The double edged sword of the immune response - Mutational analysis of a murine anti-pneumococcal, anti-DNA antibody
The double edged sword of the immune response - Mutational analysis of a murine anti-pneumococcal, anti-DNA antibody
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DOI：
10.1172/jci118666
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发表时间：
1996-05-15
影响因子：
15.9
通讯作者：
Diamond, B
中科院分区：
文献类型：
--
作者：
Putterman, C;Limpanasithikul, W;Diamond, B
抗双链（ds）DNA抗体不仅是SLE的重要诊断标志物，而且在组织损伤中发挥着重要作用，微生物抗原可能是这些抗体产生的刺激物。我们从非自身免疫 BALB/c 小鼠中分离出 99D.7E，一种 IgG2b 单克隆抗体，它与 dsDNA 和磷酸胆碱（肺炎球菌细胞壁上的主要半抗原）发生交叉反应。99D.7E 在部分保护细菌攻击的同时，对肾脏也具有致病性。为了鉴定那些赋予抗 PC 抗体潜在自身反应性的分子基序，我们创建了一组重链中具有单个氨基酸取代的 99D.7E 突变体，并检查了抗原结合和肾沉积的变化。我们的结果支持这样的假设：双链 DNA 的电荷和亲和力不足以预测抗 DNA 抗体的致病性。抗 dsDNA 抗体造成的不同肾损伤可能是由于精细特异性的差异，而不是由于对 dsDNA 的亲和力不同。重要的是，存在与细菌和自身抗原交叉反应的高亲和力 IgG 抗体，并且可以表现出致病潜力，这表明被外来抗原激活但与自身抗原交叉反应的 B 细胞外周调节缺陷可能导致自身免疫性疾病。
Anti-double-stranded (ds) DNA antibodies are not only an important diagnostic marker for SLE, but also play an important role in tissue injury, Microbial antigen may be a stimulus for the production of these antibodies. We isolated 99D.7E, an IgG2b monoclonal antibody from a nonautoimmune BALB/c mouse that is cross-reactive with both dsDNA and phosphorylcholine, the dominant hapten on the pneumococcal cell wall, While partially protective against a bacterial challenge, 99D.7E is also pathogenic to the kidney. To identify those molecular motifs that confer on anti-PC antibodies the potential for autoreactivity, we created a panel of 99D.7E mutants with single amino acid substitutions in the heavy chain, and examined the changes in antigen binding and renal deposition. Our results support the hypothesis that charge and affinity for dsDNA are not adequate predictors of the pathogenicity of anti-DNA antibodies. Differential renal damage from anti-dsDNA antibodies may be due to differences in fine specificity, rather than differential affinity for dsDNA. Importantly, high affinity IgG antibodies cross-reactive with bacterial and self antigen exist and can display pathogenic potential, suggesting that defects in peripheral regulation of B cells, activated by foreign antigen but cross-reactive with self antigen, might lead to autoimmune disorders.