Timo Hautala1,2, Paula Vähäsalo3, Outi Kuismin4, Salla Keskitalo5, Kristiina Rajamäki6, Antti Väänänen7, Marja Simojoki8, Marjaana Säily1, Ilpo Pelkonen9, Heikki Tokola10, Markus Mäkinen10, Riitta Kaarteenaho11, Airi Jartti12, Nina Hautala13, Saara Kantola14, Päivi Jackson15, Virpi Glumoff2, Janna Saarela16, Markku Varjosalo5,17, Kari K Eklund18, Mikko R J Seppänen6,19. 1. From the Department of Internal Medicine, Oulu University Hospital. 2. Research Unit of Biomedicine, University of Oulu. 3. Department of Pediatrics, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu. 4. Department of Clinical Genetics, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu. 5. Institute of Biotechnology, Helsinki Institute of Life Science (HiLIFE), University of Helsinki. 6. Clinicum, Faculty of Medicine, University of Helsinki, Helsinki. 7. Department of Infection Control, Lapland Central Hospital, Rovaniemi. 8. Department of Obstetrics and Gynecology, Oulu University Hospital. 9. Hematology Laboratory, Nordlab Oulu, Oulu University Hospital. 10. Department of Pathology, Cancer Research and Translational Medicine Research Unit, University of Oulu and Oulu University Hospital. 11. Respiratory Medicine, Research Unit of Internal Medicine, University of Oulu and Medical Research Center Oulu. 12. Department of Radiology, Oulu University Hospital. 13. Department of Ophthalmology, PEDEGO Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu. 14. Department of Dentistry, Oulu University Hospital. 15. Department of Dermatology, Oulu University Hospital, Oulu. 16. Institute for Molecular Medicine Finland, Helsinki Institute of Life Science (HiLIFE). 17. Proteomics Unit, Institute of Biotechnology, University of Helsinki. 18. Department of Rheumatology, Inflammation Center, University of Helsinki and Helsinki University Hospital. Research Institute, Invalid Foundation. Orton Orthopedic Hospital. 19. Rare Diseases Center and Pediatric Research Center, Children and Adolescents and Adult Immunodeficiency Unit, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Abstract
BACKGROUND: Tumor necrosis factor α-induced protein 3 gene (TNFAIP3, also called A20) haploinsufficiency (HA20) leads to autoinflammation and autoimmunity. We have recently shown that a p.(Lys91*) mutation in A20 disrupts nuclear factor κB signaling, impairs protein-protein interactions of A20, and leads to inflammasome activation. METHODS: We now describe the clinical presentations and drug responses in a family with HA20 p.(Lys91*) mutation, consistent with our previously reported diverse immunological and functional findings. RESULTS: We report for the first time that inflammasome-mediated autoinflammatory lung reaction caused by HA20 can be treated with interleukin 1 antagonist anakinra. We also describe severe anemia related to HA20 successfully treated with mycophenolate. In addition, HA20 p.(Lys91*) was found to associate with autoimmune thyroid disease, juvenile idiopathic arthritis, psoriasis, liver disease, and immunodeficiency presenting with specific antibody deficiency and genital papillomatosis. CONCLUSIONS: We conclude that HA20 may lead to combination of inflammation, immunodeficiency, and autoimmunity. The condition may present with variable and unpredictable symptoms with atypical treatment responses.
BACKGROUND: Tumor necrosis factor α-induced protein 3 gene (TNFAIP3, also called A20) haploinsufficiency (HA20) leads to autoinflammation and autoimmunity. We have recently shown that a p.(Lys91*) mutation in A20 disrupts nuclear factor κB signaling, impairs protein-protein interactions of A20, and leads to inflammasome activation. METHODS: We now describe the clinical presentations and drug responses in a family with HA20 p.(Lys91*) mutation, consistent with our previously reported diverse immunological and functional findings. RESULTS: We report for the first time that inflammasome-mediated autoinflammatory lung reaction caused by HA20 can be treated with interleukin 1 antagonist anakinra. We also describe severe anemia related to HA20 successfully treated with mycophenolate. In addition, HA20 p.(Lys91*) was found to associate with autoimmune thyroid disease, juvenile idiopathic arthritis, psoriasis, liver disease, and immunodeficiency presenting with specific antibody deficiency and genital papillomatosis. CONCLUSIONS: We conclude that HA20 may lead to combination of inflammation, immunodeficiency, and autoimmunity. The condition may present with variable and unpredictable symptoms with atypical treatment responses.