Pediatric Hematology/Oncology and ImmunopathologyPediatric Hematology/Oncology and ImmunopathologyВопросы гематологии/онкологии и иммунопатологии в педиатрии1726-17082414-9314Fund Doctors, Innovations, Science for Children31610.24287/1726-1708-2020-19-1-131-138LITERATURE REVIEWОБЗОР ЛИТЕРАТУРЫPathologies of the complement systemПатологии системы комплементаButilinA. A.БутылинА. А.
Russian Federation

Москва

FilippovaA. E.ФилипповаА. Е.
Russian Federation

Москва

ShakhidzhanovS. S.ШахиджановС. С.
Russian Federation

scientist, 

119991, Moscow, Кosygina st., 4

научный сотрудник,

119991, Москва, ул. Косыгина, 4 

shakhidzhanov.s@yandex.ruAtaullakhanovF. I.АтауллахановФ. И.
Russian Federation

Moscow

Москва

Lomonosov Moscow State UniversityФГБОУ ВО «Московский государственный университет им. М.В. Ломоносова»Center for Theoretical Problems of Physico-chemical Pharmacology, Russian Academy of SciencesФГБУН «Центр теоретических проблем физико-химической фармакологии» РАНDmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, Immunology Ministry of Healthcare of Russian FederationФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздрава РоссииMoscow Institute of Physics and Technology (State University)ФГАОУ ВО «Московский физико-технический институт (государственный университет)»280320201911311382803202028032020Copyright ©; 2020, «D. Rogachev NMRCPHOI»Copyright ©; 2020, ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России2020«D. Rogachev NMRCPHOI»ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава Россииhttps://creativecommons.org/licenses/by/4.0https://hemoncim.com/jour/article/view/316

Complement system is a part of the immune system that provides organism cells with protection against foreign pathogens. Various kinds of defects in the complement system can induce development of serious diseases. This review summarizes different malfunctions of the complement system and also shows how these defects can result in development of severe diseases.

Система комплемента – часть иммунной системы, которая обеспечивает защиту организма от вторжения чужеродных патогенов. Различного рода нарушения этой системы могут способствовать развитию ряда тяжелых заболеваний. В данном обзоре описаны различные нарушения в работе системы комплемента, а также показано, к каким патологиям это может привести.

complement systemparoxysmal nocturnal hemoglobinuriaatypical hemolytic uremic syndromeage-related macular degenerationcomplement system deficiencyangioedemaсистема комплементапараксизмальная ночная гемоглобинурияатипичный гемолитико-уремический синдромвозрастная макулодистрофиядефициты системы комплементаангионевротический отекРабота поддержана грантом РФФИ № 19-02-00780 и Министерством науки и высшего образования Российской Федерации в рамках Программы фундаментальных научных исследований государственных академий наук (АААА-А18-118012390250-0).1. МКБ 10, Международная Классификация Болезней, коды заболеваний, расшифровка диагнозов http://mkb-10v.ru/МКБ 10, Международная Классификация Болезней, коды заболеваний, расшифровка диагнозов http://mkb-10v.ru/2. Дефекты в системе комплемента коды МКБ 11. http://icd11.ru/defecty-v-system-komplementa/Дефекты в системе комплемента коды МКБ 11. http://icd11.ru/defecty-v-system-komplementa/3. Smith-Jackson K., Yang Y., Denton H., Pappworth I.Y., Cooke K., Barlow P.N., et al. Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice. J Clin Invest 2019 Mar 1; 129 (3): 1061–75.Smith-Jackson K., Yang Y., Denton H., Pappworth I.Y., Cooke K., Barlow P.N., et al. Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice. J Clin Invest 2019 Mar 1; 129 (3): 1061–75.4. Grumach A.S., Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol 2014 Oct; 61 (2): 110–7.Grumach A.S., Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol 2014 Oct; 61 (2): 110–7.5. Lewis L.A., Ram S. Meningococcal disease and the complement system. Virulence 2014 Jan 1; 5 (1): 98–126.Lewis L.A., Ram S. Meningococcal disease and the complement system. Virulence 2014 Jan 1; 5 (1): 98–126.6. Truedsson L. Classical pathway deficiencies - A short analytical review. Mol Immunol 2015 Nov; 68 (1): 14–9.Truedsson L. Classical pathway deficiencies - A short analytical review. Mol Immunol 2015 Nov; 68 (1): 14–9.7. Pan L., Lu M.-P., Wang J.-H., Xu M., Yang S.-R. Immunological pathogenesis and treatment of systemic lupus erythematosus. World J Pediatr 2019 Feb 22.Pan L., Lu M.-P., Wang J.-H., Xu M., Yang S.-R. Immunological pathogenesis and treatment of systemic lupus erythematosus. World J Pediatr 2019 Feb 22.8. Macedo A.C.L., Isaac L. Systemic Lupus Erythematosus and Deficiencies of Early Components of the Complement Classical Pathway. Front Immunol 2016; 7: 55.Macedo A.C.L., Isaac L. Systemic Lupus Erythematosus and Deficiencies of Early Components of the Complement Classical Pathway. Front Immunol 2016; 7: 55.9. Panelius J., Meri S. Complement system in dermatological diseases – fire under the skin. Front Med (Lausanne) 2015; 2: 3.Panelius J., Meri S. Complement system in dermatological diseases – fire under the skin. Front Med (Lausanne) 2015; 2: 3.10. Lintner K.E., Wu Y.L., Yang Y., Spencer C.H., Hauptmann G., Hebert L.A., et al. Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases. Front Immunol 2016; 7: 36.Lintner K.E., Wu Y.L., Yang Y., Spencer C.H., Hauptmann G., Hebert L.A., et al. Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases. Front Immunol 2016; 7: 36.11. Liphaus B.L., Umetsu N., Jesus A.A., Bando S.Y., Silva C.A., Carneiro-Sampaio M. Molecular characterization of the complement C1q, C2 and C4 genes in Brazilian patients with juvenile systemic lupus erythematosus. Clinics (Sao Paulo) 2015 Mar; 70 (3): 220–7.Liphaus B.L., Umetsu N., Jesus A.A., Bando S.Y., Silva C.A., Carneiro-Sampaio M. Molecular characterization of the complement C1q, C2 and C4 genes in Brazilian patients with juvenile systemic lupus erythematosus. Clinics (Sao Paulo) 2015 Mar; 70 (3): 220–7.12. Degn S.E., Jensenius J.C., Thiel S. Disease-causing mutations in genes of the complement system. Am J Hum Genet 2011 Jun 10; 88 (6): 689–705.Degn S.E., Jensenius J.C., Thiel S. Disease-causing mutations in genes of the complement system. Am J Hum Genet 2011 Jun 10; 88 (6): 689–705.13. Slade C., Bosco J., Unglik G., Bleasel K., Nagel M., Winship I. Deficiency in complement factor B. N Engl J Med 2013 Oct 24; 369 (17): 1667–9.Slade C., Bosco J., Unglik G., Bleasel K., Nagel M., Winship I. Deficiency in complement factor B. N Engl J Med 2013 Oct 24; 369 (17): 1667–9.14. Ohsawa I., Honda D., Nagamachi S., Hisada A., Shimamoto M., Inoshita H., et al. Clinical and laboratory characteristics that differentiate hereditary angioedema in 72 patients with angioedema. Allergol Int 2014 Dec; 63 (4): 595–602.Ohsawa I., Honda D., Nagamachi S., Hisada A., Shimamoto M., Inoshita H., et al. Clinical and laboratory characteristics that differentiate hereditary angioedema in 72 patients with angioedema. Allergol Int 2014 Dec; 63 (4): 595–602.15. RESERVED IU-AR. Orphanet: Search a disease [Internet]. [cited 2019 Mar 16]. Available from: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=ENRESERVED IU-AR. Orphanet: Search a disease [Internet]. [cited 2019 Mar 16]. Available from: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN16. Botto M., Kirschfink M., Macor P., Pickering M.C., Würzner R., Tedesco F. Complement in human diseases: Lessons from complement deficiencies. Mol Immunol 2009 Sep; 46 (14): 2774–83.Botto M., Kirschfink M., Macor P., Pickering M.C., Würzner R., Tedesco F. Complement in human diseases: Lessons from complement deficiencies. Mol Immunol 2009 Sep; 46 (14): 2774–83.17. Wong E.K.S., Kavanagh D. Diseases of complement dysregulation-an overview. Semin Immunopathol 2018; 40 (1): 49–64.Wong E.K.S., Kavanagh D. Diseases of complement dysregulation-an overview. Semin Immunopathol 2018; 40 (1): 49–64.18. Morgan B.P., Harris C.L. Complement, a target for therapy in inflammatory and degenerative diseases. Nat Rev Drug Discov 2015 Dec; 14 (12): 857–77.Morgan B.P., Harris C.L. Complement, a target for therapy in inflammatory and degenerative diseases. Nat Rev Drug Discov 2015 Dec; 14 (12): 857–77.19. Levy G.G., Nichols W.C., Lian E.C., Foroud T., McClintick J.N., McGee B.M., et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001 Oct 4; 413 (6855): 488–94.Levy G.G., Nichols W.C., Lian E.C., Foroud T., McClintick J.N., McGee B.M., et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001 Oct 4; 413 (6855): 488–94.20. Dragon-Durey M.-A., Frémeaux-Bacchi V. Atypical haemolytic uraemic syndrome and mutations in complement regulator genes. Springer Semin Immunopathol 2005 Nov; 27 (3): 359–74.Dragon-Durey M.-A., Frémeaux-Bacchi V. Atypical haemolytic uraemic syndrome and mutations in complement regulator genes. Springer Semin Immunopathol 2005 Nov; 27 (3): 359–74.21. Funato M., Uemura O., Ushijima K., Ohnishi H., Orii K., Kato Z., et al. A complement factor B mutation in a large kindred with atypical hemolytic uremic syndrome. J Clin Immunol 2014 Aug; 34 (6): 691–5.Funato M., Uemura O., Ushijima K., Ohnishi H., Orii K., Kato Z., et al. A complement factor B mutation in a large kindred with atypical hemolytic uremic syndrome. J Clin Immunol 2014 Aug; 34 (6): 691–5.22. Dickenmann M., Schifferli J.A. Atypical hemolytic uremic syndrome: update on the complement system and what is new. Nephron Clin Pract 2010; 114 (4): 219–35.Dickenmann M., Schifferli J.A. Atypical hemolytic uremic syndrome: update on the complement system and what is new. Nephron Clin Pract 2010; 114 (4): 219–35.23. Noris M., Bresin E., Mele C., Remuzzi G. Genetic Atypical Hemolytic-Uremic Syndrome. In: Adam M.P., Ardinger H.H., Pagon R.A., Wallace S.E., Bean L.J., Mefford H.C., et al., editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1367/Noris M., Bresin E., Mele C., Remuzzi G. Genetic Atypical Hemolytic-Uremic Syndrome. In: Adam M.P., Ardinger H.H., Pagon R.A., Wallace S.E., Bean L.J., Mefford H.C., et al., editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1367/24. Luzzatto L. PNH from mutations of another PIG gene. Blood 2013 Aug 15; 122 (7): 1099–100.Luzzatto L. PNH from mutations of another PIG gene. Blood 2013 Aug 15; 122 (7): 1099–100.25. Yamashina M., Ueda E., Kinoshita T., Takami T., Ojima A., Ono H., et al. Inherited Complete Deficiency of 20-Kilodalton Homologous Restriction Factor (CD59) as a Cause of Paroxysmal Nocturnal Hemoglobinuria. New England Journal of Medicine 1990 Oct 25; 323 (17): 1184–9.Yamashina M., Ueda E., Kinoshita T., Takami T., Ojima A., Ono H., et al. Inherited Complete Deficiency of 20-Kilodalton Homologous Restriction Factor (CD59) as a Cause of Paroxysmal Nocturnal Hemoglobinuria. New England Journal of Medicine 1990 Oct 25; 323 (17): 1184–9.26. Takeda J., Miyata T., Kawagoe K., Iida Y., Endo Y., Fujita T., et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell 1993 May 21; 73 (4): 703–11.Takeda J., Miyata T., Kawagoe K., Iida Y., Endo Y., Fujita T., et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell 1993 May 21; 73 (4): 703–11.27. de Latour R.P., Mary J.Y., Salanoubat C., Terriou L., Etienne G., Mohty M., et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood 2008 Oct 15; 112 (8): 3099–106.de Latour R.P., Mary J.Y., Salanoubat C., Terriou L., Etienne G., Mohty M., et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood 2008 Oct 15; 112 (8): 3099–106.28. Dulau-Florea A., Maric I., Calvo K.R., Braylan R.C. Detection of paroxysmal nocturnal hemoglobinuria (PNH) in bone marrow aspirates. Seminars in Hematology 2019 Jan 1; 56 (1): 65–8.Dulau-Florea A., Maric I., Calvo K.R., Braylan R.C. Detection of paroxysmal nocturnal hemoglobinuria (PNH) in bone marrow aspirates. Seminars in Hematology 2019 Jan 1; 56 (1): 65–8.29. Merrill S.A., Brodsky R.A. Complement-driven anemia: more than just paroxysmal nocturnal hemoglobinuria. Hematology Am Soc Hematol Educ Program 2018 30; 2018 (1): 371–6.Merrill S.A., Brodsky R.A. Complement-driven anemia: more than just paroxysmal nocturnal hemoglobinuria. Hematology Am Soc Hematol Educ Program 2018 30; 2018 (1): 371–6.30. Wijnsma K.L., Ter Heine R., Moes D.J.A.R., Langemeijer S., Schols S.E.M., Volokhina E.B., et al. Pharmacology, Pharmacokinetics and Pharmacodynamics of Eculizumab, and Possibilities for an Individualized Approach to Eculizumab. Clin Pharmacokinet 2019 Feb 13;Wijnsma K.L., Ter Heine R., Moes D.J.A.R., Langemeijer S., Schols S.E.M., Volokhina E.B., et al. Pharmacology, Pharmacokinetics and Pharmacodynamics of Eculizumab, and Possibilities for an Individualized Approach to Eculizumab. Clin Pharmacokinet 2019 Feb 13;31. Maller J., George S., Purcell S., Fagerness J., Altshuler D., Daly M.J., et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet 2006 Sep; 38 (9): 1055–9.Maller J., George S., Purcell S., Fagerness J., Altshuler D., Daly M.J., et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet 2006 Sep; 38 (9): 1055–9.32. Edwards A.O., Ritter R., Abel K.J., Manning A., Panhuysen C., Farrer L.A. Complement factor H polymorphism and age-related macular degeneration. Science 2005 Apr 15; 308 (5720): 421–4.Edwards A.O., Ritter R., Abel K.J., Manning A., Panhuysen C., Farrer L.A. Complement factor H polymorphism and age-related macular degeneration. Science 2005 Apr 15; 308 (5720): 421–4.33. Rohrer B., Frazer-Abel A., Leonard A., Ratnapriya R., Ward T., Pietraszkiewicz A., et al. Association of age-related macular degeneration with complement activation products, smoking, and single nucleotide polymorphisms in South Carolinians of European and African descent. Mol Vis 2019 Feb 8; 25: 79–92.Rohrer B., Frazer-Abel A., Leonard A., Ratnapriya R., Ward T., Pietraszkiewicz A., et al. Association of age-related macular degeneration with complement activation products, smoking, and single nucleotide polymorphisms in South Carolinians of European and African descent. Mol Vis 2019 Feb 8; 25: 79–92.34. Maller J.B., Fagerness J.A., Reynolds R.C., Neale B.M., Daly M.J., Seddon J.M. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet 2007 Oct; 39 (10): 1200–1.Maller J.B., Fagerness J.A., Reynolds R.C., Neale B.M., Daly M.J., Seddon J.M. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet 2007 Oct; 39 (10): 1200–1.35. Landowski M., Kelly U., Klingeborn M., Groelle M., Ding J.-D., Grigsby D., et al. Human complement factor H Y402H polymorphism causes an age-related macular degeneration phenotype and lipoprotein dysregulation in mice. PNAS 2019 Feb 26; 116 (9): 3703–11.Landowski M., Kelly U., Klingeborn M., Groelle M., Ding J.-D., Grigsby D., et al. Human complement factor H Y402H polymorphism causes an age-related macular degeneration phenotype and lipoprotein dysregulation in mice. PNAS 2019 Feb 26; 116 (9): 3703–11.36. Rhoades W., Dickson D., Do D.V. Potential role of lampalizumab for treatment of geographic atrophy. Clin Ophthalmol 2015; 9: 1049–56.Rhoades W., Dickson D., Do D.V. Potential role of lampalizumab for treatment of geographic atrophy. Clin Ophthalmol 2015; 9: 1049–56.37. ClinicalTrials.gov. A study investigating the effcacy and safety of lampalizumab intravitreal injections in participants with geographic atrophy secondary to age-related macular degeneration (SPECTRI). Available from: https://clinicaltrials.gov/ct2/show/NCT02247531. NLM identifer: NCT02247531. Accessed July 28, 2017.ClinicalTrials.gov. A study investigating the effcacy and safety of lampalizumab intravitreal injections in participants with geographic atrophy secondary to age-related macular degeneration (SPECTRI). Available from: https://clinicaltrials.gov/ct2/show/NCT02247531. NLM identifer: NCT02247531. Accessed July 28, 2017.38. Frazer-Abel A., Sepiashvili L., Mbughuni M.M., Willrich M.А.V. Overview of Laboratory Testing and Clinical Presentations of Complement Deficiencies and Dysregulation. Adv Clin Chem2016; 77: 1–75.Frazer-Abel A., Sepiashvili L., Mbughuni M.M., Willrich M.А.V. Overview of Laboratory Testing and Clinical Presentations of Complement Deficiencies and Dysregulation. Adv Clin Chem2016; 77: 1–75.39. Yuan X., Gavriilaki E., Thanassi J.A., Yang G., Baines A.C., Podos S.D., et al. Small-molecule factor D inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Haematologica 2017; 102 (3): 466–75.Yuan X., Gavriilaki E., Thanassi J.A., Yang G., Baines A.C., Podos S.D., et al. Small-molecule factor D inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Haematologica 2017; 102 (3): 466–75.40. Schrezenmeier H., Höchsmann B. Drugs that inhibit complement. Transfus Apher Sci 2012 Feb; 46 (1): 87–92.Schrezenmeier H., Höchsmann B. Drugs that inhibit complement. Transfus Apher Sci 2012 Feb; 46 (1): 87–92.