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首页> 外文期刊>Journal of Clinical Medicine >B Cell Receptor Affinity for Insulin Dictates Autoantigen Acquisition and B Cell Functionality in Autoimmune Diabetes
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B Cell Receptor Affinity for Insulin Dictates Autoantigen Acquisition and B Cell Functionality in Autoimmune Diabetes

机译：胰岛素的B细胞受体亲和力决定自身免疫性糖尿病中的自身抗原获取和B细胞功能。

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B cells have been strongly implicated in the development of human type 1 diabetes and are required for disease in the NOD mouse model. These functions are dependent on B cell antigen receptor (BCR) specificity and expression of MHC, implicating linked autoantigen recognition and presentation to effector T cells. BCR-antigen affinity requirements for participation in disease are unclear. We hypothesized that BCR affinity for the autoantigen insulin differentially affects lymphocyte functionality, including tolerance modality and the ability to acquire and become activated in the diabetogenic environment. Using combined transgenic and retrogenic heavy and light chain to create multiple insulin-binding BCRs, we demonstrate that affinity for insulin is a critical determinant of the function of these autoreactive cells. We show that both BCR affinity for insulin and genetic background affect tolerance induction in immature B cells. We also find new evidence that may explain the enigmatic ability of B cells expressing 125 anti-insulin BCR to support development of TID in NOD mice despite a reported affinity beneath requirements for binding insulin at in vivo concentrations. We report that when expressed as an antigen receptor the affinity of 125 is much higher than determined by measurements of the soluble form. Finally, we show that in vivo acquisition of insulin requires both sufficient BCR affinity and permissive host/tissue environment. We propose that a confluence of BCR affinity, pancreas environment, and B cell tolerance-regulating genes in the NOD animal allows acquisition of insulin and autoimmunity.
机译：B细胞与人类1型糖尿病的发生密切相关，是NOD小鼠模型中疾病所必需的。这些功能取决于B细胞抗原受体（BCR）的特异性和MHC的表达，这暗示了自身抗原的识别和呈递给效应T细胞。参与疾病的BCR抗原亲和力要求尚不清楚。我们假设BCR对自身抗原胰岛素的亲和力会差异性地影响淋巴细胞功能，包括耐受性以及在致糖尿病环境中获得并被激活的能力。使用组合的转基因和逆转录的重链和轻链创建多个胰岛素结合BCR，我们证明对胰岛素的亲和力是这些自反应细胞功能的关键决定因素。我们表明，BCR对胰岛素的亲和力和遗传背景都会影响未成熟B细胞的耐受性诱导。我们还发现了新的证据，可以解释表达125种抗胰岛素BCR的B细胞在NOD小鼠中支持TID发育的神秘能力，尽管据报道其亲和力低于在体内浓度下结合胰岛素的要求。我们报告说，当表达为抗原受体时，125的亲和力远高于通过测量可溶性形式所确定的亲和力。最后，我们表明体内获取胰岛素需要足够的BCR亲和力和允许的宿主/组织环境。我们提出，NOD动物中BCR亲和力，胰腺环境和B细胞耐受性调节基因的融合允许获得胰岛素和自身免疫性。

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