A TNIP1-driven systemic autoimmune disorder with elevated IgG4
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Athanasopoulos, Vicki
Bassett, Katharine
He, Yuke
Stanley, Maurice
Enosi Tuipulotu, Daniel
Cappello, Jean
Brown, Grant J
Gonzalez-Figueroa, Paula
Turnbull, Cynthia
Shanmuganandam, Somasundhari
Tummala, Padmaja
Hart, Gemma
Lea-Henry, Tom
Wang, Hao
et al.
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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.
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Nature Immunology
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25
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9
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© 2024, The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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Medhavy, A; Athanasopoulos, V; Bassett, K; He, Y; Stanley, M; Enosi Tuipulotu, D; Cappello, J; Brown, GJ; Gonzalez-Figueroa, P; Turnbull, C; Shanmuganandam, S; Tummala, P; Hart, G; Lea-Henry, T; Wang, H; Nambadan, S; Shen, Q; Roco, JA; Burgio, G; Wu, P; Cho, E; Andrews, TD; Field, MA; Wu, X; Ding, H; Guo, Q; Shen, N; Man, SM; Jiang, SH; Cook, MC; Vinuesa, CG, A TNIP1-driven systemic autoimmune disorder with elevated IgG4, Nature Immunology, 2024, 25 (9), pp. 1678-1691