Nasal-associated lymphoid tissue is the major induction site for nephritogenic IgA in murine IgA nephropathy
Nasal-associated lymphoid tissue is the major induction site for nephritogenic IgA in murine IgA nephropathy
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DOI：
10.1016/j.kint.2021.04.026
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发表时间：
2021-07-19
影响因子：
19.6
通讯作者：
Suzuki, Yusuke
中科院分区：
文献类型：
--
作者：
Kano, Toshiki;Suzuki, Hitoshi;Suzuki, Yusuke
粘膜免疫失调可能在 IgA 肾病 (IgAN) 的发病机制中发挥作用。然而，尚不清楚鼻相关淋巴组织（NALT）或肠道相关淋巴组织是否是肾炎性 IgA 合成的主要诱导部位。为了检查外源性粘膜抗原是否会加剧 IgAN 的发病机制，我们评估了无菌饲养的 IgAN 发病 ddY 小鼠的疾病表型。这些小鼠被转移到特定的无病原体环境中，并分为三组：用Toll样受体9（TLR9）配体CpG-寡脱氧核苷酸攻击的组、粪便移植组和未经处理的对照组。测量从 NALT、肠系膜淋巴结和派尔氏淋巴结纯化的培养细胞的血清和上清液中异常糖基化 IgA 和 IgG-IgA 免疫复合物的水平。尽管无菌IgANonset ddY小鼠没有出现IgAN，但在转入特定的无病原体状态后，它们表现出肾损伤加重，系膜IgA沉积。 NALT 细胞比来自肠系膜淋巴结和派尔氏集结的细胞产生更多异常糖基化 IgA，从而诱导 IgG-IgA 免疫复合物形成。此外，TLR9 增强了鼻相关淋巴细胞而非肠道相关淋巴细胞产生肾炎性 IgA 和 IgG-IgA 免疫复合物。此外，用CpG寡核苷酸鼻部免疫的无菌IgAN发病ddY小鼠显示肾损伤加重，伴有系膜IgA沉积，而接受粪便移植的小鼠则没有出现IgAN。因此，NALT 是鼠 IgAN 中异常糖基化 IgA 产生的主要诱导位点。
Dysregulation of mucosal immunity may play a role in the pathogenesis of IgA nephropathy (IgAN). However, it is unclear whether the nasal-associated lymphoid tissue (NALT) or gut-associated lymphatic tissue is the major induction site of nephritogenic IgA synthesis. To examine whether exogenous mucosal antigens exacerbate the pathogenesis of IgAN, we assessed the disease phenotypes of IgAN-onset ddY mice housed germ-free. These mice were transferred to a specific pathogen-free environment and divided into three groups: challenged with the Toll-like receptor 9 (TLR9) ligand CpG-oligodeoxynucleotide, fecal transplantation, and the untreated control group. The levels of aberrantly glycosylated IgA and IgG-IgA immune complexes were measured in the serum and supernatant of cultured cells purified from the NALT, mesenteric lymph nodes, and Peyer's patch. Although the germ-free IgANonset ddY mice did not develop IgAN, they showed aggravation of kidney injury with mesangial IgA deposition after transfer to the specific pathogen-free state. The NALT cells produced more aberrantly glycosylated IgA than those from the mesenteric lymph node and Peyer's patch, resulting in induction of IgG-IgA immune complexes formation. Additionally, TLR9 enhanced the production of nephritogenic IgA and IgG-IgA immune complexes by nasal-associated lymphoid but not gut-associated lymphatic cells. Furthermore, the germ-free IgAN-onset ddY mice nasally immunized with CpG-oligonucleotide showed aggravation of kidney injury with mesangial IgA deposition, whereas those that received fecal transplants did not develop IgAN. Thus, NALT is the major induction site of the production of aberrantly glycosylated IgA in murine IgAN.