Biswas Sheta, Kasperek Eileen M, Zhu Chengsong, Miecznikowski Jeffrey C, Osinski Jason, Romano Rose-Anne, Kramer Jill M
Department of Oral Biology, School of Dental Medicine, The University at Buffalo, State University of New York, Buffalo, NY, USA; Department of Biochemistry and Molecular Biology, Noakhali Science and Technology University, Noakhali, 3814, Bangladesh.
Department of Oral Biology, School of Dental Medicine, The University at Buffalo, State University of New York, Buffalo, NY, USA.
J Autoimmun. 2025 Jul 30;156:103467. doi: 10.1016/j.jaut.2025.103467.
Primary Sjogren's disease (pSD) is a systemic autoimmune disease. Currently, the causes of pSD remain unknown, and no curative therapies are available. Our prior studies showed Tlr7 activation was an important driver of pSD in females. Since Tlr7 is regulated by Tlr9, we hypothesized that ablation of Tlr9 would exacerbate disease in a Tlr7-dependent manner. Towards this end, we generated pSD mice that lacked systemic expression of either Tlr9 (NOD.B10) or both Tlr7 and Tlr9 (NOD.B10). We harvested tissues for histologic analysis and assessed disease-relevant immune cell populations in secondary lymphoid organs. We examined total and autoreactive antibody levels in sera. Enhanced nephritis was observed in Tlr9-deficient females, while dacryoadenitis was increased in males that lacked Tlr9, and these manifestations were dependent on Tlr7. Moreover, the percentages of splenic Tlr7+ B cells, germinal center and age-associated B cells, CD4 and CD8 activated/memory T cells, and Tfh cells were increased in NOD.B10 females as compared to sex-matched NOD.B10 mice, and this expansion was abrogated in NOD.B10 females. Finally, total IgM levels were elevated in sera from NOD.B10 females as compared to the parental strain and autoreactive IgM and IgG were also enriched in NOD.B10 females. NOD.B10 females and males showed dramatically reduced IgM and IgG titers as compared to the NOD.B10 strain and anti-nuclear autoantibodies were diminished in this strain. Overall, our study revealed that ablation of Tlr9 drives pSD in females but has negligible effects on disease in males. Moreover, Tlr9 regulates Tlr7-dependent pSD manifestations in a sex-biased manner.
原发性干燥综合征（pSD）是一种全身性自身免疫性疾病。目前，pSD的病因尚不清楚，也没有治愈性疗法。我们之前的研究表明，Tlr7激活是女性pSD的重要驱动因素。由于Tlr7受Tlr9调控，我们推测敲除Tlr9会以Tlr7依赖的方式加重疾病。为此，我们构建了缺乏Tlr9全身表达（NOD.B10）或同时缺乏Tlr7和Tlr9（NOD.B10）的pSD小鼠。我们采集组织进行组织学分析，并评估次级淋巴器官中与疾病相关的免疫细胞群体。我们检测了血清中的总抗体和自身反应性抗体水平。在缺乏Tlr9的雌性小鼠中观察到肾炎加重，而在缺乏Tlr9的雄性小鼠中泪腺炎增加，且这些表现依赖于Tlr7。此外，与性别匹配的NOD.B10小鼠相比，NOD.B10雌性小鼠脾脏中Tlr7+B细胞、生发中心和年龄相关B细胞、CD4和CD8活化/记忆T细胞以及滤泡辅助性T细胞的百分比增加，而在NOD.B10雌性小鼠中这种扩增被消除。最后，与亲代品系相比，NOD.B10雌性小鼠血清中的总IgM水平升高，且NOD.B10雌性小鼠中自身反应性IgM和IgG也有所富集。与NOD.B10品系相比，NOD.B10雌性和雄性小鼠的IgM和IgG滴度显著降低，且该品系中的抗核自身抗体减少。总体而言，我们的研究表明，敲除Tlr9会导致雌性小鼠患pSD，但对雄性小鼠疾病的影响可忽略不计。此外，Tlr9以性别偏向的方式调节Tlr7依赖的pSD表现。
