Kalluri R, Gattone V H, Noelken M E, Hudson B G
Department of Biochemistry, University of Kansas Medical Center, Kansas City 66160.
Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):6201-5. doi: 10.1073/pnas.91.13.6201.
Human Goodpasture syndrome is a lethal form of autoimmune disease that is characterized by pulmonary hemorrhage and glomerulonephritis. The tissue injury is mediated by autoantibodies that bind to glomerular and alveolar basement membrane. The target autoantigen is alpha 3(IV) collagen, one of six genetically distinct chains that comprise type IV collagen, and the epitope is sublocalized to the noncollagenous domain (NC1) of the alpha 3 chain. The present study reports the unique capacity of alpha 3(IV)NC1 dimer from bovine kidney to aberrantly engage the immune system of rabbits to respond to self, mimicking the organ-specific form of the human disease, whereas the other chains of type IV collagen are nonpathogenic. However, alpha 3(IV)NC1 hexamer was nonpathogenic, suggesting the exposure of a pathogenic epitope upon dissociation of hexamer into dimers. Exposure of the pathogenic epitope by infection or organic solvents, events which are thought to precede Goodpasture syndrome, may be the principal factor in the etiology of the disease. The pathogenicity of alpha 3(IV) collagen brings full circle a decade of research that has identified four novel chains (alpha 3-alpha 6) of type IV collagen.
人类肺出血肾炎综合征是一种致命的自身免疫性疾病，其特征为肺出血和肾小球肾炎。组织损伤由与肾小球和肺泡基底膜结合的自身抗体介导。靶自身抗原是α3(IV)胶原蛋白，它是构成IV型胶原蛋白的六条基因不同的链之一，其表位亚定位在α3链的非胶原蛋白结构域（NC1）。本研究报道了来自牛肾的α3(IV)NC1二聚体具有独特能力，能异常地激活兔的免疫系统对自身产生反应，模拟人类疾病的器官特异性形式，而IV型胶原蛋白的其他链则无致病性。然而，α3(IV)NC1六聚体无致病性，这表明六聚体解离成二聚体时会暴露致病表位。感染或有机溶剂导致致病表位暴露，这些被认为是肺出血肾炎综合征之前发生的事件，可能是该疾病病因的主要因素。α3(IV)胶原蛋白的致病性使对IV型胶原蛋白四条新链（α3 - α6）的十年研究圆满结束。
