Kleppel M M, Kashtan C, Santi P A, Wieslander J, Michael A F
Department of Pediatrics, University of Minnesota, Minneapolis.
Lab Invest. 1989 Sep;61(3):278-89.
The glomerular basement membranes (GBM) of Alport familial nephritis (FN) are laminated and split and fail to bind Goodpasture autoantibodies by indirect immunofluorescence. The Goodpasture antigen has been localized to multiple peptides of the noncollagenous C terminal (NC1) domain of type IV collagen. The principal target antigen is a 28-kDa peptide (M28) that coisolates with type IV collagen NC1 and which is derived from a larger collagenous molecule. We have shown that two novel 28-kDa peptides found in normal GBM (M28M28+) are absent from collagenase digests of X-linked dominant Alport FN GBM and that monoclonal antibodies specific for these collagen chains fail to bind to Alport GBM. In normal tissue these chains have a distribution restricted to specific basement membranes of kidney, eye, inner ear, lung, and brain, the former three of which are affected in Alport FN. Epitopes on a 26-kDa NC1 peptide identified by an antibody from a transplanted Alport patient (FN antibody) colocalized with the 28-kDa components in these tissues. The FN antibody did not bind to the GBM of homozygous Alport males. Antibodies to the 28-kDa peptides and the FN antibody colocalized in a segmental pattern in heterozygous Alport GBM by indirect immunofluorescence and were unrelated to the normal distribution of type IV collagen. Three of eight homozygous Alport FN tissues showed the presence of the 28-kDa components in Bowman's capsule in a focal distribution, and in four of eight tissues reactive antigen was present in the cytoplasm of some parietal and visceral epithelial cells. These observations support the hypothesis that the genetic abnormality in Alport FN is a defective parent chain of the 26-kDa peptide, which results in failure of normal 28-kDa collagen chain integration.
奥尔波特家族性肾炎（FN）的肾小球基底膜（GBM）呈分层和分裂状，且通过间接免疫荧光法无法结合抗肾小球基底膜自身抗体。抗肾小球基底膜抗原已定位到IV型胶原非胶原C末端（NC1）结构域的多个肽段。主要靶抗原是一种28 kDa的肽段（M28），它与IV型胶原NC1共同分离，且源自一个更大的胶原分子。我们已表明，在正常GBM中发现的两种新型28 kDa肽段（M28M28 +）在X连锁显性奥尔波特FN GBM的胶原酶消化产物中不存在，并且针对这些胶原链的单克隆抗体无法与奥尔波特GBM结合。在正常组织中，这些链的分布局限于肾脏、眼睛、内耳、肺和脑的特定基底膜，前三者在奥尔波特FN中会受到影响。来自一名移植的奥尔波特患者的抗体（FN抗体）识别出的26 kDa NC1肽段上的表位，在这些组织中与28 kDa成分共定位。FN抗体不与纯合奥尔波特男性的GBM结合。针对28 kDa肽段的抗体和FN抗体通过间接免疫荧光法在杂合奥尔波特GBM中呈节段性共定位，且与IV型胶原的正常分布无关。八份纯合奥尔波特FN组织中有三份在鲍曼囊中呈局灶性分布的28 kDa成分，并且在八份组织中的四份中，一些壁层和脏层上皮细胞的细胞质中存在反应性抗原。这些观察结果支持这样的假说：奥尔波特FN中的遗传异常是26 kDa肽段的亲本链有缺陷，这导致正常28 kDa胶原链整合失败。
