Arti Medhavy, Vicki Athanasopoulos, Katharine Bassett, Yuke He, Maurice Stanley, Daniel Enosi Tuipulotu, Jean Cappello, Grant J. Brown, Paula Gonzalez-Figueroa, Cynthia Turnbull, Somasundhari Shanmuganandam, Padmaja Tummala, Gemma Hart, Tom Lea-Henry, Hao Wang, Sonia Nambadan, Qian Shen, Jonathan A. Roco, Gaetan Burgio, Phil Wu, Eun Cho, T. Daniel Andrews, Matt A. Field, Xiaoqian Wu, Huihua Ding, Qiang Guo, Nan Shen, Si Ming Man, Simon H. Jiang, Matthew C. Cook, Carola G. Vinuesa
{"title":"一种由 TNIP1 驱动、IgG4 升高的系统性自身免疫疾病","authors":"Arti Medhavy, Vicki Athanasopoulos, Katharine Bassett, Yuke He, Maurice Stanley, Daniel Enosi Tuipulotu, Jean Cappello, Grant J. Brown, Paula Gonzalez-Figueroa, Cynthia Turnbull, Somasundhari Shanmuganandam, Padmaja Tummala, Gemma Hart, Tom Lea-Henry, Hao Wang, Sonia Nambadan, Qian Shen, Jonathan A. Roco, Gaetan Burgio, Phil Wu, Eun Cho, T. Daniel Andrews, Matt A. Field, Xiaoqian Wu, Huihua Ding, Qiang Guo, Nan Shen, Si Ming Man, Simon H. Jiang, Matthew C. Cook, Carola G. Vinuesa","doi":"10.1038/s41590-024-01902-0","DOIUrl":null,"url":null,"abstract":"Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1Q333P 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 Tnip1Q346P 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. Vinuesa et al. identify patients with systemic autoimmunity and a TNIP1 variant that result in dysregulated B cell function. Mice with the orthologous Tnip1 mutation develop spontaneous autoimmunity associated with impaired mitophagy and autophagic silencing of proteins downstream of Toll-like receptor 7 signaling.","PeriodicalId":19032,"journal":{"name":"Nature Immunology","volume":null,"pages":null},"PeriodicalIF":27.7000,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41590-024-01902-0.pdf","citationCount":"0","resultStr":"{\"title\":\"A TNIP1-driven systemic autoimmune disorder with elevated IgG4\",\"authors\":\"Arti Medhavy, Vicki Athanasopoulos, Katharine Bassett, Yuke He, Maurice Stanley, Daniel Enosi Tuipulotu, Jean Cappello, Grant J. Brown, Paula Gonzalez-Figueroa, Cynthia Turnbull, Somasundhari Shanmuganandam, Padmaja Tummala, Gemma Hart, Tom Lea-Henry, Hao Wang, Sonia Nambadan, Qian Shen, Jonathan A. Roco, Gaetan Burgio, Phil Wu, Eun Cho, T. Daniel Andrews, Matt A. Field, Xiaoqian Wu, Huihua Ding, Qiang Guo, Nan Shen, Si Ming Man, Simon H. Jiang, Matthew C. Cook, Carola G. Vinuesa\",\"doi\":\"10.1038/s41590-024-01902-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1Q333P 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 Tnip1Q346P 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. Vinuesa et al. identify patients with systemic autoimmunity and a TNIP1 variant that result in dysregulated B cell function. Mice with the orthologous Tnip1 mutation develop spontaneous autoimmunity associated with impaired mitophagy and autophagic silencing of proteins downstream of Toll-like receptor 7 signaling.\",\"PeriodicalId\":19032,\"journal\":{\"name\":\"Nature Immunology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":27.7000,\"publicationDate\":\"2024-07-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.nature.com/articles/s41590-024-01902-0.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.nature.com/articles/s41590-024-01902-0\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s41590-024-01902-0","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
A TNIP1-driven systemic autoimmune disorder with elevated IgG4
Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1Q333P 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 Tnip1Q346P 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. Vinuesa et al. identify patients with systemic autoimmunity and a TNIP1 variant that result in dysregulated B cell function. Mice with the orthologous Tnip1 mutation develop spontaneous autoimmunity associated with impaired mitophagy and autophagic silencing of proteins downstream of Toll-like receptor 7 signaling.
期刊介绍:
Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.