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

我们以前发现，阳离子抗DNA自身抗体具有致肾炎的潜力和使用特定的生殖系Vk基因，A30，有重大影响的阳离子电荷的自身抗体在人类狼疮肾炎。应用PCR技术，在9例无肾炎的SLE患者中，发现8例存在A30基因位点的缺陷。而9例狼疮性肾炎患者中有9例A30基因完整。A30基因的存在与否与狼疮性肾炎的发生有关。据报道，A30是一个潜在的功能，但很少在人类中表达的Vk基因。正常B细胞可能通过受体编辑机制编辑具有自身反应潜能的A30基因，改变B细胞Ag受体的亲和力，从而避免自身反应，而SLE B细胞可能存在这一机制的缺陷。事实上，我们发现正常B细胞可能通过倒位机制编辑其基因组中的A30-Jk 2基因，而SLE B细胞基因组中含有重排的A30-Jk 2-Ck基因，并表达A30相关的mRNA，这表明SLE患者的受体编辑机制也存在缺陷。受体编辑的失败可能导致人类致病性抗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.