Receptor editing can lead to allelic inclusion and development of B cells that retain antibodies reacting with high avidity autoantigens
Receptor editing can lead to allelic inclusion and development of B cells that retain antibodies reacting with high avidity autoantigens
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DOI：
10.4049/jimmunol.175.8.5067
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发表时间：
2005-10-15
影响因子：
4.4
通讯作者：
Pelanda, R
中科院分区：
文献类型：
--
作者：
Liu, S;Velez, MG;Pelanda, R
受体编辑是一种主要的B细胞耐受机制，它通过二次Ig基因重排来改变自身反应性发育中的B细胞的特异性。在3-83Igi小鼠模型中，受体编辑在每个自身反应性抗h - 2k (b) b细胞中起作用，提供了一种新的受体，而不会造成额外的细胞损失。尽管受体编辑在产生非自身反应性Ag受体方面效率很高，但我们在本研究中表明，该过程并不会使每个自身反应性B细胞中的自身抗体编码基因失活。事实上，受体编辑可以产生等位基因和等典型包含的B细胞，同时表达原始的自反应性和新的非自反应性Ag受体。这种双ab表达的B细胞分化为过渡性和成熟的B细胞，尽管在该系统中自身抗体和自身ag之间存在高度的相互作用，但仍保留了自身抗体的表达。此外，我们发现这些高活性的自身反应性B细胞在细胞内保留了自身反应性Ag受体，这是自身抗原参与和Src家族激酶依赖过程的结果。最后，在老年3-83Igi小鼠的血清中发现了抗h - 2k (b) IgM自身抗体，这表明双ab表达的自身反应性b细胞具有潜在的功能，并且在某些情况下能够分化为分泌IgM自身抗体的浆细胞。这些结果表明，与普遍存在的膜结合自身抗原反应的自身反应性B细胞可以通过共表达非自身反应性抗体来绕过中枢耐受机制。这些双表达抗体的自身反应性B细胞将自身抗体隐藏在细胞内，表现出表面耐受表型，可以部分克服这种表型以分泌Ig M自身抗体。
Receptor editing is a major B cell tolerance mechanism that operates by secondary Ig gene rearrangements to change the specificity of autoreactive developing B cells. In the 3-83Igi mouse model, receptor editing operates in every autoreactive anti-H-2K(b) B cell, providing a novel receptor without additional cell loss. Despite the efficiency of receptor editing in generating nonautoreactive Ag receptors, we show in this study that this process does not inactivate the autoantibody-encoding gene(s) in every autoreactive B cell. In fact, receptor editing can generate allelically and isotypically included B cells that simultaneously express the original autoreactive and a novel nonautoreactive Ag receptors. Such dual Ab-expressing B cells differentiate into transitional and mature B cells retaining the expression of the autoantibody despite the high avidity interaction between the autoantibody and the self-Ag in this system. Moreover, we find that these high avidity autoreactive B cells retain the autoreactive Ag receptor within the cell as a consequence of autoantigen engagement and through a Src family kinase-dependent process. Finally, anti-H-2K(b) IgM autoantibodies are found in the sera of older 3-83Igi mice, indicating that dual Ab-expressing autoreactive B cells are potentially functional and capable of differentiating into IgM autoantibody-secreting plasma cells under certain circumstances. These results demonstrate that autoreactive B cells reacting with ubiquitous membrane bound autoantigens can bypass mechanisms of central tolerance by coexpressing nonautoreactive Abs. These dual Ab-expressing autoreactive B cells conceal their autoantibodies within the cell manifesting a superficially tolerant phenotype that can be partially overcome to secrete Ig M autoantibodies.