糸球体IgA沈着におけるTh2型粘膜免疫反応の役割  [in Japanese] Glomerular IgA deposition through Th2-dominant mucosal immune responses  [in Japanese]

目的:近年,Th1/Th2パラダイムに基づきIgA腎症の発症機序が検討されているが,いまだ明らかにされていない.今回われわれは,Th2型免疫誘導転写因子GATA-3遺伝子導入トランスジェニック(GATA-3 Tg)マウスを用いて糸球体へのIgA沈着における粘膜免疫の関わりについて検討した.対象:GATA-3 Tgと卵白アルブミン(OVA)認識T細胞レセプター遺伝子導入トランスジェニック(TCR-Tg)マウスとの交配によりGATA-3/TCR-Tgマウスを作製した.対照として,GATA-3遺伝子非導入WT/TCR-Tgマウスを用いた.方法:免疫方法は,経口免疫と腹腔免疫の2種類について検討した.経口免疫において,(I)OVA+コレラトキシン(CT)もしくは(II)CT単独,腹腔免疫では(III)OVA+アラム(Alum)を投与した.各々の群に対して最終感作から1週間後にOVAを追加経口投与し,4日後に各群の(1)血清OVA特異的IgA抗体価,(2)尿中アルブミン・クレアチニン量,(3)腎・腸管の病理組織学的検討を行った.結果:OVA+CTの経口免疫GATA-3/TCR-Tgマウスのみに,(1)IgA・C3の糸球体への沈着,(2)メサンギウム細胞増殖を伴う基質の拡大,(3)血清OVA特異的IgA抗体価の上昇,(4)IgAと同一部位にmannan-binding lectin (MBL)の沈着,(5)糸球体内にIgG2aの沈着などを認め,ヒトIgA腎症と極めて類似した所見を呈した.結論:IgAの腎糸球体への沈着は,Th2型免疫反応優位な環境下の粘膜免疫系を介して誘導されることが示唆された.

Objective: The Th1/Th2 balance paradigm is considered related to the pathogenesis of IgA nephropathy. The present study investigated the mechanism of glomerular IgA deposition via mucosal immunity in several kinds of GATA-3 transgenic (GATA-3 Tg) mice, which have a Th2-dominant immunological background. Materials: The hemizygous GATA-3 Tg mice were crossed with the homozygous type of another transgenic (TCR-Tg) mouse for T cell receptor (TCR) recognizing OVA_<323-339> peptide in the context of I-A^d restriction. GATA-3/TCR-Tg and non-GATA-3 (WT) /TCR-Tg mice were generated by this method. Methods: Cholera enterotoxin (CT) was used as a mucosal adjuvant for Th2-dominant immune responses in oral immunization. Alum was used as an adjuvant for general immunopotentitation in intraperitoneal immunization. GATA-3/TCR-Tg mice and WT/TCR-Tg mice were orally preimmunized with OVA and CT or CT alone. The animals were orally immunized with OVA for 7 days after the final immunization. The levels of serum OVA-specific IgA antibody, urinary albumin and creatinine excretion and histopathological analysis of the kidney and intestine were examined. Measurement and Results: Only GATA-3/TCR-Tg mice that were orally immunized with OVA and CT showed mesangial proliferation with IgA/C3 depositions, the elevation of serum levels of OVA-specific IgA antibody, glomerular MBL deposition colocalized with IgA, and IgG2a deposition. These findings closely resemble clinical findings in human IgA nephropathy. Conclusions: The present data indicate that Th2-dependent mucosal immune responses may lead to glomerular IgA deposition, presumably through aberrant glycosylation of IgA.