Origin of Immunoglobulin Isotype Switching

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• 作者：Catherine Zhu¹ ; Victor Lee¹ ; Alyssa Finn¹ ; Kate Senger² ; Ali  ; A. Zarrin² ; Louis Du  ; Pasquier³ ; Ellen Hsu¹ ; ^{hsue@hscbklyn.edu}
• 刊名：Current Biology
• 出版年：2012
• 期刊代码：2_09609822
• 类别：abs
• 出版时间：22 May, 2012
• 卷：22
• 期：10
• 页码：872-880
• 文件大小：1502 K

摘要

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class="h3">Summary

class="h4">Background

From humans to frogs, immunoglobulin class switching introduces different effector functions to antibodies through an intrachromosomal DNA recombination process at the heavy-chain locus. Although there are two conventional antibody classes (IgM, IgW) in sharks, their heavy chains are encoded by 20 to >100聽miniloci. These representatives of the earliest jawed vertebrates possess a primordial immunoglobulin gene organization where each gene cluster is autonomous and contains a few rearranging gene segments (VH-D1-D2-JH) with one constant region, 渭 or 蠅.

class="h4">Results

V(D)J rearrangement always takes place within the聽渭聽cluster, but here we show that the VDJ can be expressed with聽constant regions from different clusters, although IgH genes are spatially distant, at >120 kb. Moreover, reciprocal exchanges take place between Ig蠅 and Ig渭 genes. Switching is augmented with deliberate immunization and is concomitant with somatic hypermutation activity. Because switching occurs independently of the partners' linkage position, some events involve transchromosomal recombination. The switch sites consist of direct joins between two genes in the 3鈥?intron flanking JH.

class="h4">Conclusions

Our data are consistent with a mechanism of聽cutting or joining of distal DNA lesions initiated by activation-induced cytidine deaminase (AID), in the absence of mammalian-type switch regions. We suggest that, in shark, with its many autonomous IgH targeted by programmed DNA breakage, factors predisposing broken DNA ends to translocate configured the earliest version of class switch recombination.