The role of Th2-dominant mucosal immune responses in glomerular IgA deposition

近来，包括卫生学假说在内，Th2型免疫反应被认为在IgA肾病的发病机制中起重要作用。因此，我们利用转录因子GATA-3与Th2型免疫诱导基因相关的GATA-3转基因(GATA-3TG)小鼠研究了IgA产生和沉积的机制。以卵白蛋白(OVA)和明胶为佐剂的腹腔免疫后，尽管血清IgA抗体水平显著升高，但未观察到提示IgA肾病的组织病理学和尿液检查结果。霍乱毒素具有粘膜免疫佐剂活性，经口服免疫后，可见与人IgA肾病类似的IgA、Ig G和C3沉积，系膜细胞伴随增殖的基质扩张，血清IgA抗体水平显著升高。为了评估…的作用机制此外，在细胞因子表达方面，我们观察了口服OVA和霍乱毒素的GATA-3TG小鼠在体外经OVA再刺激后，Peyer氏斑、肠系膜淋巴结和脾中产生的Th1和Th2细胞因子的数量。(1)在脾中，口服OVA后诱导了对Th1型免疫反应的耐受。这种免疫耐受诱导了IL-4对Th1型免疫应答的调节。(2)在接受OVA和CT的小鼠免疫耐受破坏的同时，Th1型免疫应答在抑制转化生长因子-β的产生和IL-2和干扰素-γ的产生方面恢复正常。(3)免疫组织学研究发现，Th1+CD25+T细胞的阳性率与免疫组织学研究中的CD4+CD25+T细胞的阳性率有关，因此，实验结果表明，通过粘膜免疫调节Th1/Th2平衡参与了IgA肾病的发病机制。结果表明，所建立的小鼠和系统可作为鉴定IgA肾病的致病物质和更详细的发病机制的有用工具。较少

A Th2-type immune response has recently been suggested to play an important role in the mechanism of pathogenesis of IgA nephropathy, including the hygiene hypothesis. We have therefore studied the mechanism of IgA production and deposition using GATA-3 transgenic (GATA-3 Tg) mice into which transcription factor GATA-3 related to the Th2 type immunity inducement gene. After intraperitoneal immunization with ovalbumin (OVA) and alum as the adjuvant, despite a significant increase in serum levels of IgA antibody, no histopathological and urinary findings suggesting IgA nephropathy were observed. However, after oral immunization with cholera toxin, which possesses adjuvant activity for mucosal immunity, deposition of IgA, IgG and C3 similar to that in association with human IgA nephropathy as well as expansion of the matrix accompanying proliferation of mesangial cells were observed, in addition to a significant increase in serum levels of IgA antibody. In order to assess the mechanism of … More this IgA deposition in terms of cytokine expression, we evaluated the amount of Thl and Th2 cytokines produced in the Peyer's patch, mesenteric lymph nodes and spleen in response to OVA restimulation in vitro in GATA-3 Tg mice receiving OVA and cholera toxin orally.(1) In the spleen, tolerance to Thl-type immune response was induced after oral administration of OVA. This immune tolerance induced regulation of Thl-type immune responses by IL-4.(2) While the disruption of immune tolerance was observed in mice receiving OVA and CT, Thl-type immune responses in inhibition of TGF-beta production and in production of IL-2 and IFN-gamma were normalized.(3) A correlation with the positive rate of interstitial CD4+CD25+T cells in the spleen in the immunohistological study was observed.Thus, the experiment result indicated that a regulation of the Th1/Th2 balance via mucosal immunity is involved in the mechanism of the pathogenesis of IgA nephropathy. The finding and result indicate that the mice and the system we generated can serve as useful tools to identify causative substances for IgA nephropathy and analyze more detailed mechanism of the pathogenesis. Less