Smith Mia J, Packard Thomas A, O'Neill Shannon K, Henry Dunand Carole J, Huang Min, Fitzgerald-Miller Lisa, Stowell Daniel, Hinman Rochelle M, Wilson Patrick C, Gottlieb Peter A, Cambier John C
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO.
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO.
Diabetes. 2015 May;64(5):1703-12. doi: 10.2337/db13-1798. Epub 2014 Dec 18.
Although dogma predicts that under normal circumstances, potentially offensive autoreactive cells are silenced by mechanisms of immune tolerance, islet antigen-reactive B lymphocytes are known to play a crucial role in the development of autoimmunity in type 1 diabetes (T1D). Thus, participation of these cells in T1D may reflect escape from silencing mechanisms. Consistent with this concept, we found that in healthy subjects, high-affinity insulin-binding B cells occur exclusively in the anergic naive IgD(+), IgM(-) B-cell (BND) compartment. Antigen receptors expressed by these cells are polyreactive and have N-region additions, Vh usage, and charged complementarity-determining region 3 consistent with autoreactivity. Consistent with a potential early role in autoimmunity, these high-affinity insulin-binding B cells are absent from the anergic compartment of some first-degree relatives and all prediabetic and new-onset (<1 year) T1D patients tested, but return to normal levels in individuals diabetic for >1 year. Interestingly, these changes were correlated by transient loss of the entire BND compartment. These findings suggest that environmental events such as infection or injury may, by disrupting B-cell anergy, dispose individuals toward autoimmunity, the precise nature of which is specified by genetic risk factors, such as HLA alleles.
尽管教条认为在正常情况下，潜在的自身反应性细胞会通过免疫耐受机制而沉默，但已知胰岛抗原反应性B淋巴细胞在1型糖尿病（T1D）自身免疫的发展中起关键作用。因此，这些细胞参与T1D可能反映了其从沉默机制中逃逸。与这一概念一致，我们发现，在健康受试者中，高亲和力胰岛素结合B细胞仅存在于无反应性的初始IgD(+)、IgM(-) B细胞（BND）亚群中。这些细胞表达的抗原受体具有多反应性，并且具有与自身反应性一致的N区添加、Vh使用情况和带电荷的互补决定区3。与自身免疫早期的潜在作用一致，在一些一级亲属以及所有检测的糖尿病前期和新发（<1年）T1D患者的无反应性亚群中不存在这些高亲和力胰岛素结合B细胞，但在糖尿病病程>1年的个体中恢复到正常水平。有趣的是，这些变化与整个BND亚群的短暂缺失相关。这些发现表明，诸如感染或损伤等环境事件可能通过破坏B细胞无反应性，使个体易患自身免疫性疾病，而自身免疫性疾病的确切性质由遗传风险因素（如HLA等位基因）决定。
