Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC170210.15690/vramn1702RHEUMATOLOGY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ РЕВМАТОЛОГИИReview ArticleInfluence of Genetic Factors on Immunopathogenesis and Clinical Phenotypes of ANCA-associated VasculitisВлияние генетических факторов на иммунопатогенез и клинические фенотипы АНЦА-ассоциированных васкулитовhttps://orcid.org/0000-0002-2388-14831933-5968VlasenkoNatalia V.ВласенкоНаталья Викторовна
Russian Federation

Research Associate

научный сотрудник

vlasenko@cmd.suhttps://orcid.org/0000-0002-3989-25907408-5706BulanovNikolay M.БулановНиколай Михайлович
Russian Federation

MD, PhD, Assistant Professor

к.м.н, доцент

nmbulanov@gmail.comhttps://orcid.org/0000-0002-7232-46403462-7884MoiseevSergey V.МоисеевСергей Валентинович
Russian Federation

MD, PhD, Professor

д.м.н., профессор

moiseev_s_v@staff.sechenov.ruhttps://orcid.org/0000-0002-6686-90118375-2270SemenenkoTatiana A.СемененкоТатьяна Анатольевна
Russian Federation

MD, PhD, Professor

д.м.н., профессор

meddy@inbox.ruhttps://orcid.org/0000-0002-0616-97771372-7623KuzinStanislav N.КузинСтанислав Николаевич
Russian Federation

MD, PhD, Professor

д.м.н., профессор

kuzin@cmd.suhttps://orcid.org/0000-0003-4228-90444038-7455AkimkinVasily G.АкимкинВасилий Геннадиевич
Russian Federation

MD, PhD, Academician of the RAS

д.м.н., академик РАН

akimkin@pcr.msCentral Research Institute of EpidemiologyЦентральный научно-исследовательский институт эпидемиологииI.M. Sechenov First Moscow State Medical University (Sechenov University)Первый Московский государственный медицинский университет имени И.М. Сеченова (Сеченовский Университет)National Research Center for Epidemiology and Microbiology named after Honorary Academician N.F. GamaleyaНациональный исследовательский центр эпидемиологии и микробиологии имени почетного академика Н.Ф. Гамалеи151220217666426512309202128112021Copyright ©; 2021, "Paediatrician" Publishers LLCCopyright ©; 2021, Издательство "Педиатръ"2021"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/about/submissionshttps://vestnikramn.spr-journal.ru/jour/article/view/1702

The review presents the recent data on assumed risk factors for the development of ANCA-associated vasculitis (AAV), among which environmental factors, such as climatic, chemical, etc., are of particular interest of researchers. Controversial opinions of various authors on the role of individual causative agents of infectious diseases in the development of AAV are analyzed. The review pays special attention to scientific data on the influence of variants of the structure of genes encoding various components of the immune system on the development of the pathogenetic process of AAV. Up-to-date information on the association of single-nucleotide polymorphisms (SNPs) with the course, risk of development and the likelihood of AAV recurrence is indicated, the most associated of which are genes encoding proteins of the main histocompatibility complex (HLA), a toll-like receptors (TLR`s), as well as an inhibitor of serine proteinases-alpha-antitrypsin (AAT). The analysis of scientific publications describing the molecular mechanism of the development of a pathological focus that forms the conditions for the synthesis of PR3–ANCA and MPO–ANCA complexes characteristic of AAV has been carried out. The data of a number of foreign studies on the relationship of individual SNPs associated with the features of the course of granulomatosis with polyangiitis, microscopic polyangiitis, as well as eosinophilic granulomatosis with polyangiitis are presented and summarized. The review presents current AAV treatment regimens and promising directions for the development of medical care for patients.

В обзоре представлены последние данные о возможных факторах риска развития АНЦА-ассоциированных васкулитов (ААВ), среди которых особое внимание исследователей привлекают факторы окружающей среды, такие как климатические, химические и др. Проанализированы противоречивые мнения различных авторов о роли отдельных возбудителей инфекционных заболеваний в развитии ААВ. Особое внимание в обзоре уделено научным данным о влиянии вариантов строения генов, кодирующих различные компоненты иммунной системы, на развитие патогенетического процесса ААВ. Указана актуальная информация об ассоциации однонуклеотидных полиморфизмов (SNP) с течением, риском развития и вероятностью рецидива ААВ, максимально ассоциированными из которых являются гены, кодирующие белки главного комплекса гистосовместимости (HLA), толл-подобные рецепторы (TLR), а также ингибитор сериновых протеиназ — альфа-антитрипсин. Проведен анализ научных публикаций, описывающих молекулярный механизм развития патологического очага, формирующего условия для синтеза комплексов PR3–АНЦА и MPO–АНЦА, характерных для ААВ. Приведены и обобщены данные ряда зарубежных исследований о связи отдельных SNP, ассоциированных с особенностями течения гранулематоза с полиангиитом, микроскопическим полиангиитом, а также эозинофильным гранулематозом с полиангиитом. Представлены актуальные схемы лечения ААВ и перспективные направления развития медикаментозной помощи пациентам.

systemic vasculitisantibodies to neutrophil cytoplasmsingle-nucleotide polymorphismsсистемные васкулитыантитела к цитоплазме нейтрофиловоднонуклеотидные полиморфизмыJennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int. 2003;63(3):1164–1177. doi: https://doi.org/10.1046/j.1523-1755.2003.00843.xTravis WD, Colby TV, Lombard C, et al. A clinicopathologic study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation. Am J Surg Pathol. 1990;14:1112–1125.Добронравов В.А., Карунная А.В., Казимирчик А.В., Смирнов А.В.. АНЦА-ассоциированные васкулиты с доминирующим поражением почек: клинико-морфологическая презентация и исходы // Нефрология. — 2019. — Т. 23. — № 6. — С. 29–44. [Dobronravov VA, Karunnaya AV, Kazimirchik AV, Smirnov AV. ANCA-associated vasculitis with dominant renal involvement: clinical and morphological presentation and outcomes. Nephrology (Saint-Petersburg). 2019;23(6):29–44. (In Russ.)] doi: https://doi.org/10.36485/1561-6274-2019-236-29-44Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1–11. doi: https://doi.org/10.1002/art.37715Сафаргалиева Л.Х., Фролова Э.Б, Тухватуллина Г.В., и др. Гранулематоз Вегенера // Вестник современной клинической медицины. — 2010. — Т. 3. — Приложение 2. — С. 107–112. [Safargalieva LH, Frolova EB, Tuhvatullina GV, i dr. Granulematoz Vegenera. Vestnik sovremennoj klinicheskoj mediciny. 2010;3(Prilozhenie2):107–112. (In Russ.)]Kubaisi B, Abu Samra K, Foster CS. Granulomatosis with polyangiitis (Wegener’s disease): An updated review of ocular disease manifestations. Intractable Rare Dis Res. 2016;5(2):61–69. doi: https://doi.org/10.5582/irdr.2016.01014Altinel Acoglu E, Yazilitas F, Gurkan A, et al. Eosinophilic Granulomatosis with Polyangiitis in a 4-Year-Old Child: Is Montelukast and/or Clarithromycin a Trigger? Arch Iran Med. 2019;22(3):161–163.Liu X, Wang L, Zhou K, et al. A delayed diagnosis of eosinophilic granulomatosis with polyangiitis complicated with extensive artery occlusion of lower extremities in children: case report and literature review. Pediatr Rheumatol. 2019;17(26). doi: https://doi.org/10.1186/s12969-019-0331-8Eleftheriou D, Gale H, Pilkington C, et al. Eosinophilic granulomatosis with polyangiitis in childhood: retrospective experience from a tertiary referral centre in the UK. Rheumatology. 2016;55(7):1263–1272. doi: https://doi.org/10.1093/rheumatology/kew029Mohammad AJ. An update on the epidemiology of ANCA-associated vasculitis. Rheumatology (Oxford). 2020;59(Suppl 3):iii42–iii50. doi: https://doi.org/10.1093/rheumatology/keaa089McDermott G, Fu X, Stone JH, et al. Association of Cigarette Smoking with Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. JAMA Intern Med. 2020;180(6):870–876. doi: https://doi.org/10.1001/jamainternmed.2020.0675Kubaisi B, Abu Samra K, Foster CS. Granulomatosis with polyangiitis (Wegener’s disease): An updated review of ocular disease manifestations. Intractable Rare Dis Res. 2016;5(2):61–69. doi: https://doi.org/10.5582/irdr.2016.01014Gómez-Puerta JA, Gedmintas L, Costenbader KH. The association between silica exposure and development of ANCA-associated vasculitis: systematic review and meta-analysis. Autoimmun Rev. 2013;12(12):1129–1135. doi: https://doi.org/10.1016/j.autrev.2013.06.016Lane SE, Watts RA, Bentham G, Innes NJ, Scott DG. Are environmental factors important in primary systemic vasculitis? A case-control study. Arthritis Rheum. 2003;48(3):814–823. doi: https://doi.org/10.1002/art.10830Li J, Cui Z, Long JY, et al. The frequency of ANCA-associated vasculitis in a national database of hospitalized patients in China. Arthritis Res Ther. 2018;20(1):226. doi: https://doi.org/10.1186/s13075-018-1708-7Pearce FA, Lanyon PC, Grainge MJ, et al. Incidence of ANCA-associated vasculitis in a UK mixed ethnicity population. Rheumatology (Oxford). 2016;55(9):1656–1663. doi: https://doi.org/10.1093/rheumatology/kew232Watts RA, Mahr A, Mohammad AJ, et al. Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Nephrol Dial Transplant. 2015;30(Suppl 1):i14–i22. doi: https://doi.org/10.1093/ndt/gfv022Dartevel A, Chaigne B, Moachon L, et al. Levamisole-induced vasculopathy: A systematic review. Semin Arthritis Rheum. 2019;48(5):921–926. doi: https://doi.org/10.1016/j.semarthrit.2018.07.010Rozina T, Fastovets S, Lee O, et al. D-penicillamine-induced autoimmune disorders. Dig Liver Dis. 2019;51(12):1741–1742. doi: https://doi.org/10.1016/j.dld.2019.08.025Popa ER, Stegeman CA, Kallenberg CG, et al. Staphylococcus aureus and Wegener’s granulomatosis. Arthritis Res. 2002;4(2):77–79. doi: https://doi.org/10.1186/ar392Ooi JD, Jiang JH, Eggenhuizen PJ, et al. A plasmid-encoded peptide from Staphylococcus aureus induces anti-myeloperoxidase nephritogenic autoimmunity. Nat Commun. 2019;10(1):3392. doi: https://doi.org/10.1038/s41467-019-11255-0Besada E, Koldingsnes W, Nossent JC. Staphylococcus Aureus carriage and long-term Rituximab treatment for Granulomatosis with polyangiitis. Peer J. 2015;3:e1051. doi: https://doi.org/10.7717/peerj.1051Bossuyt X, Cohen Tervaert JW, et al. Position paper: Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis. Nat Rev Rheumatol. 2017;13(11):683–692. doi: https://doi.org/10.1038/nrrheum.2017.140Moiseev S, Bossuyt X, Arimura Y, et al. International Consensus on ANCA Testing in Eosinophilic Granulomatosis with Polyangiitis. Am J Respir Crit Care Med. 2020;202(10):1360–1372. doi: https://doi.org/10.1164/rccm.202005-1628SOAlmaani S, Fussner LA, Brodsky S, et al. ANCA-Associated Vasculitis: An Update. J Clin Med. 2021;10(7):1446. doi: https://doi.org/10.3390/jcm10071446Takai T. Fc receptors and their role in immune regulation and autoimmunity. J Clin Immunol. 2005;25(1):1–18. doi: https://doi.org/10.1007/s10875-005-0353-8Nakazawa D, Masuda S, Tomaru U, Ishizu A. Pathogenesis and therapeutic interventions for ANCA-associated vasculitis. Nat Rev Rheumatol. 2019;15(2):91–101. doi: https://doi.org/10.1038/s41584-018-0145-yJorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med. 2017;23(3):279–287. doi: https://doi.org/10.1038/nm.4294Aringer M, Costenbader K, Daikh D, et al. European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. Arthritis Rheumatol. 2019;71(9):1400–1412. doi: https://doi.org/10.1002/art.40930Zhao X, Wen Q, Qiu Y, et al. Clinical and pathological characteristics of ANA/anti-dsDNA positive patients with antineutrophil cytoplasmic autoantibody-associated vasculitis. Rheumatol Int. 2021;41:455–462. doi: https://doi.org/10.1007/s00296-020-04704-3Yung S, Chan TM. Mechanisms of Kidney Injury in Lupus Nephritis — the Role of Anti-dsDNA Antibodies. Front Immunol. 2015;6:475. doi: https://doi.org/10.3389/fimmu.2015.00475Celhar T, Magalhães R, Fairhurst A-M. TLR7 and TLR9 in SLE: when sensing self goes wrong. Immunologic Research. 2012;53(1–3):58–77. doi: https://doi.org/10.1007/s12026-012-8270-1Moiseev S, Lee JM, Zykova A, et al. The alternative complement pathway in ANCA-associated vasculitis: further evidence and a meta-analysis. Clin Exp Immunol. 2020;202(3):394–402. doi: https://doi.org/10.1111/cei.13498Lyons PA, Smith KGC. L31. A GWAS in ANCA-associated vasculitis: Will genetics help re-define clinical classification? La Presse Médicale. 2013;42(4):589–591. doi: https://doi.org/10.1016/j.lpm.2013.02.303Merkel PA, Xie G, Monac PA, et al. Vasculitis Clinical Research Consortium. Identification of Functional and Expression Polymorphisms Associated with Risk for Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis. Arthritis & Rheumatology (Hoboken, N.J.). 2017;69(5):1054–1066. doi: https://doi.org/10.1002/art.40034Rahmattulla C, Mooyaart AL, van Hooven D, et al. Genetic variants in ANCA-associated vasculitis: a meta-analysis. Annals of the Rheumatic Diseases. 2015;75(9):1687–1692. doi: https://doi.org/10.1136/annrheumdis-2015-207601Lee KS, Kronbichler A, Pereira Vasconcelos DF, et al. Genetic Variants in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Bayesian Approach and Systematic Review. J Clin Med. 2019;8(2):266. doi: https://doi.org/10.3390/jcm8020266Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol. 2016;39(1):98–106. doi: https://doi.org/10.1097/COC.0000000000000239Chambers CA, Cado D, Truong T, et al. Thymocyte development is normal in CTLA-4-deficient mice. Proc Natl Acad Sci USA. 1997;94(17):9296–9301. doi: https://doi.org/10.1073/pnas.94.17.9296Tivol EA, Borriello F, Schweitzer AN, et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3(5):541–547. doi: https://doi.org/10.1016/1074-7613(95)90125-6Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270(5238):985–988. doi: https://doi.org/10.1126/science.270.5238.985Klocke K, Sakaguchi Sh, Holmdahl R, et al. Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood. Proc Natl Acad Sci USA. 2016;113(17):E2383–E2392. doi: https://doi.org/10.1073/pnas.1603892113Tang F., Du X., Liu M, et al. Anti-CTLA-4 antibodies in cancer immunotherapy: selective depletion of intratumoral regulatory T cells or checkpoint blockade? Cell Biosci. 2018;8:30. doi: https://doi.org/10.1186/s13578-018-0229-zZhao Y, Yang W, Huang Y, et al. Evolving Roles for Targeting CTLA-4 in Cancer Immunotherapy. Cell Physiol Biochem. 2018;47(2):721–734. doi: https://doi.org/10.1159/000490025Чикилева И.О., Шубина И.Ж., Самойленко И.В., и др. Влияние антител к CTLA-4 и PD-1 на содержание их рецепторов мишеней // Медицинская иммунология. — 2019. — Т. 21. — № 1. — С. 59–68. [Chikileva IO, Shubina IZh, Samoylenko IV, et al. Influence of antibodiesagainst CTLA-4 and PD-1 upon quantities of their target receptors. Medical Immunology (Russia) = Meditsinskaya Immunologiya. 2019;21(1):59–68. (In Russ).] doi: https://doi.org/10.15789/1563-0625-2019-1-59-68Kamesh L, Heward JM, Williams JM, et al. CT60 and +49 polymorphisms of CTLA 4 are associated with ANCA-positive small vessel vasculitis. Rheumatology. 2009;48(12):1502–1505. doi: https://doi.org/10.1093/rheumatology/kep280Ting WH, Chien MN, Lo FS, et al. Association of Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) Gene Polymorphisms with Autoimmune Thyroid Disease in Children and Adults: Case-Control Study. PLoS One. 2016;11(4):e0154394. doi: https://doi.org/10.1371/journal.pone.0154394Patel H, Mansuri MS, Singh M, et al. Association of Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Thyroglobulin (TG) Genetic Variants with Autoimmune Hypothyroidism. PLoS One. 2016;11(3):e0149441. doi: https://doi.org/10.1371/journal.pone.0149441Berce V, Potocnik U. Functional polymorphism in CTLA4 gene influences the response to therapy with inhaled corticosteroids in Slovenian children with atopic asthma. Biomarkers. 2010;15(2):158–166. doi: https://doi.org/10.3109/13547500903384318Carr EJ, Niederer HA, Williams J, et al. Confirmation of the genetic association of CTLA4 and PTPN22 with ANCA-associated vasculitis. BMC Med Genet. 2009;10:121. doi: https://doi.org/10.1186/1471-2350-10-121Xie G, Roshandel D, Sherva R, et al. Association of granulomatosis with polyangiitis (Wegener’s) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis. Arthritis Rheum. 2013;65(9):2457–2468. doi: https://doi.org/10.1002/art.38036Lyons PA, Rayner TF, Trivedi S, et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med. 2012;367(3):214–223. doi: https://doi.org/10.1056/NEJMoa1108735Santiago-Raber ML, Baudino L, Izui S. Emerging roles of TLR7 and TLR9 in murine SLE. J Autoimmun. 2009;33(3–4):231–238. doi: https://doi.org/10.1016/j.jaut.2009.10.001Santiago-Raber ML, Dunand-Sauthier I, Wu T, et al. Critical role of TLR7 in the acceleration of systemic lupus erythematosus in TLR9-deficient mice. J Autoimmun. 2010;34(4):339–348. doi: https://doi.org/10.1016/j.jaut.2009.11.001Fillatreau S, Manfroi B, Dörner T. Toll-like receptor signalling in B cells during systemic lupus erythematosus. Nat Rev Rheumatol. 2021;17:98–108. doi: https://doi.org/10.1038/s41584-020-00544-4Sakata K, Nakayamada S, Miyazaki Y, et al. Up-Regulation of TLR7-Mediated IFN-α Production by Plasmacytoid Dendritic Cells in Patients With Systemic Lupus Erythematosus. Front Immunol. 2018;9:1957. doi: https://doi.org/10.3389/fimmu.2018.01957Wang Y, Liang J, Qin H, et al. Elevated expression of miR-142-3p is related to the pro-inflammatory function of monocyte-derived dendritic cells in SLE. Arthritis Res Ther. 2016;18(1):263. doi: https://doi.org/10.1186/s13075-016-1158-zMarshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 2006;6(11):823–835. doi: https://doi.org/10.1038/nri1957Capolunghi F, Rosado MM, Cascioli S, et al. Pharmacological inhibition of TLR9 activation blocks autoantibody production in human B cells from SLE patients. Rheumatology (Oxford). 2010;49(12):2281–2289. doi: 10.1093/rheumatology/keq226Nakano S, Morimoto S, Suzuki J, et al. Role of pathogenic auto-antibody production by Toll-like receptor 9 of B cells in active systemic lupus erythematosus. Rheumatology (Oxford). 2008;47(2):145–149. doi: https://doi.org/10.1093/rheumatology/kem327Chen M, Zhang W, Xu W, et al. Blockade of TLR9 signaling in B cells impaired anti-dsDNA antibody production in mice induced by activated syngenic lymphocyte-derived DNA immunization. Mol Immunol. 2011;48(12–13):1532–1539. doi: https://doi.org/10.1016/j.molimm.2011.04.016Werwitzke S, Trick D, Kamino K, et al. Inhibition of lupus disease by anti-double-stranded DNA antibodies of the IgM isotype in the (NZB x NZW)F1 mouse. Arthritis Rheum. 2005;52(11):3629–3638. doi: https://doi.org/10.1002/art.21379Fillatreau S, Manfroi B, Dörner T. Toll-like receptor signalling in B cells during systemic lupus erythematosus. Nat Rev Rheumatol. 2021;17:98–108. doi: https://doi.org/10.1038/s41584-020-00544-4Celhar T, Magalhães R, Fairhurst A-M. TLR7 and TLR9 in SLE: when sensing self goes wrong. Immunologic Research. 2012;53(1–3):58–77. doi: https://doi.org/10.1007/s12026-012-8270-1Husmann CA, Holle JU, Moosig F, et al. Genetics of toll like receptor 9 in ANCA associated vasculitides. Annals of the Rheumatic Diseases. 2013;73(5):890–896. doi: https://doi.org/10.1136/annrheumdis-2012-202803Ito A, Ota M, Katsuyama Y, et al. Lack of association of Toll-like receptor 9 gene polymorphism with Behçet’s disease in Japanese patients. Tissue Antigens. 2007;70(5):423–426. doi: https://doi.org/10.1111/j.1399-0039.2007.00924.xShahin RMH, El Khateeb E, Khalifa RH, et al. Contribution of Toll-Like Receptor 9 Gene Single-Nucleotide Polymorphism to Systemic Lupus Erythematosus in Egyptian Patients. Immunological Investigations. 2016;45(3):235–242. doi: https://doi.org/10.3109/08820139.2015.1137934Sada T, Ota M, Katsuyama Y, et al. Association analysis of Toll-like receptor 7 gene polymorphisms and Behçet’s disease in Japanese patients. Human Immunology. 2011;72(3):269–272. doi: https://doi.org/10.1016/j.humimm.2010.12.007Raafat II, El Guindy N, Shahin RMH, et al. Toll-like receptor 7 gene single nucleotide polymorphisms and the risk for systemic lupus erythematosus: a case-control study. Einzelnukleotidpolymorphismen im Toll-like-receptor-7-Gen (TLR7) und das Risiko eines systemischen Lupus erythematodes: eine Fall-Kontroll-Studie. Z Rheumatol. 2018;77(5):416–420. doi: https://doi.org/10.1007/s00393-017-0283-7Owen CA, Campbell EJ. The cell biology of leukocyte-mediated proteolysis. J Leukoc Biol. 1999;65(2):137–150. doi: https://doi.org/10.1002/jlb.65.2.137Jerke U, Hernandez DP, Beaudette P, et al. Neutrophil serine proteases exert proteolytic activity on endothelial cells. Kidney Int. 2015;88(4):764–775. doi: https://doi.org/10.1038/ki.2015.159Owen CA, Campbell EJ. The cell biology of leukocyte-mediated proteolysis. J Leukoc Biol. 1999;65(2):137–150. doi: https://doi.org/10.1002/jlb.65.2.137Joosten LA, Netea MG, Fantuzzi G, et al. Inflammatory arthritis in caspase 1 gene-deficient mice: contribution of proteinase 3 to caspase 1-independent production of bioactive interleukin-1beta. Arthritis Rheum. 2009;60(12):3651–3662. doi: https://doi.org/10.1002/art.25006Kessenbrock K, Fröhlich L, Sixt M, et al. Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin. J Clin Invest. 2008;118(7):2438–2447. doi: https://doi.org/10.1172/JCI34694Korkmaz B, Lesner A, Guarino C, et al. Inhibitors and Antibody Fragments as Potential Anti-Inflammatory Therapeutics Targeting Neutrophil Proteinase 3 in Human Disease. Pharmacol Rev. 2016;68(3):603–630. doi: https://doi.org/10.1124/pr.115.012104Witko-Sarsat V, Lesavre P, Lopez S, et al. A large subset of neutrophils expressing membrane proteinase 3 is a risk factor for vasculitis and rheumatoid arthritis. J Am Soc Nephrol. 1999;10(6):1224–1233.Ciavatta DJ, Yang J, Preston GA, et al. Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis. J Clin Invest. 2010;120(9):3209–3219. doi: https://doi.org/10.1172/JCI40034Jones BE, Yang J, Muthigi A, et al. Gene-Specific DNA Methylation Changes Predict Remission in Patients with ANCA-Associated Vasculitis. J Am Soc Nephrol. 2017;28(4):1175–1187. doi: https://doi.org/10.1681/ASN.2016050548Lewis EC, Mizrahi M, Toledano M, et al. alpha1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in mice. Proc Natl Acad Sci USA. 2008;105(42):16236–16241. doi: https://doi.org/10.1073/pnas.0807627105Srinivasan L, Harris MC, Kilpatrick LE. Cytokines and Inflammatory Response in the Fetus and Neonate. Fetal and Neonatal Physiology. 2017;1241–1254.e4. doi: https://doi.org/10.1016/b978-0-323-35214-7.00128-1Seixas S, Marques PI. Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of SERPINA1 Variation Spectrum. Appl Clin Genet. 2021;14:173–194. doi: https://doi.org/10.2147/TACG.S257511Mahr AD, Edberg JC, Stone JH, et al. Alpha₁-antitrypsin deficiency-related alleles Z and S and the risk of Wegener’s granulomatosis. Arthritis Rheum. 2010;62(12):3760–3767. doi: https://doi.org/10.1002/art.27742Li W, Huang H, Cai M, et al. Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Update: Genetic Pathogenesis. Front Immunol. 2021;12:624848. doi: https://doi.org/10.3389/fimmu.2021.624848Новиков П.И., Моисеев С.В., Кузнецова Е.И., и др. Изменение клинического течения и прогноза гранулематоза с полиангиитом (Вегенера): результаты 40-летнего наблюдения // Клиническая фармакология и терапия. — 2014. — Т. 23. — № 1. — С. 32–37. [Novikov PI, Moiseev SV, Kuznecova EI, et al. Izmenenie klinicheskogo techenija i prognoza granulematoza s poliangiitom (Vegenera): rezul’taty 40-letnego nabljudenija. Klinicheskaja farmakologija i terapija = Clinical Pharmacology and Therapy. 2014;23(1):32–37. (In Russ).]Yates M, Watts RA, Bajema IM, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Practice Guideline Ann Rheum Dis. 2016;75(9):1583–1594. doi: https://doi.org/10.1136/annrheumdis-2016-209133Буланов Н.М., Козловская Н.Л., Тао Е.А., и др. Современные подходы к лечению АНЦА-ассоциированных васкулитов с поражением почек с позиций медицины, основанной на доказательствах // Клиническая фармакология и терапия. — 2020. — Т. 29. — № 4. — С. 72–84. [Bulanov NM, Kozlovskaya NL, Tao EA, et al. Evidence-based treatment of ANCA-associated vasculitis with kidney involvement Sovremennye podhody k lecheniju ANCA-associirovannyh vaskulitov s porazheniem pochek s pozicij mediciny, osnovannoj na dokazatel’stvah. Klinicheskaja farmakologija i terapija = Clinical Pharmacology and Therapy. 2020;29(4):72–84. (In Russ).] doi: 10.32756/0869-5490-2020-4-72-84Kelley JM, Monach PA, Ji C, et al. IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis. Proc Natl Acad Sci USA. 2011;108(51):20736–20741. doi: https://doi.org/10.1073/pnas.1109227109Robledo G, Márquez A, Dávila-Fajardo CL, et al. Association of the FCGR3A-158F/V gene polymorphism with the response to rituximab treatment in Spanish systemic autoimmune disease patients. DNA Cell Biol. 2012;31(12):1671–1677. doi: https://doi.org/10.1089/dna.2012.1799Jayne DRW, Bruchfeld AN, Harper L, et al. Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis. J Am Soc Nephrol. 2017;28(9):2756–2767. doi: https://doi.org/10.1681/ASN.2016111179