用IV型胶原α3链免疫的Wistar - Kyoto大鼠中的实验性肺出血肾炎综合征
Experimental Goodpasture's syndrome in Wistar-Kyoto rats immunized with alpha3 chain of type IV collagen.
作者信息
Abbate M, Kalluri R, Corna D, Yamaguchi N, McCluskey R T, Hudson B G, Andres G, Zoja C, Remuzzi G
机构信息
Mario Negri Institute for Pharmacological Research, Bergamo, Italy; Renal-Electrolyte and Hypertension Division, University of Pennsylvania Medical Center, Philadelphia, USA.
出版信息
Kidney Int. 1998 Nov;54(5):1550-61. doi: 10.1046/j.1523-1755.1998.00153.x.
BACKGROUND
Glomerulonephritis and lung hemorrhage of autoimmune Goodpasture syndrome develop due to immune reactions against epitope(s) of the non-collagenous (NC1) domain of alpha3-chain of type IV collagen [alpha3(IV) NC1]. Whether thymic mechanisms have a role in the loss of tolerance to the Goodpasture epitope has not been established. We studied the renal and pulmonary effects of immunization with different forms (monomer, dimer, or hexamer) of alpha3(IV) NC1 collagen in Wistar-Kyoto (WKY) rats, and assessed whether the intrathymic inoculation of the antigen may protect against anti-GBM disease.
METHODS
WKY rats were immunized with bovine alpha3(IV) monomer, dimer, or hexamer, or with alpha3(IV) NC1 synthetic peptide. Renal function, kidney and lung immunohistology, and circulating and tissue bound antibodies to type IV collagen chains were analyzed. Effects of intrathymic inoculation of antigen on subsequent disease induction were analyzed in WKY rats given alpha3(IV) NC1 dimer or GBM preparation intrathymically 48 hours before immunization.
RESULTS
Proteinuria, linear IgG deposition in GBM, and crescentic glomerulonephritis developed in WKY rats immunized with alpha3(IV) NC1 dimer or hexamer. Lesions were dose-dependent upon injections of 10 to 100 microgram dimer. The alpha3(IV) NC1 monomer induced less severe proteinuria and no crescents. Pulmonary hemorrhage was detectable in 35% of rats immunized with 25 to 100 microgram alpha3(IV) NC1 dimer; alpha3(IV) synthetic peptide (36 carboxyl terminal) did not induce disease. Rats injected intrathymically with up to 100 microgram alpha3(IV) NC1 dimer or with GBM 48 hours before immunization were not protected against subsequent development of proteinuria and glomerulonephritis.
CONCLUSIONS
These findings document that glomerulonephritis and lung hemorrhage can be elicited in WKY rats by immunization with alpha3(IV) NC1. Failure of the intrathymic inoculation of antigen to prevent disease suggests that immunological tolerance cannot be achieved by this intervention, in contrast to other autoimmune conditions, and may imply independent roles for cellular and humoral nephritogenic pathways in anti-GBM nephritis.
背景
自身免疫性Goodpasture综合征的肾小球肾炎和肺出血是由于针对IV型胶原α3链非胶原（NC1）结构域表位的免疫反应所致。胸腺机制在对Goodpasture表位的耐受性丧失中是否起作用尚未明确。我们研究了用不同形式（单体、二聚体或六聚体）的α3（IV）NC1胶原免疫Wistar - Kyoto（WKY）大鼠的肾脏和肺部效应，并评估胸腺内接种抗原是否可预防抗肾小球基底膜（GBM）疾病。
方法
用牛α3（IV）单体、二聚体或六聚体，或α3（IV）NC1合成肽免疫WKY大鼠。分析肾功能、肾脏和肺部免疫组织学，以及循环和组织中IV型胶原链抗体。在免疫前48小时胸腺内接种抗原的WKY大鼠中，分析胸腺内接种抗原对后续疾病诱导的影响，这些大鼠接受了α3（IV）NC1二聚体或GBM制剂胸腺内注射。
结果
用α3（IV）NC1二聚体或六聚体免疫的WKY大鼠出现蛋白尿、GBM中线性IgG沉积和新月体性肾小球肾炎。病变与10至100微克二聚体的注射剂量呈剂量依赖性。α3（IV）NC1单体诱导的蛋白尿较轻且无新月体形成。35%用25至100微克α3（IV）NC1二聚体免疫的大鼠可检测到肺出血；α3（IV）合成肽（36个羧基末端）未诱导疾病。在免疫前48小时胸腺内注射高达100微克α3（IV）NC1二聚体或GBM的大鼠，未预防随后蛋白尿和肾小球肾炎的发生。
结论
这些发现表明，用α3（IV）NC1免疫WKY大鼠可引发肾小球肾炎和肺出血。胸腺内接种抗原未能预防疾病表明，与其他自身免疫性疾病不同，这种干预无法实现免疫耐受，这可能意味着细胞和体液致肾炎途径在抗GBM肾炎中具有独立作用。
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