changes induced by Egr2 deletion. Global DNA hypomethylation and methylation changes at specific sites at DLK1-DIO3 region were noticed in CD4+ T cells of Egr2-/-B6/lpr mice. Overall, our research suggested a therapeutic effect of inhibiting the miR-183C expression on SLE. The interplay between epigenetic factors could help expand the possibility of controlling epigenetic regulators in autoimmune disease treatment. / Doctor of Philosophy / Systemic lupus erythematosus (SLE) is an autoimmune disease that causes damage to multiple organs. Same with other autoimmune diseases, the exacerbated immune reaction to self-antigen and auto-reactive adaptive immune cells were described in SLE. Currently, the treatment of lupus mainly uses immunosuppressive drugs to inhibit the global immune reaction. Thus, the innovative drug is desperately needed for SLE patients. MicroRNAs (miRNAs) are small RNAs that inhibit the expression of genes by binding to mRNAs in a complimentary manner. Since the discovery of the first microRNA, the pivotal role of microRNAs in immunity and autoimmunity was vigorously investigated. Our lab was the first to describe a set of miRNAs that are commonly upregulated in three murine lupus models. Among these miRNAs, miR-183, miR-96, and miR-182 belong to the miR-183-96-182 cluster (miR-183C). The aim of the study in this dissertation focused on illuminating the dysregulation pattern of miRNAs in different cell sources in the murine lupus model and the role of miR-183C in the pathogenesis of SLE. We found that miRNAs are similarly dysregulated in peripheral blood mononuclear cells and splenic lymphocytes of MRL/lpr mice. Then we conditionally knocked out the miR-183C in B6/lpr mice and investigated the effect of miR-183C loss on the pathogenesis of autoimmunity. Importantly, we found that the deletion of miR-183C led to a reduced production level of autoantibodies and ameliorated the deposition of immune complexes in the kidney. Moreover, the production of proinflammatory cytokines of splenic lymphocytes was regulated by miR-183C as well. Besides miR-183C, I also investigated the effect of early growth response 2 (EGR2), a transcription factor, on the expression of a set of lupus-related miRNAs and the methylation change at the genome location of these miRNAs. In summary, miR-183C can be a potential therapeutic target for lupus treatment while clinical human studies are needed to better clarify the effectiveness and efficiency.

Hyperacute renal failure is rarely the initial presentation of systemic lupus erythematosus (SLE). Pregnancy can predispose untreated lupus nephritis to acute renal failure. Collapsing glomerulopathy (CG) type of renal failure is not a new clinicopathological entity. There have been documented cases prior to 1979. It is thought that detection bias coupled with the predilection for HIV has caused this form of glomerulopathy to be incorrectly named or diagnosed as 'malignant focal segmental glomerulosclerosis (FSGS)'. This is a case of CG described in lupus nephritis. We present a case of untreated lupus in a female in whom pregnancy triggered the exacerbation of lupus nephritis that presented as collapsing glomerulopathy.

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