Inserm Unité 955, Faculté de Médecine-Paris 12, Créteil, France.
Blood. 2011 Jun 30;117(26):6991-8. doi: 10.1182/blood-2011-02-336164. Epub 2011 Apr 20.
Heavy chain diseases (HCDs) are B-cell proliferative disorders characterized by the production of monoclonal, incomplete, immunoglobulin (Ig) heavy chains (HCs) without associated light chains (LCs). These abnormal HCs are produced as a consequence of HC gene alterations in the neoplastic B cells. HC gene alterations will also impact on surface HC, which is part of the B-cell receptor (BCR), a crucial player in lymphocyte activation by antigen. The selective advantage conferred to mutant cells by abnormal BCR without an antigen-binding domain may be explained by activation of ligand-independent signaling, in analogy to what has been shown for mutated oncogenic growth factor receptors. Here we review data obtained from mouse models showing abnormal, constitutive activity of HCD-BCR, and we discuss the possible mechanism involved, namely, aberrant spontaneous self-aggregation. This self-aggregation might occur as a consequence of escape from the chaperone immunoglobulin binding protein (BiP) and from the anti-aggregation effect of LC association. The concept of misfolding-induced signaling elaborated here may extend to other pathologies termed conformational diseases.
重链病（HCD）是一种 B 细胞增殖性疾病，其特征是产生单克隆、不完整的免疫球蛋白（Ig）重链（HC），而没有相关的轻链（LC）。这些异常的 HC 是由于肿瘤 B 细胞中 HC 基因的改变而产生的。HC 基因的改变也会影响表面 HC，它是 B 细胞受体（BCR）的一部分，BCR 是抗原激活淋巴细胞的关键因素。异常 BCR 缺乏抗原结合域赋予突变细胞的选择性优势，可以通过配体非依赖性信号转导来解释，这与已经证明的突变致癌生长因子受体类似。在这里，我们回顾了从小鼠模型中获得的数据，这些数据显示了 HCD-BCR 的异常、组成性活性，并讨论了可能涉及的机制，即异常的自发自聚集。这种自聚集可能是由于逃避伴侣蛋白免疫球蛋白结合蛋白（BiP）和 LC 结合的抗聚集效应而发生的。这里阐述的错误折叠诱导信号的概念可能扩展到其他称为构象疾病的病理学。
