University of Athens Medical School, Athens, Greece.
University of Thessaly School of Medicine, Larissa, Greece, and The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, and Tufts University School of Medicine, Boston, Massachusetts.
Arthritis Rheumatol. 2015 Oct;67(10):2732-41. doi: 10.1002/art.39231.
To study the prevalence, clinical associations, and functional implications of the His159Tyr mutation of the BAFF receptor (BAFF-R) in patients with Sjögren's syndrome (SS).
The BAFF-R His159Tyr mutation was evaluated using polymerase chain reaction (PCR)-based assays in 247 patients with SS (of whom 70 had SS complicated by lymphoma [SS-lymphoma]), 145 with systemic lupus erythematosus (SLE), and 101 with rheumatoid arthritis (RA), as well as 180 healthy controls. Real-time PCR and Western blotting were performed for the quantification of both NF-κB1 and NF-κB2 messenger RNA (mRNA) transcript and protein levels in isolated B cells from patients with SS-lymphoma carrying the mutation (SS-lymphoma-BAFF-RHis159Tyr -derived B cells) compared to B cells from patients with SS-lymphoma who were not carriers of the mutation and healthy controls.
Both the SS-lymphoma and SS-nonlymphoma patient subgroups exhibited significantly higher frequencies of the His159Tyr BAFF-R mutation compared to healthy controls (8.6% of SS-lymphoma patients and 6.2% of SS-nonlymphoma patients versus 1.7% of healthy controls; P = 0.02 and P = 0.04, respectively). The corresponding frequencies of the His159Tyr BAFF-R mutation in SLE and RA patients were 3.5% and 3%, respectively. Of interest, 71.4% of the SS patients with mucosa-associated lymphoid tissue (MALT) lymphoma who were between the ages of 31 and 40 years at disease onset were mutation carriers. The generalized odds ratio for the development of SS-related MALT lymphoma in the younger age at onset (age <40 years) group in the presence of the BAFF-R mutation was 6.1 (95% confidence interval 2.0-18.7) (P < 0.01). Expression of NF-κB at both the mRNA and protein level was up-regulated in SS-lymphoma-BAFF-RHis159Tyr -derived B cells.
This study identifies an increased prevalence of the BAFF-R His159Tyr mutation in patients with SS, particularly in those with SS complicated by MALT lymphoma whose disease onset occurred at a younger age. BAFF-RHis159Tyr -mediated activation of the alternate NF-κB pathway might contribute to the pathogenesis of SS-related lymphoproliferative disease.
研究 BAFF 受体（BAFF-R）His159Tyr 突变在干燥综合征（SS）患者中的流行率、临床关联和功能意义。
采用聚合酶链反应（PCR）检测 247 例 SS 患者（其中 70 例 SS 合并淋巴瘤[SS-淋巴瘤]）、145 例系统性红斑狼疮（SLE）和 101 例类风湿关节炎（RA）患者及 180 例健康对照者的 BAFF-R His159Tyr 突变。对携带突变的 SS-淋巴瘤患者（SS-淋巴瘤-BAFF-RHis159Tyr 衍生 B 细胞）和未携带突变的 SS-淋巴瘤患者及健康对照者分离的 B 细胞进行 NF-κB1 和 NF-κB2 信使 RNA（mRNA）转录和蛋白水平的实时 PCR 和 Western blot 定量分析。
SS-淋巴瘤和 SS-非淋巴瘤患者亚组与健康对照组相比，BAFF-R His159Tyr 突变的频率明显更高（SS-淋巴瘤患者为 8.6%，SS-非淋巴瘤患者为 6.2%，健康对照组为 1.7%；P=0.02 和 P=0.04）。SLE 和 RA 患者中 BAFF-R His159Tyr 突变的频率分别为 3.5%和 3%。有趣的是，发病年龄在 31-40 岁的 SS 患者中，71.4%为黏膜相关淋巴组织（MALT）淋巴瘤患者，为突变携带者。在 BAFF-R 突变存在的情况下，年轻发病年龄（<40 岁）组发生 SS 相关 MALT 淋巴瘤的广义比值比为 6.1（95%置信区间 2.0-18.7）（P<0.01）。在 SS-淋巴瘤-BAFF-RHis159Tyr 衍生的 B 细胞中，NF-κB 在 mRNA 和蛋白水平的表达均上调。
本研究发现 SS 患者中 BAFF-R His159Tyr 突变的流行率增加，尤其是发病年龄较小的 SS 合并 MALT 淋巴瘤患者。BAFF-RHis159Tyr 介导的替代 NF-κB 通路的激活可能有助于 SS 相关淋巴增生性疾病的发病机制。
