人B细胞前体中激活诱导的胞苷脱氨酶表达对中枢B细胞耐受性至关重要。
Activation-Induced Cytidine Deaminase Expression in Human B Cell Precursors Is Essential for Central B Cell Tolerance.
作者信息
Cantaert Tineke, Schickel Jean-Nicolas, Bannock Jason M, Ng Yen-Shing, Massad Christopher, Oe Tyler, Wu Renee, Lavoie Aubert, Walter Jolan E, Notarangelo Luigi D, Al-Herz Waleed, Kilic Sara Sebnem, Ochs Hans D, Nonoyama Shigeaki, Durandy Anne, Meffre Eric
机构信息
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
Division of Immunology/Allergy, Centre Hospitalier de l'Université de Québec, Québec City, G1V 4G2, Canada.
出版信息
Immunity. 2015 Nov 17;43(5):884-95. doi: 10.1016/j.immuni.2015.10.002. Epub 2015 Nov 3.
Activation-induced cytidine deaminase (AID), the enzyme-mediating class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes, is essential for the removal of developing autoreactive B cells. How AID mediates central B cell tolerance remains unknown. We report that AID enzymes were produced in a discrete population of immature B cells that expressed recombination-activating gene 2 (RAG2), suggesting that they undergo secondary recombination to edit autoreactive antibodies. However, most AID+ immature B cells lacked anti-apoptotic MCL-1 and were deleted by apoptosis. AID inhibition using lentiviral-encoded short hairpin (sh)RNA in B cells developing in humanized mice resulted in a failure to remove autoreactive clones. Hence, B cell intrinsic AID expression mediates central B cell tolerance potentially through its RAG-coupled genotoxic activity in self-reactive immature B cells.
激活诱导的胞苷脱氨酶（AID）是介导免疫球蛋白基因类别转换重组（CSR）和体细胞高频突变（SHM）的酶，对于清除发育中的自身反应性B细胞至关重要。AID如何介导中枢B细胞耐受性仍不清楚。我们报告称，AID酶在表达重组激活基因2（RAG2）的离散未成熟B细胞群体中产生，这表明它们经历二次重组以编辑自身反应性抗体。然而，大多数AID+未成熟B细胞缺乏抗凋亡蛋白MCL-1，并通过凋亡被清除。在人源化小鼠中发育的B细胞中使用慢病毒编码的短发夹（sh）RNA抑制AID，导致无法清除自身反应性克隆。因此，B细胞内在的AID表达可能通过其在自身反应性未成熟B细胞中的RAG偶联基因毒性活性介导中枢B细胞耐受性。
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