Reynolds John, Moss Jill, Duda Mark A, Smith Jennifer, Karkar Ayman M, Macherla Vamshi, Shore Ian, Evans David J, Woodrow David F, Pusey Charles D
Renal Section, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, UK.
J Pathol. 2003 May;200(1):118-29. doi: 10.1002/path.1336.
Goodpasture's, or anti-glomerular basement membrane (GBM), disease presents with rapidly progressive glomerulonephritis and lung haemorrhage, and is caused by autoimmunity to the NC1 domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1). This study examines the development of crescentic nephritis and alveolar haemorrhage in a model of Goodpasture's disease, experimental autoimmune glomerulonephritis (EAG), induced in WKY rats by immunization with rat GBM in adjuvant. An increase in circulating anti-GBM antibodies and albuminuria was observed by week 2, which increased further by weeks 3 and 4, while a decrease in creatinine clearance was observed by week 2, which decreased further by weeks 3 and 4. The kidneys of animals with EAG showed linear deposits of IgG on the GBM and a transient glomerular infiltration by CD4+ T cells at week 2. By week 3 there were large deposits of fibrin in Bowman's space, and glomerular infiltration by CD8+ T cells and macrophages, accompanied by focal necrotizing glomerulonephritis with crescent formation. Ultrastructural studies showed glomerular endothelial cell swelling and epithelial cell foot process effacement at week 2. As the lesion progressed, capillary loops became occluded and the mesangium became expanded by mononuclear cells. By week 3 there was detachment of the endothelium from the GBM, and accumulation of fibrin beneath the disrupted endothelial cells and in Bowman's space. Occasional breaks were observed in the continuity of the basement membrane, and cytoplasmic projections from infiltrating mononuclear cells could be seen crossing the capillary wall between the lumen and the crescent. The lungs of animals with EAG showed patchy binding of IgG to the alveolar basement membrane (ABM) at week 2, and infiltration of the interstitium by CD8+ T cells and macrophages by weeks 3 and 4, accompanied by both interstitial and alveolar haemorrhage. Ultrastructural studies showed focal mononuclear cell infiltrates in alveolar walls at week 2. Occasional breaks were observed in the basement membrane and adjacent endothelium by weeks 3 and 4, together with accumulation of surfactant and erythrocytes within the alveolar spaces. This study defines for the first time the relationship between the immunological and pathological events during the evolution of EAG, and provides the basis for further work on the pathogenesis of Goodpasture's disease.
肺出血肾炎综合征，即抗肾小球基底膜（GBM）病，表现为快速进展性肾小球肾炎和肺出血，由针对IV型胶原α3链的NC1结构域（α3(IV)NC1）的自身免疫引起。本研究在一种肺出血肾炎综合征模型——实验性自身免疫性肾小球肾炎（EAG）中，研究新月体性肾炎和肺泡出血的发展情况。该模型是通过用佐剂中的大鼠GBM免疫WKY大鼠诱导产生的。在第2周时观察到循环抗GBM抗体增加和蛋白尿，在第3周和第4周时进一步增加，而在第2周时观察到肌酐清除率下降，在第3周和第4周时进一步下降。患有EAG的动物的肾脏在第2周时显示GBM上有IgG线性沉积，以及CD4+T细胞短暂性肾小球浸润。到第3周时，鲍曼间隙有大量纤维蛋白沉积，以及CD8+T细胞和巨噬细胞的肾小球浸润，伴有局灶性坏死性肾小球肾炎和新月体形成。超微结构研究显示在第2周时肾小球内皮细胞肿胀和上皮细胞足突消失。随着病变进展，毛细血管袢闭塞，系膜被单核细胞扩张。到第3周时，内皮细胞与GBM分离，在破坏的内皮细胞下方和鲍曼间隙有纤维蛋白积聚。在基底膜的连续性中偶尔观察到断裂，并且可以看到浸润的单核细胞的细胞质突起穿过管腔和新月体之间的毛细血管壁。患有EAG的动物的肺在第2周时显示IgG与肺泡基底膜（ABM）的斑片状结合，在第3周和第4周时间质有CD8+T细胞和巨噬细胞浸润，伴有间质和肺泡出血。超微结构研究显示在第2周时肺泡壁有局灶性单核细胞浸润。在第3周和第4周时，在基底膜和相邻内皮中偶尔观察到断裂，同时肺泡腔内有表面活性物质和红细胞积聚。本研究首次明确了EAG演变过程中免疫和病理事件之间的关系，并为进一步研究肺出血肾炎综合征的发病机制提供了基础。
