Immunological phenotype of the murine Lrba knockout
Immunological phenotype of the murine Lrba knockout
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DOI：
10.1038/icb.2017.52
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发表时间：
2017-10-01
影响因子：
4
通讯作者：
Jung, Sophie
中科院分区：
文献类型：
--
作者：
Gamez-Diaz, Laura;Neumann, Julika;Jung, Sophie
人类脂多糖反应性米色样锚定 (LRBA) 基因中的双等位基因突变会导致原发性免疫缺陷，称为 LRBA 缺陷，其特征是广泛的临床表现，包括自身免疫、器官肿大、低丙种球蛋白血症和反复感染。考虑到患者的表型异质性和疾病的严重程度，我们的目的是通过研究 Lrba 敲除（Lrba(-/-)）小鼠模型来评估 LRBA 在免疫细胞中的作用并了解潜在的病理机制。无论是在无特定病原体条件下的稳定状态下，在接种 T 依赖性和 T 非依赖性抗原后，还是在淋巴细胞性脉络膜脑膜炎病毒 (LCMV) 或鼠伤寒沙门氏菌急性感染的情况下，LRBA 缺陷小鼠均未表现出严重的临床或免疫学症状。尽管 Lrba(-/-) 小鼠能够产生正常的血清免疫球蛋白 M (IgM) 和 IgG，并在免疫后产生特异性免疫反应，但它们表现出血清和分泌性基础 IgA 水平升高。 LRBA 对于 B 细胞和 T 细胞发育以及体外 B 细胞增殖、存活、同种型转换和浆母细胞分化是不可或缺的。有趣的是，Lrba（-/-）小鼠表现出调节性T细胞的细胞毒性T淋巴细胞相关蛋白4（CTLA-4）表达减少，并激活常规CD4（+）和CD8（+）T淋巴细胞，腹膜B-1a细胞频率降低，白细胞介素10产生减少，派尔氏斑中滤泡辅助T细胞百分比增加，但没有出现明显的自身免疫迹象。我们的研究结果扩展了 LRBA 在先前报道的患者免疫调节机制中的作用，并表明其在 IgA 产生中的新作用，这对于保护粘膜表面和肠道相关的免疫耐受至关重要。
Biallelic mutations in the human lipopolysaccharide responsive beige-like anchor (LRBA) gene lead to a primary immunodeficiency known as LRBA deficiency, characterized by a broad range of clinical manifestations including autoimmunity, organomegaly, hypogammaglobulinemia and recurrent infections. Considering the phenotypic heterogeneity in patients and the severity of the disease, our aim was to assess the role of LRBA in immune cells and to understand the underlying pathomechanisms through the study of a Lrba knockout (Lrba(-/-)) mouse model. LRBA-deficient mice did not show severe clinical or immunological signs of disease, either at steady state under specific-pathogen-free conditions, after vaccination with T-dependent and T-independent antigens, or in the context of acute infections with lymphocytic choriomeningitis virus (LCMV) or Salmonella Typhimurium. Although Lrba(-/-) mice were able to produce normal serum immunoglobulin M (IgM) and IgG and to mount a specific immune response after immunization, they showed elevated serum and secretory basal IgA levels. LRBA was dispensable for B-and T-cell development, as well as for in vitro B-cell proliferation, survival, isotype switching and plasmablast differentiation. Interestingly, Lrba(-/-) mice displayed decreased cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) expression by regulatory T cells and activated conventional CD4(+) and CD8(+) T lymphocytes, reduced frequency of peritoneal B-1a cells along with diminished interleukin-10 production and increased percentages of T follicular helper cells in Peyer's patches, but without developing overt signs of autoimmunity. Our findings expand the role of LRBA in immune regulatory mechanisms previously reported in patients, and suggest a novel role in IgA production that is crucial for the protection of mucosal surfaces and gut-associated immune tolerance.