Published papers

© 2020 Japanese Society for Investigative Dermatology Background: The thymus plays an essential role in removing autoreactive T cells. Autoantigen-expressing thymic epithelial cells (TECs) contribute to the tolerogenic process. The thymus transiently shrinks as an acute thymic involution (ATI) under various inflammatory conditions. However, whether ATI occurs during local skin inflammation remains unclear, as does its influence on thymic immune tolerance. Objective: We investigated whether imiquimod-induced dermatitis causes ATI and impairs thymic immune tolerance against desmoglein 3 (Dsg3), an epidermal autoantigen of pemphigus vulgaris. Methods: 5% imiquimod cream was applied daily, at 62.5 mg/day (high dose group) or 31.25 mg/day (low dose group), for 1 week on the back of wild-type mice, and to wild-type mice that had undergone bone-marrow transplantation from Dsg3-specific T-cell receptor (TCR) transgenic-Rag2−/− mice. Next, thymocytes, TECs and other immune cells were analyzed by flow cytometry. TEC-associated Dsg3 expression was also analyzed by immunofluorescence staining. Results: Thymus weight and thymocyte number in all developmental stages decreased in a dose-dependent manner under imiquimod-induced dermatitis. The number of total TECs, specifically medullary, but not cortical, TECs, decreased in high and low dose groups. Accordingly, the number of Dsg3-experssing UEA-1+keratin 5+mTEC decreased in the thymus during imiquimod-induced dermatitis. Although Dsg3-sepcific transgenic thymocytes was usually deleted in the thymus under physiological condition by central tolerance, Dsg3-sepcific transgenic CD4+CD8− thymocytes significantly increased in number under imiquimod-induced dermatitis. Conclusion: These findings indicate a crosstalk between skin and thymus in adult mice and suggest that skin inflammation may impair thymic tolerance to autoantigens, such as Dsg3.

© 2020 European Association for the Study of the Liver Background & Aims: The number of patients with non-alcoholic steatohepatitis (NASH) is increasing globally. Recently, specific chemokine receptors have garnered interest as therapeutic targets in NASH. This is the first report to examine the role of the C-C chemokine receptor 9 (CCR9)/C-C chemokine receptor ligand 25 (CCL25) axis, and to reveal its therapeutic potential in NASH. Methods: Patients with biopsy-proven non-alcoholic liver disease (NAFLD) were recruited and their serum and hepatic chemokine expression was examined. Furthermore, wild-type (WT) and Ccr9−/− mice were fed a high-fat high-cholesterol (HFHC) diet for 24 weeks to establish NASH. Results: Serum CCL25, and hepatic CCR9 and CCL25 expression levels were increased in patients with NASH compared to healthy volunteers. Furthermore, Ccr9−/− mice were protected from HFHC diet-induced NASH progression both serologically and histologically. Flow cytometry and immunohistochemistry analysis showed that CCR9+CD11b+ inflammatory macrophages accumulated in the inflamed livers of HFHC diet-fed mice, while the number was reduced in Ccr9−/− mice. Consistent with human NASH livers, CCR9 was also expressed on hepatic stellate cells (HSCs) in mice with NASH, while CCR9-deficient HSCs showed less fibrogenic potential in vitro. Administration of a CCR9 antagonist hampered further fibrosis progression in mice with NASH, supporting its potential clinical application. Finally, we showed that CCR9 blockade attenuated the development of NAFLD-related hepatocellular carcinoma in HF diet-fed mice injected with diethylnitrosamine. Conclusions: These results highlight the role of the CCR9/CCL25 axis on macrophage recruitment and fibrosis formation in a murine NASH model, providing new insights into therapeutic strategies for NASH. Lay summary: Herein, we show that a specific chemokine axis involving a receptor (CCR9) and its ligand (CCL25) contributes to the progression of non-alcoholic steatohepatitis and carcinogenesis in humans and mice. Furthermore, treatment with a CCR9 antagonist ameliorates the development of steatohepatitis and holds promise for the treatment of patients with non-alcoholic steatohepatitis.

© 2020 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd The clinicopathological characteristics of steatosis in hepatocellular carcinoma (HCC) remain unclear. Here, we elucidate the features of macrovesicular steatosis (MaS) and microvesicular steatosis (MiS) in HCC and their relationships with background liver steatosis. A total of 165 HCC lesions were classified as MaS-HCC, MiS-HCC, or conventional HCC (cHCC) according to the cutoff value of 30% MaS or MiS in tumor cells. We analyzed the clinicopathological differences among these groups. MaS-HCC had less portal vein invasion, a higher proportion of HCC with intratumoral fibrosis, and a lower cumulative risk of recurrence than MiS-HCC or cHCC. Moreover, both MaS-HCC and MiS-HCC had lower incidences of hepatitis virus infection and higher levels of HbA1c than cHCC. Background liver steatosis was also higher in MaS-HCC than in cHCC. Immunohistochemical expression of perilipin (Plin1) and adipophilin (ADRP), major proteins expressed on lipid droplet membranes, revealed that almost all lipid droplets in HCC were Plin1 negative, whereas those in background liver were positive. In contrast, ADRP was expressed on lipid droplets in both HCC and background liver. We concluded that MaS-HCC and MiS-HCC were associated with metabolic abnormalities but exhibited different biologic behaviors. Furthermore, lipid droplets in HCC were pathophysiologically different from those in background liver.

© 2019 Georg Thieme. All rights reserved. Background Metastasis from one tumor into another is known as tumor-to-tumor metastasis. We report a case of a contiguous occurrence of meningioma and brain cancer metastasis. Patient A 91-year-old woman presented with a sudden onset of weakness in her right limbs and gait disturbance. Fourteen years previously, she had a tumor that was suspected to be a meningioma in the left frontal convexity with no change for several years. One year earlier to presentation she was diagnosed with lung carcinoma in the left lower lobe. Results Magnetic resonance images revealed enlargement of the tumor with perifocal edema. Histologic examination showed a meningioma with contiguous metastatic poorly differentiated adenocarcinoma, as well as a clearly defined border between the two components. The clinical origin of the metastasis was presumed to be from the left lower lobe of the lung. Conclusion Although our case does not strictly fulfill the definition of tumor-to-tumor metastasis, we suggest a contiguous occurrence develops by the same mechanism and may be a subtype of this process. Although previous reports suggested the loss of epithelial cadherin (E-cadherin) expression in the recipient tumor as the cause of contiguous metastasis, E-cadherin expression was positive in our case and did not seem to be involved in the localization of the metastasis.

© 2020 Increasing reports have noted an increased prevalence of lung cancer in human immunodeficiency virus (HIV)-positive patients with poor prognosis. A 51-year-old HIV-positive man was diagnosed with stage IV squamous cell lung cancer. He had high grade spike intermittent fever and persistent elevation of the white blood cell count as well as C-reactive protein (CRP) levels. Although we suspected opportunistic infections, we did not detect any infection. The autopsy showed positive immunostaining for Interleukin-6 (IL-6) in plasma cells of the stromal regions and G-CSF in tumor cells, which were considered responsible for his significant tumor fever, leukocytosis and high titers of CRP. This case report highlights the need to consider cytokine-producing tumor as a differential diagnosis of fever and high inflammatory status in HIV-positive cancer patients.