Human immunoglobulin selection associated with class switch and possible tolerogenic origins for Cδ class-switched B cells
Human immunoglobulin selection associated with class switch and possible tolerogenic origins for Cδ class-switched B cells
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DOI：
10.1172/jci200420255
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发表时间：
2004-04-01
影响因子：
15.9
通讯作者：
Wilson, PC
中科院分区：
文献类型：
--
作者：
Zheng, NY;Wilson, K;Wilson, PC
当前的外周B细胞选择范式表明，自身反应性B细胞受到克隆缺失、能量和发育停滞的控制。我们报告说，人类抗体库的变化可能是由这些机制引起的，这两种机制都是由V(H)4-34基因编码的抗体的良好特征的自身反应性和其他自反应库的标志，主要是在类别转换的B细胞中，而不是在IgM生发中心、IgM记忆或IgM浆细胞中。其他可能的自体反应性指标包括J(H)6基因片段的使用，长第三高变区B细胞的频率增加，以及远端J（kappa）基因片段偏倚。特别有趣的是，具有这些相同特征的B细胞被选择到B细胞谱系中，这些B细胞经历了不寻常的类别转换，从恒定区Cmu到Cdelta （Cdelta- cs）。CdeltaCS群体还显示出位于互补性决定区域的带电氨基酸频率增加，进一步表明了自身反应性，并且有证据表明这些B细胞经历了广泛的受体编辑。因此，Cdelta-CS谱系可能是正常人类中具有自身反应特异性的B细胞的“汇”。提出了一种新的耐受机制模型，可以解释CdeltaCS谱系。
Current paradigms of peripheral B cell selection suggest that autoreactive B cells are controlled by clonal deletion, anergy, and developmental arrest. We report that changes to the human antibody repertoire likely resulting from these mechanisms both for a well-characterized autoreactivity from antibodies encoded by the V(H)4-34 gene and for other hallmarks of an autoreactive repertoire are apparent mainly for class-switched B cells and not for IgM germinal center, IgM memory, or IgM plasma cells. Other possible indicators of autoreactivity found selected with immunoglobulin class include J(H)6 gene segment usage, increased frequency of B cells with long third hypervariable regions, and distal J(kappa) gene segment bias. Of particular interest is the finding that B cells with these same characteristics are selected into the lineage of B cells that have undergone the unusual class switch from constant region Cmu to Cdelta (Cdelta-CS). The CdeltaCS population also displays an increased frequency of charged amino acids localized to the complementarity-determining regions, further suggesting autoreactivity, and evidence is presented that these B cells had undergone extensive receptor editing. Thus, the Cdelta-CS lineage may be a "sink" for B cells harboring autoreactive specificities in normal humans. A model for a new tolerizing mechanism that could account for the CdeltaCS lineage is presented.