A TNIP1-driven systemic autoimmune disorder with elevated IgG4

• DOI: 10.1038/s41590-024-01902-0
• Publication Date: 2024-07-26T10:01:55Z
• Authors: Arti Medhavy; Vicki Athanasopoulos; Katharine Bassett; Yuke He; Maurice Stanley; Daniel Enosi Tuip...; Jean Cappello; Grant J. Brown; Paula Gonzalez-Fi...; Cynthia Turnbull; Somasundhari Shan...; 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
• Keywords: Male; Immunology; 610; Article; Salivary Glands; Autoimmune Diseases; Mice; Exome Sequencing; Animals; Humans; Mice, Knockout; B-Lymphocytes; Human Biology & Physiology; Membrane Glycoproteins; FOS: Clinical medicine; Germinal Center; Mitochondria; Pedigree; DNA-Binding Proteins; Mice, Inbred C57BL; Metabolism; Toll-Like Receptor 7; Immunoglobulin G; Antibodies, Antinuclear; Myeloid Differentiation Factor 88; Female; Genetics & Genomics; Signal Transduction

AbstractWhole-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.