Immunoglobulin heavy chain exclusion in the shark.
Immunoglobulin heavy chain exclusion in the shark.
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DOI：
10.1371/journal.pbio.0060157
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发表时间：
2008-06-24
期刊：
影响因子：
9.8
通讯作者：
Hsu E
中科院分区：
文献类型：
--
作者：
Malecek K;Lee V;Feng W;Huang JL;Flajnik MF;Ohta Y;Hsu E
The adaptive immune system depends on specific antigen receptors, immunoglobulins (Ig) in B lymphocytes and T cell receptors (TCR) in T lymphocytes. Adaptive responses to immune challenge are based on the expression of a single species of antigen receptor per cell; and in B cells, this is mediated in part by allelic exclusion at the Ig heavy (H) chain locus. How allelic exclusion is regulated is unclear; we considered that sharks, the oldest vertebrates possessing the Ig/TCR-based immune system, would yield insights not previously approachable and reveal the primordial basis of the regulation of allelic exclusion. Sharks have an IgH locus organization consisting of 15–200 independently rearranging miniloci (VH-D1-D2-JH-Cμ), a gene organization that is considered ancestral to the tetrapod and bony fish IgH locus. We found that rearrangement takes place only within a minilocus, and the recombining gene segments are assembled simultaneously and randomly. Only one or few H chain genes were fully rearranged in each shark B cell, whereas the other loci retained their germline configuration. In contrast, most IgH were partially rearranged in every thymocyte (developing T cell) examined, but no IgH transcripts were detected. The distinction between B and T cells in their IgH configurations and transcription reveals a heretofore unsuspected chromatin state permissive for rearrangement in precursor lymphocytes, and suggests that controlled limitation of B cell lineage-specific factors mediate regulated rearrangement and allelic exclusion. This regulation may be shared by higher vertebrates in which additional mechanistic and regulatory elements have evolved with their structurally complex IgH locus. Lymphocytes provide a limitless repertoire of antigen receptors, but each lymphocyte expresses only one kind of receptor per cell in order to provide specific recognition and response to pathogen invasion. The restriction, called allelic exclusion, operates in tetrapod vertebrates from frogs to human beings. In mouse, immunoglobulin (Ig) heavy chain (H) exclusion depends on ordered activation of component parts of the highly complex, three-megabase IgH locus in a process that differentiates between the two alleles. However, the regulation and mechanisms ensuring allelic exclusion remain uncertain. Sharks represent the earliest vertebrates with an adaptive immune system; their IgH organization, consisting of multiple miniloci, is considered primitive and ancestral to the classical IgH locus in other vertebrates. We show that allelic exclusion nonetheless exists in shark B lymphocytes, although attained by alternative means. Thus, major aspects of the complex pathway described for allelic exclusion in mammals evolved with their IgH organization. Elucidating shared and divergent regulatory processes allows us to gain insight into the basis and evolution of allelic exclusion, which provides the foundation for the functioning of the adaptive immune system. In B lymphocytes of most animals, only one allele is expressed at the antibody heavy-chain locus, while the other is shut down. Sharks have 15-200 such loci. How is antibody expression regulated in this early vertebrate?
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