Altered B cell homeostasis is associated with type I diabetes and carriers of the PTPN22 allelic variant.
Altered B cell homeostasis is associated with type I diabetes and carriers of the PTPN22 allelic variant.
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DOI：
10.4049/jimmunol.1102176
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Buckner JH
中科院分区：
文献类型：
--
作者：
Habib T;Funk A;Rieck M;Brahmandam A;Dai X;Panigrahi AK;Luning Prak ET;Meyer-Bahlburg A;Sanda S;Greenbaum C;Rawlings DJ;Buckner JH
PTPN 22 1858 T遗传变异体（及其基因产物Lyp 620 W）与以自身抗体产生为特征的多种自身免疫性疾病相关。由于B细胞受体（BCR）信号强度与中枢和外周耐受性紧密相关，并且Lyp 620 W导致记忆B细胞中的B细胞受体信号传导减弱，因此我们测试了Lyp 620 W是否可以直接促进B细胞耐受性的丧失。我们发现PTPN 22 1858 T变异杂合子的健康个体在外周B细胞库中显示出显著的改变，包括过渡型和无反应性IgD+ IgMl CD 27阴性B细胞亚群的扩增。此外，PTPN 22 1858 T变异体与过渡期和幼稚B细胞中显著减少的BCR信号传导和对细胞凋亡的抗性相关。引人注目的是，在I型糖尿病（T1 D）受试者中观察到BCR信号传导和外周B细胞区室组成的平行变化，与PTPN 22基因型无关;揭示了一种新的免疫表型和可能导致B细胞耐受性丧失的共同机制。我们的综合研究结果表明，Lyp 620 W介导的BCR信号转导的改变有助于外周耐受性的破坏，并暗示T1 D患者B细胞耐受性改变中的平行近端信号转导缺陷。
The PTPN22 1858T genetic variant (and its gene product Lyp620W) is associated with multiple autoimmune disorders characterized by autoantibody production. Because B cell receptor (BCR) signal strength is tightly coupled to central and peripheral tolerance, and Lyp620W results in blunted B cell receptorsignaling in memory B cells, we tested whether Lyp620W may directly promote a loss of B cell tolerance. We found that healthy individuals heterozygous for the PTPN22 1858T variant display significant alterations in the peripheral B cell pool, including an expansion of both the transitional and anergic IgD+IgMnegCD27neg B cell subsets. Further, the PTPN22 1858T variant was associated with significantly diminished BCR signaling and a resistance to apoptosis in transitional and naïve B cells. Strikingly, parallel changes in BCR signaling and composition of the peripheral B cell compartment were observed in type I diabetic (T1D) subjects, irrespective of PTPN22 genotype; revealing a novel immune phenotype and likely shared mechanisms leading to a loss of B cell tolerance. Our combined findings suggest that Lyp620W-mediated alterations in BCR signaling contribute to a breakdown of peripheral tolerance and implicate parallel, proximal signaling deficits in altered B cell tolerance in T1D.
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影响因子：
15.3
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影响因子：
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作者：
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