Our study presents a novel germline c.1715G>T (p.G572V) mutation in the gene encoding Toll-like receptor 8 (TLR8) causing an autoimmune and autoinflammatory disorder in a family with monozygotic male twins, who suffer from severe autoimmune hemolytic anemia worsening with infections, and autoinflammation presenting as fevers, enteritis, arthritis, and CNS vasculitis. The pathogenicity of the mutation was confirmed by in vitro assays on transfected cell lines and primary cells. The p.G572V mutation causes impaired stability of the TLR8 protein, cross-reactivity to TLR7 ligands and reduced ability of TLR8 to attenuate TLR7 signaling. This imbalance toward TLR7-dependent signaling leads to increased pro-inflammatory responses, such as nuclear factor-κB (NF-κB) activation and production of pro-inflammatory cytokines IL-1β, IL-6, and TNFα. This unique TLR8 mutation with partial TLR8 protein loss and hyperinflammatory phenotype mediated by TLR7 ligands represents a novel inborn error of immunity with childhood-onset and a good response to TLR7 inhibition.

Bioinformatics Group Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Prague Czech Republic

CLIP Childhood Leukaemia Investigation Prague Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Immunology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Paediatric and Adult Rheumatology University Hospital Motol Prague Czech Republic

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Paediatric Neurology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Paediatrics 1st Faculty of Medicine Charles University and Thomayer University Hospital Prague Czech Republic

Department of Software Engineering Faculty of Mathematics and Physics Charles University Prague Czech Republic

Division of Rheumatology Immunology Department of Pediatrics Washington University School of Medicine St Louis Missouri USA

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Picard C, von Bernuth H, Ghandil P, et al. Clinical features and outcome of patients with Irak-4 and MyD88 deficiency. Medicine. 2010;89(6):403-425. doi:10.1097/MD.0b013e3181fd8ec3

Aluri J, Bach A, Kaviany S, et al. Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function. Blood. 2021;137(18):2450-2462. doi:10.1182/blood.2020009620

Farrugia M, Baron B. The role of toll-like receptors in autoimmune diseases through failure of the self-recognition mechanism. Int J Inflam. 2017;2017:1-12. doi:10.1155/2017/8391230

Eigenbrod T, Pelka K, Latz E, Kreikemeyer B, Dalpke AH. TLR8 senses bacterial RNA in human monocytes and plays a nonredundant role for recognition of streptococcus pyogenes. J Immunol. 2015;195(3):1092-1099. doi:10.4049/jimmunol.1403173

Bender AT, Tzvetkov E, Pereira A, et al. TLR7 and TLR8 differentially activate the IRF and NF-κB pathways in specific cell types to promote inflammation. ImmunoHorizons. 2020;4(2):93-107. doi:10.4049/immunohorizons.2000002

Asano T, Boisson B, Onodi F, et al. X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19. Sci Immunol. 2021;6(62). doi:10.1126/sciimmunol.abl4348

de Marcken M, Dhaliwal K, Danielsen AC, Gautron AS, Dominguez-Villar M. TLR7 and TLR8 activate distinct pathways in monocytes during RNA virus infection. Sci Signal. 2019;12(605):eaaw1347. doi:10.1126/scisignal.aaw1347

Larange A, Antonios D, Pallardy M, Kerdine-Romer S. TLR7 and TLR8 agonists trigger different signaling pathways for human dendritic cell maturation. J Leukoc Biol. 2009;85(4):673-683. doi:10.1189/jlb.0808504

Wang J, Shao Y, Bennett TA, Shankar RA, Wightman PD, Reddy LG. The functional effects of physical interactions among toll-like receptors 7, 8, and 9. J Biol Chem. 2006;281(49):37427-37434. doi:10.1074/jbc.M605311200

Zhang Z, Ohto U, Shibata T, et al. Structural analyses of toll-like receptor 7 reveal detailed RNA sequence specificity and recognition mechanism of agonistic ligands. Cell Rep. 2018;25(12):3371-3381.e5. doi:10.1016/j.celrep.2018.11.081

Lee PY, Kumagai Y, Li Y, et al. TLR7-dependent and FcγR-independent production of type I interferon in experimental mouse lupus. J Exp med. 2008;205(13):2995-3006. doi:10.1084/jem.20080462

Hoffmann MH, Skriner K, Herman S, et al. Nucleic acid-stimulated antigen-presenting cells trigger T cells to induce disease in a rat transfer model of inflammatory arthritis. J Autoimmun. 2011;36(3-4):288-300. doi:10.1016/j.jaut.2011.02.007

Guiducci C, Gong M, Cepika A-M, et al. RNA recognition by human TLR8 can lead to autoimmune inflammation. J Exp med. 2013;210(13):2903-2919. doi:10.1084/jem.20131044

Deane JA, Pisitkun P, Barrett RS, et al. Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation. Immunity. 2007;27(5):801-810. doi:10.1016/j.immuni.2007.09.009

Fairhurst A, Hwang S, Wang A, et al. Yaa autoimmune phenotypes are conferred by overexpression of TLR7. Eur J Immunol. 2008;38(7):1971-1978. doi:10.1002/eji.200838138

Demaria O, Pagni PP, Traub S, et al. TLR8 deficiency leads to autoimmunity in mice. J Clin Invest. 2010;120(10):3651-3662. doi:10.1172/JCI42081

Desnues B, Macedo AB, Roussel-Queval A, et al. TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice. Proc Natl Acad Sci. 2014;111(4):1497-1502. doi:10.1073/pnas.1314121111

Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754-1760. doi:10.1093/bioinformatics/btp324

Koboldt DC, Zhang Q, Larson DE, et al. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 2012;22(3):568-576. doi:10.1101/gr.129684.111

Li H, Handsaker B, Wysoker A, et al. The sequence alignment/map format and SAMtools. Bioinformatics. 2009;25(16):2078-2079. doi:10.1093/bioinformatics/btp352

Tangye SG, Al-Herz W, Bousfiha A, et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40(1):24-64. doi:10.1007/s10875-019-00737-x

Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: A Matching Tool for Connecting Investigators with an Interest in the Same Gene. Human Mutation. 2015;36(10):928-930. doi:10.1002/humu.22844

Brüggemann M, Kotrová M, Knecht H, et al. Standardized next-generation sequencing of immunoglobulin and T-cell receptor gene recombinations for MRD marker identification in acute lymphoblastic leukaemia; a EuroClonality-NGS validation study. Leukemia. 2019;33(9):2241-2253. doi:10.1038/s41375-019-0496-7

Bystry V, Reigl T, Krejci A, et al. ARResT/interrogate: an interactive immunoprofiler for IG/TR NGS data. Bioinformatics. 2016;33(3):435-437. doi:10.1093/bioinformatics/btw634

Tanji H, Ohto U, Motoi Y, Shibata T, Miyake K, Shimizu T. Autoinhibition and relief mechanism by the proteolytic processing of toll-like receptor 8. Proc Natl Acad Sci U S A. 2016;113(11):3012-3017. doi:10.1073/pnas.1516000113

Tanji H, Ohto U, Shibata T, et al. Toll-like receptor 8 senses degradation products of single-stranded RNA. Nat Struct Mol Biol. 2015;22(2):109-115. doi:10.1038/nsmb.2943

Tanji H, Ohto U, Shibata T, Miyake K, Shimizu T. Structural reorganization of the toll-like receptor 8 dimer induced by agonistic ligands. Science. 2013;339(6126):1426-1429. doi:10.1126/science.1229159

Itoh H, Tatematsu M, Watanabe A, et al. UNC93B1 physically associates with human TLR8 and regulates TLR8-mediated signaling. PLoS One. 2011;6(12):e28500. doi:10.1371/journal.pone.0028500

Mukherjee R, Kanti Barman P, Kumar Thatoi P, Tripathy R, Kumar Das B, Ravindran B. Non-classical monocytes display inflammatory features: validation in sepsis and systemic lupus erythematous. Sci Rep. 2015;5(July):1-14. doi:10.1038/srep13886

Bundhun PK, Kumari A, Huang F. Differences in clinical features observed between childhood-onset versus adult-onset systemic lupus erythematosus. Medicine. 2017;96(37):e8086. doi:10.1097/MD.0000000000008086

Peng G, Guo Z, Kiniwa Y, et al. Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science. 2005;309(5739):1380-1384. doi:10.1126/science.1113401

La Cava A. Tregs are regulated by cytokines: implications for autoimmunity. Autoimmun Rev. 2008;8(1):83-87. doi:10.1016/j.autrev.2008.08.002

Tran NL, Manzin-Lorenzi C, Santiago-Raber ML. Toll-like receptor 8 deletion accelerates autoimmunity in a mouse model of lupus through a toll-like receptor 7-dependent mechanism. Immunology. 2015;145(1):60-70. doi:10.1111/imm.12426