Department of Pediatrics, University of Genova and Pediatria II, Institute G Gaslini, 16148 Genova, Italy.
Cell Rep. 2013 Jun 27;3(6):1824-31. doi: 10.1016/j.celrep.2013.05.022. Epub 2013 Jun 13.
Immunoglobulin (Ig) isotype diversification by class switch recombination (CSR) is an essential process for mounting a protective humoral immune response. Ig CSR deficiencies in humans can result from an intrinsic B cell defect; however, most of these deficiencies are still molecularly undefined and diagnosed as common variable immunodeficiency (CVID). Here, we show that extracellular adenosine critically contributes to CSR in human naive and IgM memory B cells. In these cells, coordinate stimulation of B cell receptor and toll-like receptors results in the release of ATP stored in Ca(2+)-sensitive secretory vesicles. Plasma membrane ectonucleoside triphosphate diphosphohydrolase 1 CD39 and ecto-5'-nucleotidase CD73 hydrolyze ATP to adenosine, which induces CSR in B cells in an autonomous fashion. Notably, CVID patients with impaired class-switched antibody responses are selectively deficient in CD73 expression in B cells, suggesting that CD73-dependent adenosine generation contributes to the pathogenesis of this disease.
免疫球蛋白 (Ig) 同种型转换重组 (CSR) 是产生保护性体液免疫应答的必要过程。人类的 Ig CSR 缺陷可能源于内在 B 细胞缺陷；然而，大多数此类缺陷在分子上仍未得到明确界定，被诊断为普通可变免疫缺陷 (CVID)。在这里，我们表明细胞外腺苷对人类初始和 IgM 记忆 B 细胞的 CSR 起着至关重要的作用。在这些细胞中，B 细胞受体和 Toll 样受体的协调刺激导致储存在 Ca(2+) 敏感分泌小泡中的 ATP 释放。质膜外核苷酸三磷酸二磷酸水解酶 1 (CD39) 和外核苷酸 5'-磷酸二酯酶 CD73 将 ATP 水解为腺苷，后者以自主方式诱导 B 细胞的 CSR。值得注意的是，抗体反应发生 CSR 缺陷的 CVID 患者的 B 细胞中 CD73 表达选择性缺失，这表明 CD73 依赖性腺苷生成有助于该疾病的发病机制。
