The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans
The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans
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DOI：
10.1172/jci45790
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发表时间：
2011-09-01
影响因子：
15.9
通讯作者：
Meffre, Eric
中科院分区：
文献类型：
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作者：
Menard, Laurence;Saadoun, David;Meffre, Eric
蛋白酪氨酸磷酸酶非受体22型（PTPN22）基因多态性与许多自身免疫性疾病相关。主要的风险等位基因编码一个R620W氨基酸改变，该改变会改变参与中枢B细胞耐受调节的B细胞受体（BCR）信号传导。为了评估这种PTPN22风险等位基因是否影响发育中的自身反应性B细胞的清除，我们通过酶联免疫吸附测定（ELISA）检测了从携带一个或两个编码PTPN22 R620W变体的PTPN22风险等位基因的无症状健康个体的单个B细胞中分离出的重组抗体的反应性。我们发现，与非携带者相比，来自这种PTPN22风险等位基因携带者的新迁出/过渡型和成熟的初始B细胞含有高频率的自身反应性克隆，这揭示了中枢和外周B细胞耐受检查点存在缺陷。因此，单个PTPN22风险等位基因在自身免疫发生之前对改变自身反应性B细胞的反选择具有显性作用。此外，对显示PTPN22风险等位基因的成熟初始B细胞进行的基因芯片实验表明，PTPN22与自身免疫的关联强度可能不仅是由于自身反应性B细胞清除受损，还由于诸如CD40、TRAF1和IRF5等基因的上调，这些基因编码促进B细胞活化的蛋白质，并且已被确定为与自身免疫性疾病相关的易感基因。这些数据表明，自身免疫中早期B细胞耐受缺陷可由特定的多态性导致，且发生在疾病发作之前。
Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene polymorphisms are associated with many autoimmune diseases. The major risk allele encodes an R620W amino acid change that alters B cell receptor (BCR) signaling involved in the regulation of central B cell tolerance. To assess whether this PTPN22 risk allele affects the removal of developing autoreactive B cells, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from asymptomatic healthy individuals carrying one or two PTPN22 risk allele(s) encoding the PTPN22 R620W variant. We found that new emigrant/transitional and mature naive B cells from carriers of this PTPN22 risk allele contained high frequencies of autoreactive clones compared with those from non-carriers, revealing defective central and peripheral B cell tolerance checkpoints. Hence, a single PTPN22 risk allele has a dominant effect on altering autoreactive B cell counterselection before any onset of autoimmunity. In addition, gene array experiments analyzing mature naive B cells displaying PTPN22 risk allele(s) revealed that the association strength of PTPN22 for autoimmunity may be due not only to the impaired removal of autoreactive B cells but also to the upregulation of genes such as CD40, TRAF1, and IRF5, which encode proteins that promote B cell activation and have been identified as susceptibility genes associated with autoimmune diseases. These data demonstrate that early B cell tolerance defects in autoimmunity can result from specific polymorphisms and precede the onset of disease.