Analysis of variable region genes encoding a human anti-DNA antibody of normal origin. Implications for the molecular basis of human autoimmune responses.
Analysis of variable region genes encoding a human anti-DNA antibody of normal origin. Implications for the molecular basis of human autoimmune responses.
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编码正常来源的人抗 DNA 抗体的可变区基因的分析。
DOI：
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发表时间：
1989
影响因子：
4.4
通讯作者：
Katherine A. Siminovitch
中科院分区：
文献类型：
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作者：
E. Cairns;P. C. Kwong;V. Misener;P. Ip;David A. Bell;Katherine A. Siminovitch
为了研究天然抗DNA免疫应答的遗传基础，我们分离并测定了编码由正常来源的人杂交瘤(Kim4.6)表达的抗DNA抗体的可变基因元件(VH和VL)，并将这些序列与报道的其他四种人抗DNA抗体的序列进行了比较。该抗体的前导片段和VH片段与VH1.9III胚系VH3基因的核苷酸序列完全一致，而Kim4.6VL片段的核苷酸序列与Burkitt淋巴瘤中表达的V lambda I亚群基因有98%的同源性。对Kim4.6和其他人类杂交瘤抗DNA抗体的比较分析表明，抗DNA免疫反应在VH和VL基因的利用方面是不同的，但可能倾向于重排在胎儿前B细胞谱系中过度表达的VH基因。此外，Kim4.6和其他四个测序的人类抗DNA抗体中的三个似乎使用了胚系多样性基因DxP‘1，它可能代表了DFL16.1片段的对应物，该片段用于小鼠对半抗原硝基苯基的反应。综上所述，我们的发现表明，抗DNA免疫反应可以由非突变的VH基因编码，而产生这种反应的元件和分子机制在自然和狼疮相关的抗DNA抗体中基本上是相同的。我们的数据还表明，自然的自身免疫反应起源于B细胞个体发育的早期，这与自身反应性在形成正常免疫谱系中起主要作用的假设是一致的。
In order to investigate the genetic basis for natural anti-DNA immune responses, we isolated and sequenced the variable gene elements (VH and VL) encoding an anti-DNA antibody expressed by a human hybridoma of normal origin (Kim4.6) and compared these sequences with those reported for four other human anti-DNA antibodies. The Kim4.6 antibody leader and VH segments were identical in nucleotide sequence with the VH1.9III germ-line VH3 gene, and the Kim4.6VL segment showed 98% nucleotide sequence identity with a V lambda I subgroup gene expressed in a Burkitt's lymphoma. Comparative analysis of Kim4.6 and other human hybridoma anti-DNA antibodies indicated that anti-DNA immune responses are diverse in terms of VH and VL gene utilization but may exhibit a bias toward rearrangement of VH genes that are over-represented in the fetal pre-B cell repertoire. Moreover, Kim4.6 and three of four other sequenced human anti-DNA antibodies appear to use a germ-line diversity gene, DXP'1, which may represent a counterpart of the DFL16.1 segment utilized in murine responses to the hapten nitrophenyl. Taken together, our findings indicate that anti-DNA immune responses can be encoded by nonmutated VH genes and that the elements and molecular mechanisms which engender this response are essentially the same among natural and lupus-associated anti-DNA antibodies. Our data also suggest that natural autoimmune responses originate early in B cell ontogeny as is consistent with the hypothesis that autoreactivity plays a major role in shaping the normal immune repertoire.