Persson Ulf, Hertz Jens Michael, Carlsson Malin, Hellmark Thomas, Juncker Inger, Wieslander Jörgen, Segelmark Mårten
Department of Nephrology, Lund University, Sweden.
Nephrol Dial Transplant. 2004 Aug;19(8):2030-5. doi: 10.1093/ndt/gfh355. Epub 2004 Jun 15.
Goodpasture's disease (GP) is a rare but severe disease characterized by anti-glomerular basement membrane antibodies, rapidly progressive glomerulonephritis and lung haemorrhage. The autoantibodies are restricted to a narrow epitope region on the NC1 domain of the alpha 3 chain of type IV collagen. GP is strongly associated with major histocompatibility complex (MHC) allele HLA DRB1-15. Recent research, however, has failed to identify a T-cell epitope with molecular characteristics that explain the relationship between the MHC class II molecule and the autoantibody generation. We hypothesized that an as yet unidentified sequence variant in exons 48-52 of the COL4A3 gene that encodes the NC1 domain of the type IV collagen alpha 3 chain could generate a new peptide sequence that, through interaction with specific MHC class II molecules, would increase the risk of developing GP.
All patients previously treated for GP at the Lund and Malmö University Hospitals, who were alive at the time of the study, were asked to participate. DNA was extracted from leukocytes and subjected to genomic tissue typing and sequencing of the COL4A3 gene exons 48-52.
All 15 patients in the study had a nucleotide sequence in the COL4A3 gene encoding a protein identical to GenBank entry NM_000091. HLA D allele distribution was in line with previous publications, showing a strong positive association between HLA DRB1-15, HLA DQB1-6 and GP (P<0.02). Of the 15 GP patients, 73% carried HLA DRB1-15 and 87% carried the HLA DQB1-6 antigen. Corresponding figures for the controls were 27 and 50%.
This study effectively falsifies the hypothesis that a minor alteration in the COL4A3 gene could be a major factor in the aetiology of GP. Scandinavian GP patients have an MHC distribution similar to that which has been described previously for Anglo-Saxon patients.
肺出血肾炎综合征（GP）是一种罕见但严重的疾病，其特征为抗肾小球基底膜抗体、快速进展性肾小球肾炎和肺出血。自身抗体局限于IV型胶原α3链NC1结构域上的一个狭窄表位区域。GP与主要组织相容性复合体（MHC）等位基因HLA DRB1-15密切相关。然而，最近的研究未能确定具有分子特征的T细胞表位，以解释II类MHC分子与自身抗体产生之间的关系。我们推测，编码IV型胶原α3链NC1结构域的COL4A3基因第48-52外显子中一个尚未确定的序列变异可能产生一个新的肽序列，该序列通过与特定的II类MHC分子相互作用，会增加患GP的风险。
邀请所有曾在隆德和马尔默大学医院接受过GP治疗且在研究时仍存活的患者参与。从白细胞中提取DNA，并对COL4A3基因第48-52外显子进行基因组组织分型和测序。
研究中的15名患者COL4A3基因的核苷酸序列编码的蛋白质与GenBank登录号NM_000091相同。HLA D等位基因分布与先前的出版物一致，显示HLA DRB1-15、HLA DQB1-6与GP之间存在强正相关（P<0.02）。15名GP患者中，73%携带HLA DRB1-15，87%携带HLA DQB1-6抗原。对照组的相应数字分别为27%和50%。
本研究有效地证伪了COL4A3基因的微小改变可能是GP病因学中的主要因素这一假设。斯堪的纳维亚GP患者的MHC分布与先前描述的盎格鲁-撒克逊患者相似。
