Yale University School of Medicine, New Haven, Connecticut.
Sorbonne Universités, UPMC Université Paris 06, UMR 7211, Inflammation-Immunopathology-Biotherapy Department, INSERM, UMR S 959, CNRS, FRE3632, and AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, National Reference Center for Autoimmune and Autoinflammatory Diseases, Paris, France.
Arthritis Rheumatol. 2018 Feb;70(2):298-307. doi: 10.1002/art.40352. Epub 2018 Jan 18.
Patients with Sjögren's syndrome (SS) are prone to develop malignant lymphomas, and a correlation has been established between the lymphoproliferations occurring in these disorders and the presence in patients' blood of an unusual B cell population that down-regulates complement receptor 2/CD21. This study was undertaken to identify the B cell compartment from which these lymphoproliferations emerge and determine the mechanisms that promote clonal B cell expansion in patients with SS.
The reactivity of antibodies expressed by CD19+CD10-CD27-IgM+CD21 cells isolated from the blood of patients with SS was tested using a polymerase chain reaction-based approach that allows us to clone and express, in vitro, recombinant antibodies produced by single B cells.
Clonal expansions were identified in CD21 B cells isolated from the peripheral blood of 3 patients with SS. These lymphoproliferations expressed B cell receptors (BCRs) that displayed somatic hypermutation lineage trees characteristic of a strong selection by antigens; one of these antigens was identified as a ribosomal self antigen. When the mutated BCR sequences expressed by the expanded CD21 B cell clones from patients with SS were reverted in vitro to their germline counterparts, one clone remained autoreactive.
Clonal lymphoproliferations in patients with SS preferentially accumulate in the autoreactive CD21 B cell compartment often expanded in these subjects, and recognition of self antigens may drive the clonal B cell expansion while further refining BCR self-reactivity.
干燥综合征（SS）患者易发生恶性淋巴瘤，这些疾病中发生的淋巴增生与患者血液中存在一种异常的 B 细胞群体有关，该群体下调补体受体 2/CD21。本研究旨在确定这些淋巴增生源自哪个 B 细胞群，并确定促进 SS 患者克隆 B 细胞扩增的机制。
使用基于聚合酶链反应的方法测试从 SS 患者血液中分离的 CD19+CD10-CD27-IgM+CD21 细胞表达的抗体的反应性，该方法允许我们克隆和表达单个 B 细胞产生的重组抗体。
从 3 例 SS 患者的外周血中分离的 CD21 B 细胞中鉴定出克隆扩增。这些淋巴增生表达 B 细胞受体（BCR），其体细胞超突变谱系树具有强烈的抗原选择特征；其中一种抗原被鉴定为核糖体自身抗原。当 SS 患者的扩增 CD21 B 细胞克隆表达的突变 BCR 序列在体外恢复为其原始序列时，一个克隆仍然具有自身反应性。
SS 患者的克隆性淋巴增生优先积累在这些患者中经常扩增的自身反应性 CD21 B 细胞群中，识别自身抗原可能驱动克隆 B 细胞扩增，同时进一步细化 BCR 自身反应性。
