A TNIP1-driven systemic autoimmune disorder with elevated IgG4.

Autor: Medhavy A; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Athanasopoulos V; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Bassett K; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., He Y; China Australia Center for Personalized Immunology, Shanghai Renji Hospital, Shanghai Jiaotong University, Shanghai, China., Stanley M; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Enosi Tuipulotu D; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Cappello J; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Brown GJ; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Gonzalez-Figueroa P; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Turnbull C; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Shanmuganandam S; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Tummala P; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Hart G; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Lea-Henry T; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Wang H; Francis Crick Institute, London, UK., Nambadan S; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Shen Q; Francis Crick Institute, London, UK., Roco JA; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Burgio G; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Wu P; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Cho E; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Andrews TD; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Field MA; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.; Center for Tropical Bioinformatics and Molecular Biology, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia., Wu X; China Australia Center for Personalized Immunology, Shanghai Renji Hospital, Shanghai Jiaotong University, Shanghai, China., Ding H; Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China., Guo Q; Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China., Shen N; China Australia Center for Personalized Immunology, Shanghai Renji Hospital, Shanghai Jiaotong University, Shanghai, China.; Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China., Man SM; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Jiang SH; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia., Cook MC; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.; Department of Medicine, University of Cambridge, Cambridge, UK., Vinuesa CG; Division of Immunology and Infectious Disease, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia. carola.vinuesa@crick.ac.uk.; China Australia Center for Personalized Immunology, Shanghai Renji Hospital, Shanghai Jiaotong University, Shanghai, China. carola.vinuesa@crick.ac.uk.; Francis Crick Institute, London, UK. carola.vinuesa@crick.ac.uk.
Jazyk: angličtina
Zdroj: Nature immunology [Nat Immunol] 2024 Sep; Vol. 25 (9), pp. 1678-1691. Date of Electronic Publication: 2024 Jul 26.
DOI: 10.1038/s41590-024-01902-0
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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