Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma

Myasthenia Gravis and thymoma are frequently associated with patients suffering from both diseases. Here the authors perform single cell sequencing of thymoma and find that there are autoimmune antigens such as neuromuscular proteins expressed aberrantly in neuromuscular mTECs in patients with both diseases

Hepatic Crown-Like Structure: A Unique Histological Feature in Non-Alcoholic Steatohepatitis in Mice and Humans

<div><p>Although macrophages are thought to be crucial for the pathogenesis of chronic inflammatory diseases, how they are involved in disease progression from simple steatosis to non-alcoholic steatohepatitis (NASH) is poorly understood. Here we report the unique histological structure termed “hepatic crown-like structures (hCLS)” in the mouse model of human NASH; melanocortin-4 receptor deficient mice fed a Western diet. In hCLS, CD11c-positive macrophages aggregate to surround hepatocytes with large lipid droplets, which is similar to those described in obese adipose tissue. Histological analysis revealed that hCLS is closely associated with activated fibroblasts and collagen deposition. When treatment with clodronate liposomes effectively depletes macrophages scattered in the liver, with those in hCLS intact, hepatic expression of inflammatory and fibrogenic genes is unaffected, suggesting that hCLS is an important source of inflammation and fibrosis during the progression of NASH. Notably, the number of hCLS is positively correlated with the extent of liver fibrosis. We also observed increased number of hCLS in the liver of non-alcoholic fatty liver disease/NASH patients. Collectively, our data provide evidence that hCLS is involved in the development of hepatic inflammation and fibrosis, thereby suggesting its pathophysiologic role in disease progression from simple steatosis to NASH.</p></div

Serological parameters and hepatic lipid content of MC4R-KO and WT mice fed a WD for 20 weeks.

<p>± SE. ^*<i>P</i><0.05 vs. WT-SD; ^§<i>P</i><0.05 vs. WT-WD; ^†<i>P</i><0.05 vs. MC4R-SD. <i>n</i> = 5-7. WT, wildtype; SD, standard diet; WD, western diet; BG, blood glucose; TC, total cholesterol; TG, triglyceride; FFA, free fatty acid; ALT, alanine aminotransferase. Data are expressed as the mean </p

Effect of Macrophage depletion on inflammatory and fibrotic changes in the liver during WD feeding.

<p>Representative F4/80 immunostaining (A) and hepatic mRNA expression of inflammatory markers (F4/80, and tumor necrosis factor α (TNFα) and fibrogenic factors (transforming growth factor-β1 (TGFβ1) and tissue inhibitor of metalloproteinase-1 (TIMP1)) (B) in the liver from wildtype mice fed a WD for 20 weeks, at which wildtype mice showed simple steatosis. Representative F4/80 immunostaining (C, E) and hepatic mRNA expression levels (D, F) in the liver from MC4R-KO mice fed a WD for 4 (C, D) and 20 weeks (E, F), at which MC4R-KO mice showed simple steatosis and NASH respectively. Arrows indicate hCLS. Quantification of F4/80-positive area (G), hCLS number (H) and αSMA-positive area (I) at 20 weeks. PBS, PBS liposome; CL, clodronate liposome. Scale bars, 50 µm. * <i>P</i><0.05, ** <i>P</i><0.01, n.s., not significant. <i>n</i> = 5–7.</p

Clinical data of patients with NAFLD/NASH and chronic viral hepatitis.

<p>± SE. ^**<i>P</i><0.01. NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; BMI, body mass index; AST, aspartate aminotransferase; ALT, alanine aminotransferase. Data are expressed as the mean </p

hCLS formation by macrophages and liver fibrosis in MC4R-KO mice fed a WD.

<p>Body weight (A) and liver weight (B) of male MC4R-KO (MC) and wildtype (WT) mice fed a western diet (WD) for 20 weeks. (C) Masson-trichrome staining of the liver sections from MC4R-KO and wildtype mice after 20 weeks of WD feeding. Time-dependent changes in liver fibrosis (Sirius red-positive area) (D) and activated fibroblasts (αSMA-positive area) (E) during WD feeding. (F) F4/80 staining at 20 weeks. Characteristic histological features by macrophage, hepatic crown-like structures (hCLS), in the liver from MC4R-KO mice were indicated by arrows. Time-dependent changes in F4/80-positive area (G) and hCLS number (H) during WD feeding. Correlation of fibrosis area with F4/80-positive area (I) and hCLS number (J). Scale bars, 50 µm. * <i>P</i><0.05, ** <i>P</i><0.01, n.s., not significant. <i>n</i> = 5–7.</p

Histological analysis of hCLS in the liver from MC4R-KO mice fed a WD.

<p>(A) Serial sections of the liver from MC4R-KO mice fed a WD for 20 weeks stained with F4/80, αSMA, and type I collagen antibodies. Immunofluorescent analysis for F4/80 (B-G), type I collagen (B, E), glial fibrillary acidic protein (GFAP) (C, F), and fibroblast specific protein 1 (FSP1) (D, G) in the liver from wildtype and MC4R-KO mice at 20 weeks. (H) Immunofluorescent analysis for F4/80 and CD11c. (I) Immunofluorescent analysis for F4/80 and lipid droplet (BODIPY). The nuclei were counterstained with DAPI (B–I). Scale bars, 50 µm. (J) Electron micrograph of hCLS. Aggregated macrophages around a lipid droplet (arrows). Fibroblasts (*F) and hepatocytes (*H) are detected around hCLS.</p