BACKGROUND Kabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified. OBJECTIVE We sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses). METHODS We performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d+/βGeo) mouse model and validated select findings in a patient with KS. RESULTS Compared with wild-type littermates, Kmt2d+/βGeo mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d+/βGeo mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d+/βGeo mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line. CONCLUSIONS Kmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA+ plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency.

中文翻译：

---

歌舞uki症候群中异常的Peyer斑块发育和B细胞肠归巢会导致IgA缺乏。

背景技术歌舞uki综合症（KS）通常是由组蛋白修饰酶赖氨酸甲基转移酶2D（KMT2D）中的突变引起的。在KS患者中经常观察到免疫功能障碍，但尚未确定KMT2D在免疫系统功能中的作用。目的我们试图了解引起KS相关免疫缺陷（低球蛋白血症[低IgA]，脾肿大和免疫应答降低）的机制。方法我们在已建立的KS（Kmt2d + /βGeo）小鼠模型中对体液免疫力和继发性淋巴组织进行了全面评估，并验证了KS患者的选择结果。结果与野生型同窝仔相比，Kmt2d + /βGeo小鼠在多个B细胞谱系中均表现出缺陷，并在多个年龄段中均降低了血清IgA并提高了IgM水平。骨髓，脾脏，Kmt2d + /βGeo小鼠的肠道中含有减少的IgA分泌细胞，而在肠系膜淋巴结和Peyer斑中发现了生发中心B细胞升高。Kmt2d + /βGeo小鼠的Peyer斑块大小和数量均减少，这一发现已在人类样品中得到证实。我们确定了Itgb7 RNA和蛋白质表达的缺失，该基因编码一种介导肠归巢的粘附蛋白，并且我们证明了在人细胞系中ITGB7表达的KMT2D依赖性控制。结论Kmt2d单倍体不足对B细胞分化具有广泛的有害作用，特别是阻碍肠道淋巴细胞的归巢和IgA +浆细胞的分化。由ITGB7缺乏引起的肠淋巴缺损以前在KS中未被发现，