This article reviews the commonly used murine strains for studying lupus and lupus nephritis, including strains that develop lupus spontaneously, congenic strains, induced models of lupus, as well as genetically engineered mouse models of lupus bearing transgenes or knockouts. The review then summarizes the main cellular and molecular pathways that lead to the pathogenesis of this autoimmune disease, including autoantibodies. Finally, it concludes with therapeutic insights gained from using mouse models of lupus. To sum, much of what we have learned about lupus has arisen from studying mouse models of the disease, and the laboratory mouse continues to be one of the best tools for studying human SLE.
In the search for improved stool biomarkers for inflammatory bowel disease (IBD), an aptamer-based screen of 1129 stool proteins was conducted using stool samples from an IBD cohort. Here we report that of the 20 proteins subsequently validated by ELISA, stool Ferritin, Fibrinogen, Haptoglobin, Hemoglobin, Lipocalin-2, MMP-12, MMP-9, Myeloperoxidase, PGRP-S, Properdin, Resistin, Serpin A4, and TIMP-1 are significantly elevated in both ulcerative colitis (UC) and Crohn’s disease (CD) compared to controls. When tested in a longitudinal cohort of 50 UC patients at 4 time-points, fecal Fibrinogen, MMP-8, PGRP-S, and TIMP-2 show the strongest positive correlation with concurrent PUCAI and PGA scores and are superior to fecal calprotectin. Unlike fecal calprotectin, baseline stool Fibrinogen, MMP-12, PGRP-S, TIMP-1, and TIMP-2 can predict clinical remission at Week-4. Here we show that stool proteins identified using the comprehensive aptamer-based screen are superior to fecal calprotectin alone in disease monitoring and prediction in IBD.
Epigallocatechin-3-gallate (EGCG) has been shown to attenuate obesity, fatty liver disease, hepatic inflammation and lipid profiles. Here, we validate the efficacy of EGCG in a murine model of non-alcoholic fatty liver disease (NAFLD) and extend the mechanistic insights. NAFLD was induced in mice by a high-fat diet (HFD) with 30% fructose. EGCG was administered at a low dose (25 mg/kg/day, EGCG-25) or high dose (50 mg/kg/day, EGCG-50) for 8 weeks. In HFD-fed mice, EGCG attenuated body and liver weight by ~22% and 47%, respectively, accompanied by ~47% reduction in hepatic triglyceride (TG) accumulation and ~38% reduction in serum cholesterol, resonating well with previous reports in the literature. In EGCG-treated mice, the hepatic steatosis score and the non-alcoholic steatohepatitis activity score were both reduced by ~50% and ~57%, respectively, accompanied by improvements in hepatic inflammation grade. Liver enzymes were improved ~2–3-fold following EGCG treatment, recapitulating previous reports. Hepatic flow cytometry demonstrated that EGCG-fed mice had lower Ly6C+, MHCII+ and higher CD206+, CD23+ hepatic macrophage infiltration, indicating that EGCG impactedM1/M2 macrophage polarization. Our study further validates the salubrious effects of EGCG on NAFLD and sheds light on a novel mechanistic contribution of EGCG, namely hepatic M1-to-M2 macrophage polarization. These findings offer further support for the use of EGCG in human NAFLD.
Background: In this study, we investigate the impact of epigallocatechin gallate (EGCG), the most abundant and potent catechin in green tea, on a mouse model of inflammatory bowel disease (IBD) and the underlying mechanisms of action. Methods: C57BL/6J mice were subjected to dextran sulfate sodium (DSS)-induced IBD-like disease and then randomly divided into three groups: Model group (MD), low-dose EGCG group (LE, 20 mg/kg/d), and high-dose EGCG group (HE, 50 mg/kg/d). DSS-induced clinical and macroscopic changes were monitored daily. Intestinal permeability was assessed by FITC-Dextran assay. Results: Both high- and low-dose EGCG treatment alleviated clinical manifestations including body weight loss and disease activity index (DAI) of DSS-induced colitis. The DAI score was significantly improved after two days of EGCG treatment. At the end of the study, the macroscopic severity score (MSS) of HE and LE treatment groups were 2.4 ± 1.2, and 2.2 ± 1.0, respectively, significantly lower than that of the controls (5.0 ± 2.1). EGCG treatment also prevented colon shortening, and improved intestinal permeability and histopathological changes. In addition, EGCG treatment attenuated colon inflammation by suppressing colonic levels of pro-inflammatory cytokines IL-6, MCP-1, and TNF-alpha, and inhibited CD3+ T cell and CD68+ macrophage infiltration. Conclusion: EGCG is effective in inflammatory colitis because it reduces cellular and molecular inflammation, and reduces intestinal permeability.
Background: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that causes regions of ulceration within the interior of the colon. UC is estimated to afflict hundreds of thousands of people in the United States alone. In addition to traditional colonoscopy, ultrasonic techniques can detect colitis, but have limited spatial resolution, which frequently results in underdiagnoses. Nevertheless, clinical diagnosis of colitis is still generally performed via colonoscopy. Optical techniques such as confocal microscopy and optical coherence tomography (OCT) have been proposed to detect UC with higher resolution. However, UC can potentially alter tissue biomechanical properties, providing additional contrast for earlier and potentially more accurate detection. Although clinically available elastography techniques have been immensely useful, they do not have the resolution for imaging small tissues, such as in small mammalian disease models. However, OCT-based elastography, optical coherence elastography (OCE), is well-suited for imaging the biomechanical properties of small mammal colon tissue.Methods: In this work, we induced elastic waves in ex vivo mouse colon tissue using a focused air-pulse.The elastic waves were detected using a phase-stabilized swept source OCE system, and the wave velocity was translated into stiffness. Measurements were taken at six positions for each sample to assess regional sample elasticity. Additional contrast between the control and diseased tissue was detected by analyzing the dispersion of the elastic wave and tissue optical properties obtained from the OCT structural image. Results:The results show distinct differences (P<0.05) in the stiffness between control and colitis disease samples, with a Young's modulus of 11.8±8.0 and 5.1±1.5 kPa, respectively. The OCT signal standard deviations for control and diseased samples were 5.8±0.3 and 5.5±0.2 dB, respectively. The slope of the OCT signal spatial frequency decay in the control samples was 92.7±10.0 and 87.3±4.7 dB•μm in the colitis samples. The slope of the linearly fitted dispersion curve in the control samples was 1.5 mm, and 0.8 mm in the colitis samples. Conclusions:Our results show that OCE can be utilized to distinguish tissue based on stiffness and optical properties. Our estimates of tissue stiffness suggest that the healthy colon tissue was stiffer than diseased tissue. Furthermore, structural analysis of the tissue indicates a distinct difference in tissue optical properties between the healthy and UC-like diseased tissue.
Objective. To obtain the comprehensive transcriptome profile of human citrulline-specific B cells from patients with rheumatoid arthritis (RA).Methods. Citrulline-and hemagglutinin-specific B cells were sorted by flow cytometry using peptide-streptavidin conjugates from the peripheral blood of RA patients and healthy individuals. The transcriptome profile of the sorted cells was obtained by RNA-sequencing, and expression of key protein molecules was evaluated by aptamer-based SOMAscan assay and flow cytometry. The ability of these proteins to effect differentiation of osteoclasts and proliferation and migration of synoviocytes was examined by in vitro functional assays.Results. Citrulline-specific B cells, in comparison to citrulline-negative B cells, from patients with RA differentially expressed the interleukin-15 receptor α (IL-15Rα) gene as well as genes related to protein citrullination and cyclic AMP signaling. In analyses of an independent cohort of cyclic citrullinated peptide-seropositive RA patients, the expression of IL-15Rα protein was enriched in citrulline-specific B cells from the patients' peripheral blood, and surprisingly, all B cells from RA patients were capable of producing the epidermal growth factor ligand amphiregulin (AREG). Production of AREG directly led to increased migration and proliferation of fibroblast-like synoviocytes, and, in combination with anti-citrullinated protein antibodies, led to the increased differentiation of osteoclasts.Conclusion. To the best of our knowledge, this is the first study to document the whole transcriptome profile of autoreactive B cells in any autoimmune disease. These data identify several genes and pathways that may be targeted by repurposing several US Food and Drug Administration-approved drugs, and could serve as the foundation for the comparative assessment of B cell profiles in other autoimmune diseases.
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