Wloch M K, Alexander A L, Pippen A M, Pisetsky D S, Gilkeson G S
Department of Medicine, Duke University Medical Center, Durham, NC 27705, USA.
J Immunol. 1997 May 1;158(9):4500-6.
To elucidate the mechanism of Ag drive in the anti-DNA response, the Ab response to bacterial DNA has been analyzed in normal and autoimmune mice. Preautoimmune NZB/W mice immunized with Escherichia coli dsDNA produce Abs that resemble spontaneous autoantibodies and bind mammalian dsDNA. In contrast, normal mice, when immunized similarly, produce Abs that bind only bacterial dsDNA. To characterize further the responsiveness of NZB/W mice to bacterial DNA, we determined the molecular properties of mAbs from preautoimmune NZB/W mice immunized with E. coli DNA. Of nine Abs studied, all were IgM and all bound mammalian ssDNA, while four had appreciable reactivity with mammalian dsDNA. The induced anti-dsDNA resembled spontaneous anti-DNA from autoimmune mice in V gene utilization and V(H) CDR3 arginine content. These Abs lacked evidence of somatic mutation, however, indicating that affinity maturation via somatic mutation is not essential for dsDNA reactivity. The findings suggest that preautoimmune NZB/W mice have immunoregulatory defects that allow activation of mammalian dsDNA reactive B cells by bacterial DNA.
为阐明抗DNA反应中抗原驱动的机制，已对正常小鼠和自身免疫小鼠针对细菌DNA的抗体反应进行了分析。用大肠杆菌双链DNA免疫自身免疫前的NZB/W小鼠会产生类似于自发自身抗体且能结合哺乳动物双链DNA的抗体。相比之下，正常小鼠经类似免疫后产生的抗体仅结合细菌双链DNA。为进一步表征NZB/W小鼠对细菌DNA的反应性，我们测定了用大肠杆菌DNA免疫的自身免疫前NZB/W小鼠单克隆抗体的分子特性。在研究的9种抗体中，全部为IgM，且都能结合哺乳动物单链DNA，其中4种对哺乳动物双链DNA有明显反应性。诱导产生的抗双链DNA抗体在V基因利用和V(H) CDR3精氨酸含量方面类似于自身免疫小鼠的自发抗DNA抗体。然而，这些抗体缺乏体细胞突变的证据，这表明通过体细胞突变进行亲和力成熟对于双链DNA反应性并非必不可少。这些发现表明，自身免疫前的NZB/W小鼠存在免疫调节缺陷，使得细菌DNA能够激活对哺乳动物双链DNA有反应性的B细胞。
