慶應義塾研究者情報データベース

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• Germline variants and mosaic chromosomal alterations affect COVID-19 vaccine immunogenicity

  Sonehara K., Uwamino Y., Saiki R., Takeshita M., Namba S., Uno S., Nakanishi T., Nishimura T., Naito T., Sato G., Kanai M., Liu A., Uchida S., Kurafuji T., Tanabe A., Arai T., Ohno A., Shibata A., Tanaka S., Wakui M., Kashimura S., Tomi C., Hara A., Yoshikawa S., Gotanda K., Misawa K., Tanaka H., Azekawa S., Wang Q.S., Edahiro R., Shirai Y., Yamamoto K., Nagao G., Suzuki T., Kiyoshi M., Ishii-Watabe A., Higashiue S., Kobayashi S., Yamaguchi H., Okazaki Y., Matsumoto N., Masumoto A., Koga H., Kanai A., Oda Y., Suzuki Y., Matsuda K., Kitagawa Y., Koike R., Kimura A., Kumanogoh A., Yoshimura A., Imoto S., Miyano S., Kanai T., Fukunaga K., Hasegawa N., Murata M., Matsushita H., Ogawa S., Okada Y., Namkoong H.

  Cell Genomics 5 （ 3 ）  2025年03月

  　概要を見る

  Vaccine immunogenicity is influenced by the vaccinee's genetic background. Here, we perform a genome-wide association study of vaccine-induced SARS-CoV-2-specific immunoglobulin G (IgG) antibody titers and T cell immune responses in 1,559 mRNA-1273 and 537 BNT162b2 vaccinees of Japanese ancestry. SARS-CoV-2-specific antibody titers are associated with the immunoglobulin heavy chain (IGH) and major histocompatibility complex (MHC) locus, and T cell responses are associated with MHC. The lead variants at IGH contain a population-specific missense variant (rs1043109-C; p.Leu192Val) in the immunoglobulin heavy constant gamma 1 gene (IGHG1), with a strong decreasing effect (β = −0.54). Antibody-titer-associated variants modulate circulating immune regulatory proteins (e.g., LILRB4 and FCRL6). Age-related hematopoietic expanded mosaic chromosomal alterations (mCAs) affecting MHC and IGH also impair antibody production. MHC-/IGH-affecting mCAs confer infectious and immune disease risk, including sepsis and Graves’ disease. Impacts of expanded mosaic loss of chromosomes X/Y on these phenotypes were examined. Altogether, both germline and somatic mutations contribute to adaptive immunity functions.

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• Exercise changes the intrahepatic immune cell profile and inhibits the progression of nonalcoholic steatohepatitis in a mouse model

  Tsutsui Y., Mori T., Yoshio S., Sato M., Sakata T., Yoshida Y., Kawai H., Yoshikawa S., Yamazoe T., Matsuda M., Kakazu E., Osawa Y., Oyama C., Nakano M.T., Kawaguchi T., Yoshizumi T., Kanto T.

  Hepatology Communications 7 （ 10 ）  2023年10月

  　概要を見る

  Background: NASH is an increasingly common cause of chronic liver disease and can progress to cirrhosis and HCC. Although exercise suppresses inflammation during acute hepatitis, its impact on the progression of chronic liver disease remains unclear. Here, we investigated the effects of exercise on disease progression and intrahepatic immune cell composition in a mouse model of NASH. Method: Mice were assigned to 4 groups: 2 control groups (normal diet) and 2 NASH groups (western diet and low-dose carbon tetrachloride injection). One of each group remained sedentary and one was exercised on a treadmill for 12 weeks (60 min/d, 5 times/wk). All mice were then analyzed for liver histomorphology, steatosis, inflammation, and fibrosis; liver, adipose tissue, and skeletal muscle expression of genes related to metabolism and inflammation; and intrahepatic immune cell composition. Result: Compared with the normal diet mice, NASH mice exhibited enhanced liver steatosis, inflammation, and fibrosis; upregulated expression of liver lipogenesis-related and inflammation-related genes; and increased frequencies of intrahepatic F4/80int CD11bhi bone marrow-derived macrophages and programmed death receptor-1 (PD-1)+ CD8+ T cells. Expression of inflammatory cytokines and the frequencies of bone marrow-derived macrophages and PD-1+ CD8+ T cells correlated positively with liver steatosis, inflammation, and fibrosis. Exercise was shown to reduce NASH-induced hepatic steatosis, liver inflammation, and fibrosis; induce alterations in metabolism-related genes and inflammatory cytokines in the liver; and suppress accumulation of liver bone marrow-derived macrophages and PD-1+ CD8+ T cells. In addition, we showed that exercise induced increased expression of IL-15 in muscle and its deficiency exacerbated the pathology of NASH. Conclusions: Exercise alters the intrahepatic immune cell profile and protects against disease progression in a mouse model of NASH.

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• Toll-like receptor 7 agonist, GS-986, is an immune-stimulant inducing follicular helper T cells and expanding HBs antigen-specific B cells in vitro

  Mori T., Yoshio S., Yoshikawa S., Tsustui Y., Sakata T., Yoshida Y., Sakamoto Y., Kawai H., Osawa Y., Yamazoe T., Aoki Y., Fletcher S.P., Kanto T.

  Liver International 43 （ 6 ） 1213 - 1224 2023年06月

  ISSN  14783223

  　概要を見る

  Backgrounds and Aims: Toll-like receptor (TLR) agonists have been developed as adjuvants to efficiently induce antiviral immune responses. Specificity and potency of these compounds are essential requirements for clinical trial applications. In patients with hepatitis B virus (HBV) infections, sustained loss of hepatitis B surface antigen (HBsAg) is a therapeutic goal, which may be achievable by the sequential activation of follicular helper T cells (Tfh) and antibody-secreting B cells. We aimed to elucidate whether novel TLR7 agonist, GS-986, could activate immune responses involved in HBV elimination. Methods: To clarify the impact of GS-986 on pDCs, we quantified the expression levels of surface markers and evaluated for Tfh induction in a culture model consisting of human pDCs with allogeneic naïve CD4+ T cells. In addition, we examined whether GS-986 could enhance HBs antibody production capacity using PBMC from CHB patients. Results: pDCs from CHB patients had lower OX40L expression and as well as impaired capacity for Tfh induction compared with those from healthy donors. However, GS-986–stimulated pDCs from CHB patients expressed OX40L and produced IL-6 and IL-12, resulting in the induction of IL-21–producing Tfh cells (CXCR5+PD-1+CD4+) from naïve CD4+ T cells. The Tfh-inducing capacity of GS-986 was reduced in the presence of an anti-OX40L blocking antibody. Furthermore, GS-986 promoted HBsAg-specific antibody production in PBMCs from CHB patients. Conclusions: GS-986 is an adjuvant that stimulates pDCs to induce Tfh differentiation and antigen-specific B-cell production. This immune profile may be beneficial for therapeutic application as an immune modulator in CHB patients.

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• Peripheral-dominant liver fibrosis and tumor distribution in a mouse model of congestive hepatopathy

  Kawai H., Osawa Y., Tsunoda T., Matsuda M., Okawara M., Sakamoto Y., Shimagaki T., Tsutsui Y., Yoshida Y., Yoshikawa S., Doi H., Mori T., Yamazoe T., Yoshio S., Okamura T., Sugiyama M., Okuzaki D., Komatsu H., Inui A., Yanaga K., Ikegami T., Kanto T.

  Hepatology Research 53 （ 4 ） 370 - 376 2023年04月

  ISSN  13866346

  　概要を見る

  Aim: Congestive hepatopathy often leads to liver fibrosis and hepatocellular carcinoma. Imaging modalities provided clinical evidence that elevation of liver stiffness and tumor occurrence are mainly induced in the periphery of the liver in patients with congestive hepatopathy. However, clinical relevance of liver stiffness and liver fibrosis is unclear because liver congestion itself increases liver stiffness in congestive hepatopathy. It also unclear which factors configure such regional disparity of tumor development in patients with congestive hepatopathy. To answer these questions, we evaluated the macroscopic spatial distribution of liver fibrosis and tumors in the murine model of congestive hepatopathy. Methods: Chronic liver congestion was induced by partial ligation of the suprahepatic inferior vena cava. Distribution of liver congestion, fibrosis, and tumors in partial ligation of the suprahepatic inferior vena cava mice were assessed by histological findings, laser microdissection (LMD)-based qPCR and enhanced computed tomography. LMD-based RNA-sequencing was performed to identify causal factors that promote tumor development in congestive hepatopathy. Results: Liver fibrosis was mainly induced in the periphery of the liver and co-localized with distribution of liver congestion. Liver tumors were also induced in the periphery of the liver where liver congestion and fibrosis occurred. LMD-based RNA-sequencing revealed the upregulation of extracellular matrix/collagen fibril-, wound healing-, angiogenesis-, morphogenesis-, and cell motility-related signaling pathways in periphery of liver compared with liver center. Conclusions: Our findings showed the experimental relevance of liver congestion, fibrosis, and tumor development in congestive hepatopathy, and may provide important locational information. Macroscopic regional disparity observed in this murine model should be considered to manage patients with congestive hepatopathy.

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• Preoperative serum brain-derived neurotrophic factor as a predictive biomarker for sepsis after living-donor liver transplantation

  Tsutsui Y., Yoshio S., Tomiyama T., Shimagaki T., Itoh S., Harada N., Yoshida Y., Yoshikawa S., Kakazu E., Kanto T., Yoshizumi T.

  Hepatology Research 53 （ 1 ） 72 - 83 2023年01月

  ISSN  13866346

  　概要を見る

  Aim: Although the survival rate after living-donor liver transplantation (LDLT) is improving, sepsis still limits the prognosis. Immune dysfunction and sarcopenia are often observed in LDLT patients, and increase susceptibility to infection. Brain-derived neurotrophic factor (BDNF) is a myokine produced by immune cells and skeletal muscle. We aimed to determine whether serum BDNF could be a feasible biomarker for sepsis of LDLT patients. Methods: We measured serum samples from 124 patients who underwent LDLT and 9 healthy volunteers for BDNF. We examined its correlation with incidence rate of sepsis. To clarify the source of BDNF, we examined its expression in lymphocytes, skeletal muscle cells, and hepatocytes. Results: Patients who experienced sepsis showed worse short-term survival. Preoperative serum BDNF was lower in LDLT patients compared with healthy volunteers, and was also lower in Child–Pugh C compared with Child–Pugh A or B. Serum BDNF was inversely correlated with Model for End-Stage Liver Disease and controlling nutritional status (CONUT) scores, but had a weak positive correlation with skeletal muscle mass index (SMI). Multivariate analysis revealed that serum BDNF was independently associated with sepsis. Preoperative serum BDNF was a better predictor of sepsis in LDLT patients than CONUT score or SMI. Serum BDNF was positively correlated with lymphocyte counts, especially T cells. In vitro, T cells and skeletal muscle cells produced BDNF. Conclusions: Preoperative serum BDNF could be a predictive biomarker for sepsis after LDLT, by reflecting the systemic condition including hepatic function, nutritional status, and immune status.

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