Endo Yushiro, Koga Tomohiro, Mohamed Lamiaa, Tsuji Yoshika, Umeda Masataka, Hayashi Hiroko, Kishino Tatsuya, Kawakami Atsushi
Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Department of Pathology, Sasebo City General Hospital, Sasebo, Japan.
Front Immunol. 2025 Jul 7;16:1571208. doi: 10.3389/fimmu.2025.1571208. eCollection 2025.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of immune tolerance, leading to systemic inflammation and organ damage. The () gene, primarily linked to familial Mediterranean fever (FMF), has been suggested to have a protective role against SLE. However, comprehensive whole-exon analyses of and research on or FMF in non-Mediterranean populations, where exon 10 mutations are relatively rare, are limited.
We conducted a whole-exon analysis of the gene in 55 Japanese patients with SLE. Patients were classified based on the presence or absence of variants, and their clinical characteristics were compared. In addition, we generated MRL/lpr mice with the human E148Q variant using CRISPR technology to examine its impact on disease phenotypes. Disease activity and kidney pathology were assessed using the established clinical and histological scoring systems.
Among the 55 patients, those carrying variants exhibited a significantly lower prevalence of lupus nephritis than non-carriers (P = 0.007). The number of variants was inversely associated with the risk of lupus nephritis (P = 0.03). In MRL/lpr mice, the E148Q variant was associated with reduced anti-dsDNA antibody production, reduced formation of memory B cells, and milder kidney pathology, indicating a shift from adaptive immunity to innate immune responses.
Our findings suggest that variants, particularly the E148Q variant, may play a protective role against lupus nephritis in Japanese patients with SLE by modulating immune responses. These results provide valuable insights into the genetic factors influencing SLE severity.
系统性红斑狼疮（SLE）是一种自身免疫性疾病，其特征为免疫耐受丧失，导致全身炎症和器官损伤。主要与家族性地中海热（FMF）相关的（）基因被认为对SLE具有保护作用。然而，在非地中海人群中，外显子10突变相对罕见，对该基因的全面全外显子分析以及对该基因或FMF的研究有限。
我们对55例日本SLE患者的该基因进行了全外显子分析。根据是否存在该基因变异对患者进行分类，并比较他们的临床特征。此外，我们使用CRISPR技术构建了携带人类该基因E148Q变异的MRL/lpr小鼠，以研究其对疾病表型的影响。使用既定的临床和组织学评分系统评估疾病活动度和肾脏病理情况。
在这55例患者中，携带该基因变异的患者狼疮性肾炎的患病率显著低于非携带者（P = 0.007）。该基因变异的数量与狼疮性肾炎的风险呈负相关（P = 0.03）。在MRL/lpr小鼠中，E148Q变异与抗双链DNA抗体产生减少、记忆B细胞形成减少以及较轻的肾脏病理情况相关，表明从适应性免疫向先天性免疫反应转变。
我们的研究结果表明，该基因变异，尤其是E148Q变异，可能通过调节免疫反应对日本SLE患者的狼疮性肾炎起到保护作用。这些结果为影响SLE严重程度的遗传因素提供了有价值的见解。
