Duret Pierre-Marie, Schleiss Cedric, Kawka Lou, Meyer Nicolas, Ye Tao, Saraux Alain, Devauchelle-Pensec Valérie, Seror Raphaele, Larroche Claire, Perdriger Aleth, Sibilia Jean, Vallat Laurent, Fornecker Luc-Matthieu, Nocturne Gaetane, Mariette Xavier, Gottenberg Jacques-Eric
Department of Rheumatology, Colmar Civilian Hospital, Colmar, France.
CNRS, Immunopathologie et Chimie Thérapeutique/Laboratory of Excellence Medalis, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.
Arthritis Rheumatol. 2023 Oct;75(10):1798-1811. doi: 10.1002/art.42550. Epub 2023 Jul 28.
We undertook this study to analyze whole blood gene expression and to investigate the role of B cell genes in primary Sjögren's syndrome-related non-Hodgkin lymphoma (primary SS-NHL).
Peripheral whole blood samples were collected from 345 well-phenotyped patients with primary SS enrolled in the prospective Assessment of Systemic Signs and Evolution in Sjögren's Syndrome (ASSESS) cohort. Transcriptomic analysis was performed using human Clariom S Arrays (Affymetrix). In our primary analysis, we considered patients with incident lymphoma (i-primary SS-NHL) as the case group and all patients without lymphoma as the comparison group. In our sensitivity analyses, we considered all patients with primary SS-NHL, including those with a history of lymphoma (h-primary SS-NHL), as the case group and primary SS patients without lymphoma, stratified on their risk factors of lymphoma, as the comparison group.
Twenty-one patients with primary SS-NHL (including 8 with i-primary SS-NHL and 13 h-primary SS-NHL) were eligible for transcriptomic analysis; we compared these patients to 324 primary SS controls without lymphoma, including 110 with moderate to severe disease activity and 61 with no risk factor of lymphoma. Functional clustering analyses revealed an enrichment of genes related to innate and adaptive immunity, including B cell-related genes. Bruton's tyrosine kinase (BTK) and a proliferation-inducing ligand (APRIL) genes were overexpressed before the occurrence of lymphoma in patients with incident lymphoma compared with patients without lymphoma. In sensitivity analyses, BTK was consistently up-regulated across all comparisons performed. BTK expression was associated with risk of lymphoma on multivariate analyses, which considered 9 validated predictors of lymphoma in primary SS.
BTK and APRIL were overexpressed in the peripheral blood of primary SS patients prior to lymphoma. The association between BTK, APRIL, and primary SS-NHL requires confirmation in other prospective cohorts.
我们开展这项研究以分析全血基因表达，并探究B细胞基因在原发性干燥综合征相关非霍奇金淋巴瘤（原发性干燥综合征 - 非霍奇金淋巴瘤）中的作用。
从345例符合表型特征的原发性干燥综合征患者中采集外周全血样本，这些患者均纳入了前瞻性干燥综合征全身症状与病情演变评估（ASSESS）队列研究。使用人类Clariom S阵列（Affymetrix）进行转录组分析。在我们的初步分析中，将新发淋巴瘤患者（原发性干燥综合征 - 非霍奇金淋巴瘤新发患者）作为病例组，所有无淋巴瘤患者作为对照组。在敏感性分析中，我们将所有原发性干燥综合征 - 非霍奇金淋巴瘤患者，包括有淋巴瘤病史的患者（原发性干燥综合征 - 非霍奇金淋巴瘤病史患者）作为病例组，将无淋巴瘤的原发性干燥综合征患者按淋巴瘤危险因素分层后作为对照组。
21例原发性干燥综合征 - 非霍奇金淋巴瘤患者（包括8例原发性干燥综合征 - 非霍奇金淋巴瘤新发患者和13例原发性干燥综合征 - 非霍奇金淋巴瘤病史患者）符合转录组分析条件；我们将这些患者与324例无淋巴瘤的原发性干燥综合征对照者进行比较，其中包括110例中度至重度疾病活动患者和61例无淋巴瘤危险因素患者。功能聚类分析显示与先天性和适应性免疫相关的基因富集，包括B细胞相关基因。与无淋巴瘤患者相比，原发性干燥综合征 - 非霍奇金淋巴瘤新发患者在淋巴瘤发生前布鲁顿酪氨酸激酶（BTK）和增殖诱导配体（APRIL）基因表达上调。在敏感性分析中，在所有进行的比较中BTK均持续上调。在多变量分析中，BTK表达与淋巴瘤风险相关，该分析考虑了原发性干燥综合征中9个已验证的淋巴瘤预测因子。
在淋巴瘤发生之前，BTK和APRIL在原发性干燥综合征患者外周血中表达上调。BTK、APRIL与原发性干燥综合征 - 非霍奇金淋巴瘤之间的关联需要在其他前瞻性队列中得到证实。
