B Lymphocyte "Original Sin" in the Bone Marrow Enhances Islet Autoreactivity in Type 1 Diabetes-Prone Nonobese Diabetic Mice
B Lymphocyte "Original Sin" in the Bone Marrow Enhances Islet Autoreactivity in Type 1 Diabetes-Prone Nonobese Diabetic Mice
复制标题
DOI：
10.4049/jimmunol.1201359
复制
发表时间：
2013-06-15
影响因子：
4.4
通讯作者：
Thomas, James W.
中科院分区：
文献类型：
--
作者：
Henry-Bonami, Rachel A.;Williams, Jonathan M.;Thomas, James W.
需要有效的中枢耐受性来控制通常存在于发育中的B细胞库中的大程度的自身反应性。胰岛素反应性B细胞是NOD小鼠中1型糖尿病所必需的，因为缺乏该群体的工程小鼠免受疾病的影响。使用Cg-Tg（Igh-6/Igh-V125）2 Jwt/JwtJ（VH 125 Tg）模型来定义该群体，与非自身免疫性C57 BL/6 VH 125 Tg小鼠相比，在NOD小鼠的外周中发现该群体的频率增加;然而，这种差异的个体发生是未知的。为了更好地了解这些有害B细胞的起源，在VH 125 Tg小鼠的多克隆谱系发育期间追踪了抗胰岛素B细胞。在NOD小鼠骨髓中Ag定型的最早点，胰岛素结合B细胞的比例增加是明显的。在结合异源胰岛素的B细胞中鉴定出两种主要的L链。有趣的是，赋予CDR 3 Pro-Pro基序的Vk 4 -57-1多态性增强了VH 125 Tg/NOD小鼠的自身反应性。尽管在体内结合循环自身抗原，但抗胰岛素B细胞在NOD小鼠的骨髓中从实质过渡到窦状隙，并不受阻碍地进入外周。抗胰岛素B细胞在胰腺中自身免疫攻击部位扩增，并与库中IFN-γ产生细胞数量增加相关。这些数据确定了未能剔除骨髓中的自身反应性B细胞作为NOD小鼠中抗胰岛素B细胞的主要来源，并表明中枢耐受的失调允许它们逃逸到外周中以促进疾病。
Effective central tolerance is required to control the large extent of autoreactivity normally present in the developing B cell repertoire. Insulin-reactive B cells are required for type 1 diabetes in the NOD mouse, because engineered mice lacking this population are protected from disease. The Cg-Tg(Igh-6/Igh-V125) 2Jwt/JwtJ (VH125Tg) model is used to define this population, which is found with increased frequency in the periphery of NOD mice versus nonautoimmune C57BL/6 VH125Tg mice; however, the ontogeny of this disparity is unknown. To better understand the origins of these pernicious B cells, anti-insulin B cells were tracked during development in the polyclonal repertoire of VH125Tg mice. An increased proportion of insulin-binding B cells is apparent in NOD mice at the earliest point of Ag commitment in the bone marrow. Two predominant L chains were identified in B cells that bind heterologous insulin. Interestingly, Vk4-57-1 polymorphisms that confer a CDR3 Pro-Pro motif enhance self-reactivity in VH125Tg/NOD mice. Despite binding circulating autoantigen in vivo, anti-insulin B cells transition from the parenchyma to the sinusoids in the bone marrow of NOD mice and enter the periphery unimpeded. Anti-insulin B cells expand at the site of autoimmune attack in the pancreas and correlate with increased numbers of IFN-gamma-producing cells in the repertoire. These data identify the failure to cull autoreactive B cells in the bone marrow as the primary source of anti-insulin B cells in NOD mice and suggest that dysregulation of central tolerance permits their escape into the periphery to promote disease.