Kolijn P Martijn, Huijser Erika, Wahadat M Javad, van Helden-Meeuwsen Cornelia G, van Daele Paul L A, Brkic Zana, Rijntjes Jos, Hebeda Konnie M, Groenen Patricia J T A, Versnel Marjan A, Thurlings Rogier M, Langerak Anton W
Department of Immunology, Laboratory Medical Immunology, Erasmus MC, Rotterdam, Netherlands.
Department of Immunology, Erasmus MC, Rotterdam, Netherlands.
Front Oncol. 2023 Mar 23;13:1130686. doi: 10.3389/fonc.2023.1130686. eCollection 2023.
Activated B cells play a key role in the pathogenesis of primary Sjögren's syndrome (pSS) through the production of autoantibodies and the development of ectopic germinal centers in the salivary glands and other affected sites. Around 5-10% of pSS patients develop B-cell lymphoma, usually extranodal marginal zone lymphomas (eMZL) of the mucosa-associated lymphoid tissue (MALT). The aim of the current study is to investigate if the eMZL clonotype is detectable in prediagnostic blood and tissue biopsies of pSS patients.
METHODS/RESULTS: We studied prediagnostic tissue biopsies of three pSS patients diagnosed with eMZL and four pSS controls through immunoglobulin (IG) gene repertoire sequencing. In all three cases, we observed the eMZL clonotype in prediagnostic tissue biopsies. Among controls, we observed transient elevation of clonotypes in two pSS patients. To evaluate if eMZL clonotypes may also be detected in the circulation, we sequenced a peripheral blood mononuclear cell (PBMC) sample drawn at eMZL diagnosis and two years prior to eMZL relapse in two pSS patients. The eMZL clonotype was detected in the peripheral blood prior to diagnosis in both cases. Next, we selected three pSS patients who developed eMZL lymphoma and five additional pSS patients who remained lymphoma-free. We sequenced the IG heavy chain (IGH) gene repertoire in PBMC samples taken a median of three years before eMZL diagnosis. In two out of three eMZL patients, the dominant clonotype in the prediagnostic PBMC samples matched the eMZL clonotype in the diagnostic biopsy. The eMZL clonotypes observed consisted of stereotypic IGHV gene combinations (IGHV1-69/IGHJ4 and IGHV4-59/IGHJ5) associated with rheumatoid factor activity, a previously reported feature of eMZL in pSS.
In conclusion, our results indicate that eMZL clonotypes in pSS patients are detectable prior to overt eMZL diagnosis in both tissue biopsies and peripheral blood through immunogenetic sequencing, paving the way for the development of improved methods of early detection of eMZL.
活化的B细胞通过产生自身抗体以及在唾液腺和其他受累部位形成异位生发中心，在原发性干燥综合征（pSS）的发病机制中起关键作用。约5%-10%的pSS患者会发展为B细胞淋巴瘤，通常是黏膜相关淋巴组织（MALT）的结外边缘区淋巴瘤（eMZL）。本研究的目的是调查在pSS患者的诊断前血液和组织活检中是否可检测到eMZL克隆型。
方法/结果：我们通过免疫球蛋白（IG）基因库测序研究了3例诊断为eMZL的pSS患者和4例pSS对照的诊断前组织活检。在所有3例病例中，我们在诊断前组织活检中观察到了eMZL克隆型。在对照组中，我们在2例pSS患者中观察到克隆型短暂升高。为了评估在循环中是否也能检测到eMZL克隆型，我们对2例pSS患者在eMZL诊断时及eMZL复发前两年采集的外周血单个核细胞（PBMC）样本进行了测序。在这两个病例中，诊断前在外周血中均检测到了eMZL克隆型。接下来，我们选择了3例发展为eMZL淋巴瘤的pSS患者和另外5例未发生淋巴瘤的pSS患者。我们对在eMZL诊断前中位时间为三年采集的PBMC样本中的IG重链（IGH）基因库进行了测序。在3例eMZL患者中的2例中，诊断前PBMC样本中的优势克隆型与诊断活检中的eMZL克隆型相匹配。观察到的eMZL克隆型由与类风湿因子活性相关的定型IGHV基因组合（IGHV1-69/IGHJ4和IGHV4-59/IGHJ5）组成，这是先前报道的pSS中eMZL的一个特征。
总之，我们的结果表明，通过免疫遗传学测序，在组织活检和外周血中，pSS患者的eMZL克隆型在明显的eMZL诊断之前即可检测到，这为开发改进的eMZL早期检测方法铺平了道路。
