Suzuki N, Harada T, Mihara S, Sakane T
Division of Allergy and Rheumatic Diseases, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
J Clin Invest. 1996 Oct 15;98(8):1843-50. doi: 10.1172/JCI118985.
We found previously that cationic anti-DNA autoantibodies (autoAbs) have nephritogenic potential and usage of a specific germline Vk gene, A30, has major influences on cationic charge of the autoAb in human lupus nephritis. In the present study, we have characterized A30 germline Vk gene using cosmid cloning technique in patients with SLE. A30 gene locus locates in less than 250 kb from the Ck region, and the cationic anti-DNA mRNA used the upstream Jk2 gene, indicating that cationic anti-DNA mRNA is a product of primary gene rearrangement. By using PCR technique, we found that A30 gene locus in the genome was defective in eight out of nine SLE patients without nephritis. In contrast, all nine patients with lupus nephritis had intact A30 gene. The presence and absence of A30 gene was associated with the development of lupus nephritis or not (P < 0.01, by Fisher's exact test, two-sided). It was thus suggested that absence of functional A30 gene may rescue from developing lupus nephritis in the patients. A30 is reported to be 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 may have 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 Ig Vk locus, and failure of receptor editing may contribute to the development of pathogenic anti-DNA responses in humans.
我们先前发现阳离子抗DNA自身抗体（自身抗体）具有致肾炎潜力，并且特定种系Vk基因A30的使用对人类狼疮性肾炎中自身抗体的阳离子电荷有重大影响。在本研究中，我们使用黏粒克隆技术对系统性红斑狼疮（SLE）患者的A30种系Vk基因进行了表征。A30基因座位于距Ck区域不到250 kb处，阳离子抗DNA mRNA使用上游Jk2基因，这表明阳离子抗DNA mRNA是初级基因重排的产物。通过使用聚合酶链反应（PCR）技术，我们发现9例无肾炎的SLE患者中有8例基因组中的A30基因座存在缺陷。相比之下，所有9例狼疮性肾炎患者的A30基因均完整。A30基因的存在与否与狼疮性肾炎的发生与否相关（通过双侧Fisher精确检验，P<0.01）。因此表明功能性A30基因的缺失可能使患者免于发生狼疮性肾炎。据报道，A30是人类中一种潜在功能性但很少表达的Vk基因。正常B细胞可能通过受体编辑机制对具有自身反应性潜力的初级重排A30基因进行编辑，以改变B细胞抗原受体的亲和力，从而避免自身反应性，而SLE B细胞在这一机制中可能存在缺陷。实际上，我们发现正常B细胞可能通过倒位机制在其基因组中编辑A30-Jk2基因，而SLE B细胞在基因组中含有重排的A30-Jk2-Ck基因并表达与A30相关的mRNA，这表明SLE患者中受体编辑机制也存在缺陷。我们的研究表明，Ig Vk基因座的多态性以及受体编辑功能障碍可能导致人类致病性抗DNA反应发展。
