OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press81910.17650/1818-8346-2023-18-2-60-67NEW DIRECTIONS, DIAGNOSTIC OPPORTUNITIES, AND TREATMENT ADVANCESНОВЫЕ НАПРАВЛЕНИЯ, ВОЗМОЖНОСТИ ДИАГНОСТИКИ И УСПЕХИ ЛЕЧЕНИЯAutoimmune hemolytic anemia: the current state of the issueАутоиммунная гемолитическая анемия: современное состояние вопросаhttps://orcid.org/0000-0002-0837-5603VasilchenkovaP. I.ВасильченковаП. И.
Russian Federation

Polina Igorevna Vasilchenkova

4 Novyy Zykovskiy Proezd, Moscow 125167, Russia

Полина Игоревна Васильченкова 

Россия, 125167 Москва, Новый Зыковский пр-д, 4

myatnikovap@mail.ruhttps://orcid.org/0000-0002-8490-6066GaltsevaI. V.ГальцеваИ. В.
Russian Federation

4 Novyy Zykovskiy Proezd, Moscow 125167, Russia

Россия, 125167 Москва, Новый Зыковский пр-д, 4

https://orcid.org/0000-0002-8774-850XLukinaE. A.ЛукинаЕ. А.
Russian Federation

4 Novyy Zykovskiy Proezd, Moscow 125167, Russia

Россия, 125167 Москва, Новый Зыковский пр-д, 4

National Medical Research Center for Hematology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава России300520231820202202328052023https://oncohematology.abvpress.ru/ongm/article/view/819

Autoimmune hemolytic anemia is a rare disease characterized by the appearance of anti-erythrocyte autoantibodies and subsequent destruction of red blood cells by cells of the immune system. The destruction mechanisms of erythrocytes loaded with autoantibodies are well studied; however, the initial mechanisms that trigger the production of antibodies to own erythrocytes antigens remain unclear. In the pathogenesis of autoimmune hemolytic anemia, an important role is played by impaired immunological tolerance, in which T-lymphocytes play a key role. The study of T-lymphocytes subpopulation in patients with autoimmune hemolytic anemia by flow cytometry can provide valuable information for studying the disease pathogenesis and developing new approaches to its treatment.

Аутоиммунная гемолитическая анемия – редкое заболевание, характеризующееся появлением антиэритроцитарных аутоантител и последующим разрушением эритроцитов клетками иммунной системы. Механизмы разрушения эритроцитов, нагруженных аутоантителами, достаточно хорошо изучены, однако инициальные механизмы, запускающие продукцию антител к антигенам собственных эритроцитов, остаются неясными. В патогенезе аутоиммунной гемолитической анемии важная роль отводится нарушению иммунологической толерантности, в которой ключевую роль играют Т-лимфоциты. Исследование субпопуляционного состава Т-лимфоцитов у больных аутоиммунной гемолитической анемией методом проточной цитометрии может предоставить ценную информацию для изучения патогенеза данного заболевания и разработки новых подходов к его лечению.

autoimmune hemolytic anemiacold agglutinin diseaseautoantibodieshemolysisT-helpersT-killersregulatory T-cellsflow cytometryrituximabаутоиммунная гемолитическая анемияхолодовая агглютининовая болезньаутоантителагемолизТ-хелперыТ-киллерырегуляторные Т-клеткипроточная цитометрияритуксимабFreedman J. Autoimmune hemolysis: a journey through time. Transfus Med Hemother 2015;42(5):278–85. DOI: 10.1159/000437195Jaime-Pérez J.C., Aguilar-Calderón P., Salazar-Cavazos L. et al. Treatment of autoimmune hemolytic anemia: real world data from a reference center in Mexico. Blood Res 2019;54(2):131–6. DOI: 10.5045/br.2019.54.2.131Hill Q.A., Stamps R., Massey E. et al. The diagnosis and management of primary autoimmune haemolytic anaemia. Br J Haematol 2017;176(3):395–411. DOI: 10.1111/bjh.14478Wang‐Rodriguez J., Rearden A. Reduced frequency of HLA‐DQ6 in individuals with a positive direct antiglobulin test. Transfusion 1996;36(11–12):979–84. DOI: 10.1046/j.1537-2995.1996.36111297091742.xHill Q.A., Hill A., Berentsen S. Defining autoimmune hemolytic anemia: a systematic review of the terminology used for diagnosis and treatment. Blood Adv 2019;3(12):1897–906. DOI: 10.1182/bloodadvances.2019000036Garratty G. Immune hemolytic anemia. Semin Hematol 2005;42(3):119–21. DOI: 10.1053/j.seminhematol.2005.04.001Bass G.F., Tuscano E.T., Tuscano J.M. Diagnosis and classification of autoimmune hemolytic anemia. Autoimmun Rev 2014;13(4–5): 560–4. DOI: 10.1016/j.autrev.2013.11.01Barcellini W., Fattizzo B., Zaninoni A. et al. Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Blood 2014;124(19):2930–6. DOI: 10.1182/blood-2014-06-583021Barcellini W. New insights in the pathogenesis of autoimmune hemolytic anemia. Transfus Med Hemother 2015;42(5):287–93. DOI: 10.1159/000439002Shanbhag S., Spivak J. Paroxysmal cold hemoglobinuria. Hematol Oncol Clin North Am 2015;29(3):473–8. DOI: 10.1016/j.hoc.2015.01.004Kuzminova Zh.A., Smetanina N.S. Autoimmune haemolytic anaemia: modern diagnosis and therapy. Voprosy gematologii/onkologii i immunopatologii v pediatrii = Pediatric Hematology/Oncology and Immunopathology 2016;15(3):5–11. (In Russ.). DOI: 10.24287/1726-1708-2016-15-3-5-11Кузьминова Ж.А., Сметанина Н.С. Аутоиммунная гемолитическая анемия: современная диагностика и терапия. Вопросы гематологии/онкологии и иммунопатологии в педиатрии 2016;15(3):5–11. DOI: 10.24287/1726-1708-2016-15-3-5-11Barcellini W., Zaninoni A., Giannotta J.A., Fattizzo B. New insights in autoimmune hemolytic anemia: from pathogenesis to therapy. J Clin Med 2020;9(12):3859. DOI: 10.3390/jcm9123859Berentsen S. How I manage cold agglutinin disease. Br J Haematol 2011;153(3):309–17. DOI: 10.1111/j.1365-2141.2011.08643.xBerentsen S., Hill A., Hill Q.A. et al. Novel insights into the treatment of complement-mediated hemolytic anemias. Ther Adv Hematol 2019;10:2040620719873321. DOI: 10.1177/2040620719873321Marcus N., Attias D., Tamary H. Autoimmune hemolytic anemia: current understanding of pathophysiology. Hematology Education: the education program for the annual congress of the European Hematology Association, 2014;8:331–8.Xu L., Zhang T., Liu Z. et al. Critical role of Th17 cells in development of autoimmune hemolytic anemia. Exp Hematol 2012;40(12):994–1004.e4. DOI: 10.1016/j.exphem.2012.08.008Nasonov E.L., Denisov L.N., Stanislav M.L. Interleukin-17 is a new target for anti-cytokine therapy of immune inflammatory rheumatic diseases. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice 2013;51(5):545–52. (In Russ.). DOI: 10.14412/1995-4484-2013-1547Насонов Е.Л., Денисов Л.Н., Станислав М.Л. Интерлейкин 17 – новая мишень для антицитокиновой терапии иммуновоспалительных ревматических заболеваний. Научно-практическая ревматология 2013;51(5):545–52. DOI: 10.14412/1995-4484-2013-1547Veldhoen M., Uyttenhove C., van Snick J. et al. Transforming growth factor-β ’reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9–producing subset. Nat Immunol 2008;9(12):1341–6. DOI: 10.1038/ni.1659Li Y., Yu Q., Zhang Z. et al. TH9 cell differentiation, transcriptional control and function in inflammation, autoimmune diseases and cancer. Oncotarget 2016;7(43):71001–12. DOI: 10.18632/oncotarget.11681Khaidukov S.V. Minor subsets of T-helper cells (Th thymic naive, Th central naive, Th9, Th22 and CD4+CD8+ double positive T-cells). Meditsinskaya immunologiya = Medical Immunology 2013;15(6): 503–12. (In Russ.).Хайдуков С.В. Малые субпопуляции Т-хелперов (Th наивные тимические, Th наивные центральные, Th9, Th22 и CD4+CD8+ дважды положительные Т-клетки). Медицинская иммунология 2013;15(6):503–12.Duhen T., Geiger R., Jarrossay D. et al. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol 2009;10(8):857–63. DOI: 10.1038/ni.1767Zhang N., Pan H.F., Ye D.Q. Th22 in inflammatory and autoimmune disease: prospects for therapeutic intervention. Mol Cell Biochem 2011;353(1–2):41–6. DOI: 10.1007/s11010-011-0772-yVoronina E.V., Talaev V.Yu. Maturation of follicular T-helpers. Immunologiya = Immunology 2018;39(4):230–8. (In Russ.).Воронина Е.В., Талаев В.Ю. Созревание фолликулярных Т-хелперов. Иммунология 2018;39(4):230–8.Breitfeld D., Ohl L., Kremmer E. et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J Exp Med 2000;192(11):1545–52. DOI: 10.1084/jem.192.11.1545Chavez-Galan L., Arenas-Del Angel M.C., Zenteno E. et al. Cell death mechanisms induced by cytotoxic lymphocytes. Cell Mol Immunol 2009;6(1):15–25. DOI: 10.1038/cmi.2009.3Valentine K.M., Davini D., Lawrence T.J. et al. CD8 follicular T cells promote B cell antibody class switch in autoimmune disease. J Immunol 2018;201(1):31–40. DOI: 10.4049/jimmunol.1701079Sakaguchi S., Miyara M., Costantino C.M., Hafler D.A. FOXP3+regulatory T cells in the human immune system. Nat Rev Immunol 2010;10(7):490–500. DOI: 10.1038/nri2785Pavkovic M., Georgievski B., Cevreska L. et al. CTLA‐4 exon 1 polymorphism in patients with autoimmune blood disorders. Am J Hematol 2003;72(2):147–9. DOI: 10.1002/ajh.10278Visco C., Barcellini W., Maura F. et al. Autoimmune cytopenias in chronic lymphocytic leukemia. Am J Hematol 2014;89(11):1055–62. DOI: 10.1002/ajh.23785Zhu H., Zhao M., Cao Z. et al. The clinical characteristics of autoimmune haemolytic anaemia/Evans syndrome patients with clonal immunoglobulin/T cell receptor gene rearrangement. Autoimmunity 2020;53(7):394–9. DOI: 10.1080/08916934.2020.1818231Klonowski K.D., Monestier M. Ig heavy-chain gene revision: leaping towards autoimmunity. Trends Immunol 2001;22(7):400–5. DOI: 10.1016/s1471-4906(01)01953-6Barcellini W., Zaninoni A., Fattizzo B. et al. Predictors of refractoriness to therapy and healthcare resource utilization in 378 patients with primary autoimmune hemolytic anemia from eight Italian reference centers. Am J Hematol 2018;93(9):E243–6. DOI: 10.1002/ajh.25212Smirnova S.Yu. Clonal rearrangements of immunoglobulin heavy and light chain genes and T-cell receptor genes in patients with blood system diseases. Dis. ... candidate of medical sciences. Moscow, 2019. (In Russ.).Смирнова С.Ю. Клональные реаранжировки генов тяжелых и легких цепей иммуноглобулинов и генов Т-клеточного рецептора у пациентов с заболеваниями системы крови. Дис. … канд. мед. наук. М., 2019.Segel G.B., Lichtman M.A. Direct antiglobulin (“Coombs”) testnegative autoimmune hemolytic anemia: a review. Blood Cells Mol Dis 2014;52(4):152–60. DOI: 10.1016/j.bcmd.2013.12.003Mineeva N.V., Krobinets I.I., Bodrova N.N., Bogdanova I.O. The use of direct antiglobulin test to detect autoantibodies in patients with anemia of various origins. Onkogematologiya = Oncohematology 2017;12(3):57–62. (In Russ.). DOI: 10.17650/1818-8346-2017-12-3-57-62Минеева Н.В., Кробинец И.И., Бодрова Н.Н., Богданова И.О. Применение прямого антиглобулинового теста для выявления аутоантител при анемиях различного генеза. Онкогематология 2017;12(3):57–62. DOI: 10.17650/1818-8346-2017-12-3-57-62Hill A., Hill Q.A. Autoimmune hemolytic anemia. Hematology Am Soc Hematol Educ Program 2018;2018(1):382–9. DOI: 10.1182/asheducation-2018.1.382Nikulina O.F. Treatment of acute and resistant autoimmune hemolytic anemia and hemolysis activity monitoring. Dis. ... candidate of medical sciences. Moscow, 2008. (In Russ.).Никулина О.Ф. Лечение острых и резистентных форм аутоиммунной гемолитической анемии и мониторинг активности гемолиза. Дис. … канд. мед. наук. М., 2008.Birgens H., Frederiksen H., Hasselbalch H.C. et al. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol 2013;163(3):393–9. DOI: 10.1111/bjh.12541Gildeeva G.N., Kudlay D.A., Lukianov S.V. Rituximab mechanism of action. Eksperimentalnaya i klinicheskaya farmakologiya = Experimental and Clinical Pharmacology 2015;78(12):51–6. (In Russ.). DOI: 10.30906/0869-2092-2015-78-12-51-56Гильдеева Г.Н., Кудлай Д.А., Лукьянов С.В. Механизмы действия ритуксимаба. Экспериментальная и клиническая фармакология 2015;78(12):51–6. DOI: 10.30906/0869-2092-2015-78-12-51-56Michel M., Terriou L., Roudot-Thoraval F. et al. A randomized and double‐blind controlled trial evaluating the safety and efficacy of rituximab for warm auto‐immune hemolytic anemia in adults (the RAIHA study). Am J Hematol 2017;92(1):23–7. DOI: 10.1002/ajh.24570Lechner K., Jäger U. How I treat autoimmune hemolytic anemias in adults. Blood 2010;116(11):1831–8. DOI: 10.1182/blood-2010-03-259325Alonso H.C., Manuel A.A.V., Amir C.G.C. et al. Warm autoimmune hemolytic anemia: experience from a single referral center in Mexico City. Blood Res 2017;52(1):44–9. DOI: 10.5045/br.2017.52.1.44Michel M., Godeau B., Aladjidi N., Perel Y. Protocole national de diagnostic et de soins (PNDS). Accessed 30 April 2018.Reynaud Q., Durieu I., Dutertre M. et al. Efficacy and safety of rituximab in auto-immune hemolytic anemia: a meta-analysis of 21 studies. Autoimmun Rev 2015;14(4):304–13. DOI: 10.1016/j.autrev.2014.11.014Flores G., Cunningham-Rundles C., Newland A.C., Bussel J.B. Efficacy of intravenous immunoglobulin in the treatment of autoimmune hemolytic anemia: results in 73 patients. Am J Hematol 1993;44(4):237–42. DOI: 10.1002/ajh.2830440404Berentsen S., Ulvestad E., Langholm R. et al. Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. Haematologica 2006;91(4):460–6.Treatment and prognosis of cold-antibody AIHA. In: The Haemolytic Anaemias, Vol. 3. Ed.: J. Dacie. London: Churchill Livingstone, 1992.Berentsen S., Tjønnfjord G.E., Brudevold R. et al. Favourable response to therapy with the anti‐CD20 monoclonal antibody rituximab in primary chronic cold agglutinin disease. Br J Haematol 2001;115(1):79–83. DOI: 10.1046/j.1365-2141.2001.03078.xBerentsen S., Ulvestad E., Tore Gjertsen B. et al. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood 2004;103(8):2925–8. DOI: 10.1182/blood-2003-10-3597Schöllkopf C., Kjeldsen L., Weiss Bjerrum O. et al. Rituximab in chronic cold agglutinin disease: a prospective study of 20 patients. Leuk Lymphoma 2006;47(2):253–60. DOI: 10.1080/10428190500286481Berentsen S., Randen U., Vågan A.M. et al. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Blood 2010;116(17):3180–4. DOI: 10.1182/blood-2010-06-288647