B cells are exquisitely sensitive to central tolerance and receptor editing induced by ultralow affinity, membrane-bound antigen
B cells are exquisitely sensitive to central tolerance and receptor editing induced by ultralow affinity, membrane-bound antigen
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DOI：
10.1084/jem.184.5.1685
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发表时间：
1996-11-01
影响因子：
15.3
通讯作者：
Nemazee, D
中科院分区：
文献类型：
--
作者：
Lang, J;Jackson, M;Nemazee, D
为了评估B细胞耐受性对受体/自身抗原亲和力的敏感性，我们鉴定了3-83（抗主要组织相容性复合物I类）抗体的低亲和力配体，并测试了这些配体在3-83转基因小鼠中诱导中枢和外周耐受性的能力。包括K-bm 3和D-k在内的几种I类蛋白质同种异型物对3-83显示出非常低但可检测的亲和力。3-83抗体结合K-b的K-A类似于2 × 10（5）M（-1），与K-bm 3（K-A类似于2 × 10（4）M（-1））和D-k抗原的结合弱10倍。用表达这些超低亲和力K-bm 3和D-k配体的小鼠繁殖3-83免疫球蛋白转基因小鼠导致外周淋巴组织中自身反应性B细胞几乎完全缺失。这些低亲和力抗原还诱导受体编辑，如通过骨髓中RAG mRNA水平升高和脾脏中携带λ轻链的id（-）变体B细胞的过量水平所测量的。当注射到3-83转基因小鼠的腹腔中时，反应性I类抗原也能够介导成熟B细胞的缺失。尽管最高亲和力的配体K-k始终能够诱导3-83腹膜B细胞的消除，但较低亲和力的配体仅部分有效。这些结果证明了未成熟B细胞中缺失和受体编辑机制的显著敏感性，并且可能表明外周成熟B细胞缺失的亲和力阈值更高。
To assess the sensitivity of B cell tolerance with respect to receptor/autoantigen affinity, we identified low affinity ligands to the 3-83 (anti-major histocompatibility complex class I) antibody and tested the ability of these ligands to induce central and peripheral tolerance in 3-83 transgenic mice. Several class I protein alloforms, including K-bm3 and D-k, showed remarkably low, but detectable, affinity to 3-83. The 3-83 antibody bound K-b with K-A similar to 2 X 10(5) M(-1) and bound 10-fold more weakly to the K-bm3 (K-A similar to 2 X 10(4) M(-1)) and D-k antigens. Breeding 3-83 immunoglobulin transgenic mice with mice expressing these ultralow affinity K-bm3 and D-k ligands resulted in virtually complete deletion of the autoreactive B cells from the peripheral lymphoid tissues. These low affinity antigens also induced receptor editing, as measured by elevated RAG mRNA levels in the bone marrow and excess levels of id(-) variant B cells bearing lambda light chains in the spleen. Reactive class I antigens were also able to mediate deletion of mature B cells when injected into the peritoneal cavity of 3-83 transgenic mice. Although the highest affinity ligand, K-k, was consistently able to induce elimination of the 3-83 peritoneal B cells, the lower affinity ligands were only partially effective. These results demonstrate the remarkable sensitivity of the deletion and receptor-editing mechanisms in immature B cells, and may suggest a higher affinity threshold for deletion of peripheral, mature B cells.