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.

中枢 B 细胞耐受性是限制许多新生成的自身反应性 B 细胞发育的过程，已在小鼠细胞中进行了深入研究，而人类研究因无法在表型上区分自身反应性和非自身反应性未成熟 B 细胞克隆以及难以获得而受到阻碍新鲜的人骨髓样本。使用人类免疫系统小鼠模型，其中所有人类 Igκ ⁺B 细胞经历中枢耐受，我们发现人类自身反应性未成熟 B 细胞表现出独特的表型，包括较低的 ERK 激活和 CD69、CD81、CXCR4 和其他糖蛋白的差异表达。在新鲜的人骨髓组织活检标本中观察到表现出这些特征的人 B 细胞，尽管标记表达的差异小于人源化小鼠模型。此外，这些标记物的表达在植入了一些具有自身免疫遗传倾向的人类免疫系统的人源化小鼠的自身反应性 B 细胞中略有改变。最后，通过用药理学拮抗剂治疗小鼠和人类免疫系统小鼠，我们表明 CXCR4 的信号传导对于防止人类和小鼠自身反应性 B 细胞克隆流出骨髓是必要的，