論文種別	原著(症例報告除く)
言語種別	英語
査読の有無	その他(不明)
表題	rs57494551 increases CXCR5 expression and IgM+ CXCR5+ B-cell infiltration in the portal area of primary biliary cholangitis.
掲載誌名	正式名：Journal of gastroenterology 略　 称：J Gastroenterol ISSNコード：14355922/09441174
掲載区分	国外
巻・号・頁	pp.Online ahead of print
著者・共著者	Yuki Hitomi, Yoshihiro Aiba, Kazuko Ueno, Haruka Takahashi, Michihiro Kono, Kazuhiro Sugi, Yuji Teraoka, Shintaro Takaki, Atsushi Naganuma, Motoyuki Kojima, Nao Nishida, Yosuke Kawai, Minae Kawashima, Seik-Soon Khor, Michio Yasunami, Atsumasa Komori, Shinji Shimoda, Kazuyoshi Ishigaki, Masao Nagasaki, Katsushi Tokunaga, Minoru Nakamura
発行年月	2026/08
概要	BACKGROUND:Primary biliary cholangitis (PBC) is a chronic, progressive, cholestatic liver disease caused by autoimmune reactions. A previous international meta-analysis of a genome-wide association study (GWAS) reported a robust association of the human chr.11q23.3 locus including C-X-C motif chemokine receptor 5 (CXCR5) with susceptibility to PBC. However, the molecular mechanism by which CXCR5 confers disease susceptibility in PBC remains unclear.METHODS:Cutting-edge post-GWAS analyses were conducted using in silico and in vitro functional approaches, including multi-omics analysis, machine-learning-based transcription factor prediction, and prime editor as a genome-editing technology. Expression data for CXCR5 and correlated genes were obtained by RNA-seq and immunohistochemistry analyses.RESULTS:Among the variants around CXCR5, rs57494551 was identified as a disease-causal variant for PBC. rs57494551 regulates endogenous CXCR5 expression in B-cells through binding to the transcription repressor TEA domain transcription factor 3 (TEAD3). CXCR5 expression was correlated with disease activity, as identified by hierarchical clustering of mRNA expression patterns, and portal inflammation markers, such as serum IgM, Aspartate Transferase (AST), and Mac-2 binding protein glycosylation isomer (M2BPGi). The number of IgM+ CXCR5+ B-cells was increased in the portal area of PBC with high-disease activity.CONCLUSIONS:Immune dysregulation and portal inflammation are affected by increased expression of CXCR5 on IgM+ B-cells in PBC patients who have the risk allele of rs57494551, indicating that CXCR5 is a potential therapeutic target for PBC.HIGHLIGHTS:Among hundreds of genetic variants in CXCR5, rs57494551 was identified as a disease-causal variant using cutting-edge post-GWAS in silico and in vitro analyses, including multi-omics analysis, machine learning-based prediction, and the genome-editing technology "Prime Editor." The disease risk allele of rs57494551 increases endogenous CXCR5 expression in B-cells by releasing the binding of the transcriptional repressor TEAD3. RNA-seq and immunohistochemistry analyses revealed that CXCR5 expression is correlated with disease activity and portal inflammation markers. Furthermore, the number of IgM+ CXCR5+ B-cells was increased in the portal area of PBC with high disease activity. As well as PBC, the signifi cant associations between CXCR5 and susceptibility to various autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, systemic sclerosis, celiac disease, and Sjögren's syndrome, could be explained by the effect of rs57494551.
DOI	10.1007/s00535-026-02493-3
PMID	42573624