Targets of alloantibodies in Alport anti-glomerular basement membrane disease after renal transplantation
Targets of alloantibodies in Alport anti-glomerular basement membrane disease after renal transplantation
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DOI：
10.1046/j.1523-1755.1998.00794.x
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发表时间：
1998-03-01
影响因子：
19.6
通讯作者：
Turner, AN
中科院分区：
文献类型：
--
作者：
Brainwood, D;Kashtan, C;Turner, AN
少数Alport综合征患者在肾移植后的同种异体移植物中发生抗GBM疾病。在临床上，肾脏疾病似乎与天然肾脏的古德帕斯彻氏病无法区分，其中自身抗体的靶点已被鉴定为IV型胶原α 3链的NC 1结构域，α 3（IV）NC 1。然而，在大多数情况下，Alport综合征是由于位于X染色体上的编码IV型胶原α 5链的基因突变所致。在大多数Alport综合征患者的肾小球基底膜（GBM）中，两条链都检测不到。我们研究了12名Alport患者的同种抗体的目标，这些患者通过Western印迹法在昆虫细胞中制备的重组NC 1结构域上形成移植后抗GBM疾病。对于典型的Goodpasture和Alport抗GBM抗体，与这些抗原的结合是强的和构象敏感的。9种抗体显示出与α 5（IV）NC 1的选择性结合。通过间接免疫荧光法证明与胶原酶溶解的人GBM的26 kDa条带结合和/或与正常表皮和肾基底膜结合，证实了这种特异性。一种抗体显示与α 5和α 3（IV）NC 1结合，而两种抗体显示与α 3（IV）NC 1的主要结合。所有7例患者的系谱或突变分析显示X连锁遗传主要抗α 5反应。一个主要的抗α 3反应有一个COL 4A 3突变。这些发现表明，人类抗GBM疾病可能与针对不同分子靶标的抗体相关。α 5（N）NC 1是大多数发生移植后抗GBM疾病的X连锁Alport综合征患者的主要靶点。
A minority of patients with Alport syndrome develop anti-GBM disease in their allografts after renal transplantation. Clinically, the renal disease appears indistinguishable from Goodpasture's disease of native kidneys, in which the target of autoantibodies has been identified as the NC1 domain of the alpha 3 chain of type IV collagen, alpha 3(IV)NC1. However, in the majority of cases, Alport syndrome is due to mutations in the gene encoding the alpha 5 chain of type IV collagen, located on the X chromosome. Neither chain is detectable in the glomerular basement membrane (GBM) of most patients with Alport syndrome. We investigated the targets of the alloantibodies of 12 Alport patients who developed post-transplant anti-GBM disease by Western blotting onto recombinant NC1 domains made in insect cells. Binding to these antigens, for both typical Goodpasture and Alport anti-GBM antibodies, was strong and conformation-sensitive. Nine antibodies showed selective binding to alpha 5(IV)NC1. This specificity was confirmed by the demonstration of binding to a 26 kDa band of collagenase-solubilized human GBM, and/or binding to normal epidermal as well as renal basement membranes by indirect immunofluorescence. One antibody showed binding to alpha 5 and alpha 3(IV)NC1, while two showed predominant binding to alpha 3(IV)NC1. All seven patients whose pedigree or mutation analysis showed X-linked inheritance had predominant anti-alpha 5 reactivity. One with predominant anti-alpha 3 reactivity had a COL4A3 mutation. These findings show that human anti-GBM disease can be associated with antibodies directed towards different molecular targets. alpha 5(N)NC1 is the primary target in most patients with X-linked Alport syndrome who develop post-transplant anti-GBM disease.