Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORgamma t and LTi cells.
Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORgamma t and LTi cells.
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DOI：
10.1084/jem.20100052
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发表时间：
2011-01-17
期刊：
影响因子：
--
通讯作者：
Eberl G
中科院分区：
文献类型：
--
作者：
Lochner M;Ohnmacht C;Presley L;Bruhns P;Si-Tahar M;Sawa S;Eberl G
在缺乏核激素受体Rorγt的小鼠中，微生物群驱动三级淋巴组织形成，导致肠道炎症和消耗性疾病。个体发育期间淋巴结和派伊尔集合淋巴结的程序化发育需要表达核激素受体RORγt的淋巴组织诱导（LTi）细胞。出生后，肠道中的LTi细胞聚集成隐睾，即孤立淋巴滤泡（ILF）的前体，其由共生细菌诱导形成并维持肠道内稳态。我们发现，在RORγ t缺陷小鼠中，缺乏LTi细胞、程序化淋巴组织、ILF和Th17细胞，细菌遏制需要通过B细胞的活性产生大量的三级淋巴组织（tLT）。然而，在上皮损伤时，这些小鼠发展严重的肠道炎症，其特征在于嗜中性粒细胞和IgG+ B细胞的广泛募集、tLT中活化诱导的脱氨酶的高表达和消耗性疾病。通过抗生素治疗或抑制淋巴组织形成可预防病理学，并通过静脉注射免疫球蛋白G（IVIG）治疗显著降低。我们的数据表明，肠道免疫缺陷，如RORγ t介导的促炎性免疫的缺乏，可以通过增加淋巴组织生成来补偿。然而，这对宿主来说是高成本的，并且可能导致失调的B细胞应答和加重的炎性病理。
Microbiota drive tertiary lymphoid tissue formation in mice lacking the nuclear hormone receptor Rorγt, leading to intestinal inflammation and wasting disease. The programmed development of lymph nodes and Peyer’s patches during ontogeny requires lymphoid tissue inducer (LTi) cells that express the nuclear hormone receptor RORγt. After birth, LTi cells in the intestine cluster into cryptopatches, the precursors of isolated lymphoid follicles (ILFs), which are induced to form by symbiotic bacteria and maintain intestinal homeostasis. We show that in RORγt-deficient mice, which lack LTi cells, programmed lymphoid tissues, ILFs, and Th17 cells, bacterial containment requires the generation of large numbers of tertiary lymphoid tissues (tLTs) through the activity of B cells. However, upon epithelial damage, these mice develop severe intestinal inflammation characterized by extensive recruitment of neutrophils and IgG+ B cells, high expression of activation-induced deaminase in tLTs, and wasting disease. The pathology was prevented by antibiotic treatment or inhibition of lymphoid tissue formation and was significantly decreased by treatment with intravenous immunoglobulin G (IVIG). Our data show that intestinal immunodeficiency, such as an absence in RORγt-mediated proinflammatory immunity, can be compensated by increased lymphoid tissue genesis. However, this comes at a high cost for the host and can lead to a deregulated B cell response and aggravated inflammatory pathology.
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