Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1^Q333P variant segregating with disease. Mice with the orthologous Q346P variant developed antinuclear autoantibodies, salivary gland inflammation, elevated IgG2c, spontaneous germinal centers and expansion of age-associated B cells, plasma cells and follicular and extrafollicular helper T cells. B cell phenotypes were cell-autonomous and rescued by ablation of Toll-like receptor 7 (TLR7) or MyD88. The variant increased interferon-β without altering nuclear factor kappa-light-chain-enhancer of activated B cells signaling, and impaired MyD88 and IRAK1 recruitment to autophagosomes. Additionally, the Q333P variant impaired TNIP1 localization to damaged mitochondria and mitophagosome formation. Damaged mitochondria were abundant in the salivary epithelial cells of Tnip1^Q346P mice. These findings suggest that TNIP1-mediated autoimmunity may be a consequence of increased TLR7 signaling due to impaired recruitment of downstream signaling molecules and damaged mitochondria to autophagosomes and may thus respond to TLR7-targeted therapeutics.

对患有系统性自身免疫性疾病的两个不相关亲属进行全外显子组测序，其特征是 IgG4 升高的抗核抗体，发现了与疾病分离的相同的极其罕见的杂合TNIP1 ^Q333P变异。具有直系同源 Q346P 变体的小鼠产生抗核自身抗体、唾液腺炎症、IgG2c 升高、自发生发中心以及与年龄相关的 B 细胞、浆细胞以及滤泡和滤泡外辅助 T 细胞的扩增。 B 细胞表型是细胞自主的，并通过消除 Toll 样受体 7 (TLR7) 或 MyD88 来挽救。该变异体增加了干扰素-β，但不改变激活 B 细胞信号传导的核因子 kappa-轻链增强子，并损害了 MyD88 和 IRAK1 向自噬体的募集。此外，Q333P 变体损害了 TNIP1 定位到受损的线粒体和线粒体吞噬体的形成。 Tnip1 ^Q346P小鼠的唾液上皮细胞中存在大量受损的线粒体。这些发现表明，TNIP1 介导的自身免疫可能是由于下游信号分子募集受损和自噬体线粒体受损而导致 TLR7 信号传导增加的结果，因此可能对 TLR7 靶向治疗产生反应。