Impaired early B cell tolerance in patients with rheumatoid arthritis
Impaired early B cell tolerance in patients with rheumatoid arthritis
复制标题
DOI：
10.1084/jem.20042321
复制
发表时间：
2005-05-16
影响因子：
15.3
通讯作者：
Meffre, E
中科院分区：
文献类型：
--
作者：
Samuels, J;Ng, YS;Meffre, E
自身抗体的产生是包括类风湿性关节炎(RA)在内的大多数自身免疫性疾病的特征。这些自身抗体在类风湿关节炎发病机制中的作用仍不清楚，但它们在临床疾病发病前多年就出现在血清中，表明B细胞耐受性的早期打破。类风湿性关节炎B细胞耐受性被打破的B细胞发育阶段尚不清楚。我们之前在健康捐赠者中证实，大多数多反应发展中的B细胞在骨髓中是沉默的，而额外的自身反应B细胞在外周被移除。通过检测从单个B细胞克隆的重组抗体的特异性来分析未经治疗的活动期RA患者的B细胞耐受性。我们发现，在所有6名RA患者中，自身反应性B细胞都没有被移除，并且占成熟幼稚B细胞隔室的35-52%，而健康捐赠者的这一比例为20%。在一些患者中，RA B细胞表达能够识别免疫球蛋白和环瓜氨酸多肽的多反应抗体比例增加，这表明中枢B细胞耐受性早期存在缺陷。因此，RA患者表现出缺陷的B细胞耐受检查点，这可能有利于自身免疫的发展。
Autoantibody production is a characteristic of most autoimmune diseases including rheumatoid arthritis (RA). The role of these autoantibodies in the pathogenesis of RA remains elusive, but they appear in the serum many years before the onset of clinical disease suggesting an early break in B cell tolerance. The stage of B cell development at which B cell tolerance is broken in RA remains unknown. We previously established in healthy donors that most polyreactive developing B cells are silenced in the bone marrow, and additional autoreactive B cells are removed in the periphery. B cell tolerance in untreated active RA patients was analyzed by testing the specificity of recombinant antibodies cloned from single B cells. We find that autoreactive B cells fail to be removed in all six RA patients and represent 35 - 52% of the mature naive B cell compartment compared with 20% in healthy donors. In some patients, RA B cells express an increased proportion of polyreactive antibodies that can recognize immunoglobulins and cyclic citrullinated peptides, suggesting early defects in central B cell tolerance. Thus, RA patients exhibit defective B cell tolerance checkpoints that may favor the development of autoimmunity.