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oai:repisalud.isciii.es:20.500.12105/149742024-09-27T20:02:32Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19609

00925njm 22002777a 4500 dc Alves da Costa, Thiago author Peterson, Jacob N author Lang, Julie author Shulman, Jeremy author Liang, Xiayuan author Freed, Brian M author Boackle, Susan A author Lauzurica, Pilar author Torres, Raul M author Pelanda, Roberta author 2021-04-20 Central B cell tolerance, the process restricting the development of many newly generated autoreactive B cells, has been intensely investigated in mouse cells while studies in humans have been hampered by the inability to phenotypically distinguish autoreactive and nonautoreactive immature B cell clones and the difficulty in accessing fresh human bone marrow samples. Using a human immune system mouse model in which all human Igκ+ B cells undergo central tolerance, we discovered that human autoreactive immature B cells exhibit a distinctive phenotype that includes lower activation of ERK and differential expression of CD69, CD81, CXCR4, and other glycoproteins. Human B cells exhibiting these characteristics were observed in fresh human bone marrow tissue biopsy specimens, although differences in marker expression were smaller than in the humanized mouse model. Furthermore, the expression of these markers was slightly altered in autoreactive B cells of humanized mice engrafted with some human immune systems genetically predisposed to autoimmunity. Finally, by treating mice and human immune system mice with a pharmacologic antagonist, we show that signaling by CXCR4 is necessary to prevent both human and mouse autoreactive B cell clones from egressing the bone marrow, indicating that CXCR4 functionally contributes to central B cell tolerance. Proc Natl Acad Sci USA. 2021 Apr 20;118(16):e2021570118. 10.1073/pnas.2021570118 1091-6490 Proceedings of the National Academy of Sciences of the United States of America 33850015 http://hdl.handle.net/20.500.12105/14974 B cell tolerance CXCR4 Autoimmunity Hu-mice Central human B cell tolerance manifests with a distinctive cell phenotype and is enforced via CXCR4 signaling in hu-mice