Properties of HLA class II molecules divergently associated with Goodpasture's disease
Properties of HLA class II molecules divergently associated with Goodpasture's disease
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DOI：
10.1093/intimm/12.8.1135
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发表时间：
2000-08-01
影响因子：
4.4
通讯作者：
Rees, AJ
中科院分区：
文献类型：
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作者：
Phelps, RG;Jones, V;Rees, AJ
Goodpasture氏病提供了一个机会，分析可能导致MHC II类与自身免疫性疾病相关的分子机制，因为它是由对特定抗原[IV型胶原α 3链的230个氨基酸的NC 1结构域（w α 3（1V）NC 1）]的自身免疫引起的，并且具有强烈的HLA II类相关性。我们使用抑制结合试验和跨越α 3（1V）NCI序列的短合成肽比较了具有强阳性（DR 15）和显性阴性（DR 7/1）关联的II类分子的α 3（1V）NC 1肽结合。DR 15通常以低亲和力结合肽（23个中的3个< 100 nM）与DR 1和DR 7相比（分别为12和10 < 100 nM），并且没有肽以比DR 1和DR 7两者高得多的亲和力（10倍）结合DR 15，因此，DR 15分子不太可能通过独特良好地呈递特定的α 3（IV）NC 1衍生肽而增加对古德帕斯彻氏病的易感性，并且DR 1/DR 15分子不太可能增加对古德帕斯彻氏病的易感性。7不太可能通过它们不能呈递特定肽来保护。然而，DR 1/7可以通过捕获α 3（IV）NCI肽并阻止它们与DR 15结合来进行保护;结合数据表明，由DR 15纯合抗原呈递细胞（APC）呈递的与DR 15结合的所有主要（生物化学可检测的）α 3（IV）NCI肽将优先与DR 15，1/7杂合APC中的DR 1/7结合。
Goodpasture's disease provides an opportunity to analyse molecular mechanisms that may underlie MHC class II associations with autoimmune disease because it is caused by autoimmunity to a defined antigen [the 230 amino acid NC1 domain of the alpha 3 chain of type IV collagen (w alpha 3(1V)NC1)] and has strong HLA class II associations. We compared the alpha 3(1V)NC1 peptide binding of class II molecules with strong positive (DR15) and dominant negative (DR7/1) associations using an inhibition binding assay and short synthetic peptides spanning the sequence of alpha 3(1V)NCI. DR15 in general bound the peptides with low affinity (three of 23 < 100 nM) compared to DR1 and DR7 (12 and 10 < 100 nM respectively), and no peptide bound DR15 with much higher affinity (10-fold) than both DR1 and DR7, Thus DR15 molecules are unlikely to increase susceptibility to Goodpasture's disease by presenting a particular alpha 3(IV)NC1-derived peptide uniquely well and DR1/7 are unlikely to protect by their inability to present particular peptides. However DR1/7 could protect by capturing a3(1V)NCI peptides and preventing their display bound to DR15; the binding data suggest that all the major (biochemically detectable) alpha 3(1V)NCI peptides presented bound to DR15 by DR15 homozygous antigen-presenting cells (APC) would bind preferentially to DR1/7 in DR15, 1/7 heterozygote APC.