Identification of the gene responsible of the development of systemic lupus erythematosus

我们先前发现阳离子抗dna自身抗体具有致肾潜能，并且使用特定种系Vk基因A30对人狼疮性肾炎自身抗体的阳离子电荷有重要影响。通过PCR技术，我们发现9例无肾炎的SLE患者中有8例基因组中A30基因位点存在缺陷。相比之下，9例狼疮肾炎患者中有9例具有完整的A30基因。A30基因的存在与否与狼疮性肾炎的发生与否有关。据报道，A30是一个潜在的功能，但很少表达的Vk基因在人类。正常B细胞可能主要通过受体编辑机制编辑具有自身反应电位的重排A30基因，从而改变B细胞Ag受体的亲和力，避免自身反应性，而SLE B细胞可能在这一机制上存在缺陷。事实上，我们发现正常B细胞可能通过逆转录机制编辑其基因组中的A30-JK2基因，而SLE B细胞在基因组中含有A30-JK2 - ck基因重排并表达a30 -相关mRNA，提示SLE患者的受体编辑机制也存在缺陷。我们的研究表明，lg Vk位点的多态性和受体编辑的失败可能有助于人类致病性抗dna反应的发展。

We found previously that cationic anti-DNA autoantibodies have nephritogenic potential and usage of a specific germline Vk gene, A30, has major influences on cationic charge of the autoantibodies in human lupus nephritis. By using PCR technique, we found that A30 gene locus in the genome was defective in 8 out of 9 SLE patients without nephritis. In contrast, 9 out of 9 patients with lupus nephritis had intact A30 gene. The presence or absence of A30 gene was associated with the development of lupus nephritis or not. It is reported the A30 is a potentially functional but rarely expressed Vk gene in humans. It is possible that normal B cells edit primarily rearranged A30 gene with autoreactive potentials by receptor editing mechanism, for changing the affinity of the B cell Ag receptor to avoid self-reactivity, whereas SLE B cells mayhave a defect in this mechanism. Indeed, we found that normal B cells edit A30-JK2 gene in their genome possibly by inversion mechanism, whereas SLE B cells contain rearranged A30-Jk2-Ck gene in the genome and express A30-associated mRNA,suggesting that receptor editing mechanism is also defective in patients with SLE.Our study suggests that polymorphism of lg Vk locus, and failure of receptor editing may contribute to the development of pathogenic anti-DNA responses in humans.