Amsterdam University Medical Center and University of Amsterdam, Amsterdam, The Netherlands.
AIMM Therapeutics, Amsterdam, The Netherlands.
Arthritis Rheumatol. 2020 Aug;72(8):1330-1340. doi: 10.1002/art.41263. Epub 2020 Jul 8.
Patients with Sjӧgren's syndrome (SS) have an increased risk of developing malignant B cell lymphomas, particularly mucosa-associated lymphoid tissue (MALT)-type lymphomas. We have previously shown that a predominant proportion of patients with SS-associated salivary gland MALT lymphoma express somatically hypermutated IgM with strong amino acid sequence homology with stereotypic rheumatoid factors (RFs). The present study was undertaken in a larger cohort of patients with SS-associated MALT lymphoma to more firmly assess the frequency of RF reactivity and the significance of somatic IGV-region mutations for RF reactivity.
B cell antigen receptors (BCRs) of 16 patients with SS-associated salivary gland MALT lymphoma were analyzed. Soluble recombinant IgM was produced of 12 MALT lymphoma samples, including 1 MALT lymphoma sample that expressed an IgM antibody fitting in a novel IGHV3-30-encoded stereotypic IGHV subset. For 4 of the 12 IgM antibodies from MALT lymphoma samples, the somatically mutated IGHV and IGKV gene sequences were reverted to germline configurations. Their RF activity and binding affinity were determined by enzyme-linked immunosorbent assay and surface plasmon resonance, respectively.
Nine (75%) of the 12 IgM antibodies identified in patients with SS-associated salivary gland MALT lymphoma displayed strong monoreactive RF activity. Reversion of the IGHV and IGKV mutations to germline configuration resulted in RF affinities for IgG that were significantly lower for 3 of the 4 somatically mutated IgM antibodies. In stereotypic IGHV3-7/IGKV3-15-encoded RFs, a recurrent replacement mutation in the IGKV3-15-third complementarity-determining region was found to play a pivotal role in the affinity for IgG-Fc.
A majority of patients with SS-associated salivary gland MALT lymphoma express somatically mutated BCRs that are selected for monoreactive, high-affinity binding of IgG-Fc. These data underscore the notion that soluble IgG, most likely in immune complexes in inflamed tissues, is the principal autoantigen in the pathogenesis of a variety of B cell lymphomas, particularly SS-associated MALT lymphomas.
干燥综合征（SS）患者发生恶性 B 细胞淋巴瘤的风险增加，特别是黏膜相关淋巴组织（MALT）型淋巴瘤。我们之前已经表明，SS 相关涎腺 MALT 淋巴瘤患者中，相当大一部分患者表达体细胞高突变的 IgM，与定型类风湿因子（RF）具有很强的氨基酸序列同源性。本研究在更大的 SS 相关 MALT 淋巴瘤患者队列中进行，以更坚定地评估 RF 反应性的频率以及体细胞 IGV 区突变对 RF 反应性的意义。
分析了 16 例 SS 相关涎腺 MALT 淋巴瘤患者的 B 细胞抗原受体（BCR）。对 12 例 MALT 淋巴瘤样本中的可溶性重组 IgM 进行了生产，其中包括 1 例表达新型 IGHV3-30 编码定型 IGHV 亚群的 IgM 抗体的 MALT 淋巴瘤样本。对 12 例 MALT 淋巴瘤样本中的 4 例 IgM 抗体，将体细胞突变的 IGHV 和 IGKV 基因序列恢复到 germline 构型。通过酶联免疫吸附试验和表面等离子体共振分别测定它们的 RF 活性和结合亲和力。
在 SS 相关涎腺 MALT 淋巴瘤患者中鉴定的 12 种 IgM 抗体中，有 9 种（75%）表现出强烈的单反应性 RF 活性。将 IGHV 和 IGKV 突变恢复到 germline 构型，导致 4 例体细胞突变 IgM 抗体中的 3 种 IgG 的 RF 亲和力显著降低。在定型的 IGHV3-7/IGKV3-15 编码的 RF 中，在 IGKV3-15 第三个互补决定区中发现的反复替换突变在 IgG-Fc 的亲和力中起着关键作用。
大多数 SS 相关涎腺 MALT 淋巴瘤患者表达体细胞突变的 BCR，这些 BCR 被选择用于单反应性、高亲和力结合 IgG-Fc。这些数据强调了可溶性 IgG，很可能在炎症组织中的免疫复合物中，是各种 B 细胞淋巴瘤，特别是 SS 相关 MALT 淋巴瘤发病机制中的主要自身抗原。
