mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2017-3-255-266mimmun-1259Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESИНТЕРФЕРОН-АЛЬФА-ИНДУЦИРОВАННЫЕ ДЕНДРИТНЫЕ КЛЕТКИ У БОЛЬНЫХ РЕВМАТОИДНЫМ АРТРИТОМ И ИХ ЧУВСТВИТЕЛЬНОСТЬ К ДЕКСАМЕТАЗОНУIFNα-INDUCED DENDRITIC CELLS IN PATIENTS WITH RHEUMATOID ARTHRITIS AND THEIR SENSITIVITY TO DEXAMETHASONEЧерныхЕ. Р.ChernykhE. R.

д.м.н., профессор, член-корр. РАН, заведующая лабораторией клеточной иммунотерапии

PhD, MD (Medicine), Professor, Corresponding Member, Russian Academy of Sciences, Head, Laboratory of Cellular Immunotherapy

ct_lab@mail.ruКурочкинаЮ. Д.KurochkinaYu. D.

аспирант лаборатории клеточной иммунотерапии, врач-ревматолог клиники иммунопатологии

Postgraduate Student, Laboratory of Cellular Immunotherapy, Physician (Rheumatology), Immunopathology Clinics

ct_lab@mail.ruЛеплинаО. Ю.LeplinaO. Yu.

д.м.н., ведущий научный сотрудник лаборатории клеточной иммунотерапии

PhD, MD (Medicine), Leading Research Associate, Laboratory of Cellular Immunotherapy

ct_lab@mail.ruТихоноваМ. А.TikhonovaM. A.

к.б.н., старший научный сотрудник лаборатории клеточной иммунотерапии

PhD (Biology), Senior Research Associate, Laboratory of Cellular Immunotherapy

ct_lab@mail.ruТыриноваТ. В.TyrinovaT. V.

к.м.н., научный сотрудник лаборатории клеточной иммунотерапии

PhD (Medicine), Research Associate, Laboratory of Cellular Immunotherapy

ct_lab@mail.ruСизиковА. Э.SizikovA. E.

к.м.н., заведующий отделением ревматологии Клиники иммунопатологии

PhD (Medicine), Head, Rheumatology Department, Immunopathology Clinics

ct_lab@mail.ruЧумасоваО. А.ChumasovaO. A.

к.м.н., врач-ревматолог отделения ревматологии клиники иммунопатологии

PhD (Medicine), Physician (Rheumatology), Immunopathology Clinics

ct_lab@mail.ruОстанинА. А.OstaninA. A.

д.м.н., профессор, главный научный сотрудник лаборатории клеточной иммунотерапии

PhD, MD (Medicine), Professor, Main Research Associate, Laboratory of Cellular Immunotherapy

ct_lab@mail.ruФГБНУ «Научно-исследовательский институт фундаментальной и клинической иммунологии», г. НовосибирскРоссияResearch Institute of Fundamental and Clinical Immunology, NovosibirskRussian Federation201704072017193255266Copyright © Черных Е.Р., Курочкина Ю.Д., Леплина О.Ю., Тихонова М.А., Тыринова Т.В., Сизиков А.Э., Чумасова О.А., Останин А.А., 20172017Черных Е.Р., Курочкина Ю.Д., Леплина О.Ю., Тихонова М.А., Тыринова Т.В., Сизиков А.Э., Чумасова О.А., Останин А.А.Chernykh E.R., Kurochkina Y.D., Leplina O.Y., Tikhonova M.A., Tyrinova T.V., Sizikov A.E., Chumasova O.A., Ostanin A.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/1259

Дендритные клетки (ДК) играют важную роль в патогенезе ревматоидного артрита (РА) и рассматриваются в качестве новых мишеней терапевтических воздействий. Известно, что при воспалении тканевые ДК нелимфоидных органов могут дифференцироваться из моноцитов. При этом важная роль в дифференцировке и активации ДК при РА, отводится интерферону-альфа. Целью работы является изучение фенотипических и функциональных свойств ДК, генерируемых из моноцитов в присутствии интерферона-альфа (IFN-ДК) у больных РА и оценка их чувствительности к толерогенному действию дексаметазона. В исследование были включены 14 больных РА с умеренной или высокой активностью заболевания, получавших терапию болезнь-модифицирующими препаратами. Контролем служили 20 сопоставимых по полу и возрасту доноров крови. IFN-ДК генерировали из моноцитов путем культивирования адгезивной к пластику фракции мононуклеарных клеток с GM-CSF и IFNα в отсутствие или присутствии декасаметазона (10-6 M). IFN-ДК больных РА отличались повышенным содержанием CD14+CD83- и сниженным содержанием СD14- CD83+ клеток, что свидетельствует о задержке созревания ДК. Кроме того, IFN-ДК пациентов характеризовались более высокой экспрессией B7-H1 и TLR2. Фенотипические изменения не оказывали значимого влияния на функциональную активность ДК, в частности их способность продуцировать TNFα, IL-10 и IL-6, стимулировать пролиферацию аллогенных Т-клеток и индуцировать Т-клетки к продукции Th1- и Th2-цитокинов. Генерация ДК в присутствии дексаметазона у больных РА приводила к снижению экспрессии CD83 и СD86, подавлению продукции TNFα и ингибиции аллостимуляторной активности IFN-ДК. Кроме того, дексаметазон угнетал способность ДК активировать Т-клетки к продукции Th1-цитокинов, смещая баланс в сторону Th2-стимулирующей активности. Полученные данные свидетельствуют, что IFN-ДК больных РА сохраняют чувствительность к толерогенному действию дексаметазона. При этом выявленная гетерогенность больных по чувствительности ДК к ингибирующему эффекту дексаметазона может представлять интерес в прогностическом аспекте при проведении пульс-терапии глюкокортикоидами. Полученные результаты также обосновывают возможность использования IFN-ДК в качестве новой клеточной платформы при получении ДК с толерогенными свойствами. 

Dendritic cells (DCs) play an important role in pathogenesis of rheumatoid arthritis (RA) and are considered a novel target for immune therapy. Under inflammatory conditions, local dendritic cells of non-lymphoid organs are thought to be differentiated from monocytes. Moreover, DCs differentiation and activation in RA may be largely controlled by interferon-alpha. The aim of the present study was to investigate phenotypic and functional properties of monocyte-derived DCs generated in the presence of interferonalpha (IFN-DCs) in RA patients, and to specify, whether IFN-DCs are sensitive to a tolerogenic effect of dexamethasone. Fourteen RA patients with moderate-to-high disease activity treated with disease-modifying drugs have been included into the study. Twenty sex- and age-related healthy donors were used as a control. IFN-DCs were generated from monocytes by culturing adherent fraction of mononuclear cells for 5 days with GM-CSF and IFNα in the absence or presence of dexamethasone (10-6 M). IFN-DCs from RA patients were characterized by increased numbers of CD14+CD83- and lower amounts of CD14- CD83+ cells, thus presuming a delayed maturation. Furthermore, IFN-DCs from patients were characterized by higher expression of B7-H1 and TLR2. The phenotypic changes did not significantly influence specific functional activities of DCs, in particular, the capacity of DCs to produce TNFα, IL-10, IL-6, to stimulate proliferation of allogeneic T-cells and to activate T-cells for Th1 and Th2 cytokine production. Generation of patients’ DCs in presence of dexamethasone caused a decrease in CD83 and CD86 expression, reduced TNFα production, and suppressed allostimulatory activity of the DCs. Moreover, dexamethasone inhibited the ability of DC to stimulate Th1 response, along with shifting the balance towards Th2-stimulating activity. The data obtained provide an evidence that IFN-DCs from RA patients remain sensitive to the tolerogenic effects of dexamethasone. Furthermore, the revealed variations in sensitivity of patient’s DCs to dexamethasone-mediated inhibitory effect may be of interest for prediction of therapeutic response to glucocorticoid therapy. Our results also provide an evidence for possible implementation of IFN-DCs as a new cell platform for obtaining tolerogenic DCs.

 

дендритные клеткиинтерферон-αдексаметазоналло-СКЛцитокиныревматоидный артритdendritic cellsinterferon-αdexamethasoneallo-MLCcytokinesrheumatoid arthritisReferencesКурочкина Ю.Д., Леплина О.Ю., Тихонова М.А., Тыринова Т.В., Баторов Е.В., Сизиков А.Э., Оста- нин А.А., Черных Е.Р. Влияние дексаметазона на интерферон-α-индуцированную дифференцировку моноцитов в дендритные клетки // Медицинская иммунология, 2016, Т. 18, № 4, с. 347-356. [Kurochkina Yu.D., Leplina O.Yu., Tikhonova M.A., Tyrinova T.V., Batorov E.V., Sizikov A.E., Ostanin A.A., Chernykh E.R. Effect of dexamethasone on interferon-α-induced differentiation of monocytes to dendritic cells. Meditsinskaya immunologiya = Medical Immunology (Russia), 2016, Vol. 18, no. 4, pp. 347-356. (In Russ.) doi: 10.15789/1563-0625- 2016-4-347-356Курочкина Ю.Д., Леплина О.Ю., Тихонова М.А., Тыринова Т.В., Баторов Е.В., Сизиков А.Э., Оста- нин А.А., Черных Е.Р. Влияние дексаметазона на интерферон-α-индуцированную дифференцировку моноцитов в дендритные клетки // Медицинская иммунология, 2016, Т. 18, № 4, с. 347-356. [Kurochkina Yu.D., Leplina O.Yu., Tikhonova M.A., Tyrinova T.V., Batorov E.V., Sizikov A.E., Ostanin A.A., Chernykh E.R. Effect of dexamethasone on interferon-α-induced differentiation of monocytes to dendritic cells. Meditsinskaya immunologiya = Medical Immunology (Russia), 2016, Vol. 18, no. 4, pp. 347-356. (In Russ.) doi: 10.15789/1563-0625- 2016-4-347-356Ahmed M.S., Bae Y.S. Dendritic cell-based immunotherapy for rheumatoid arthritis: from bench to bedside. Immune Netw., 2016, Vol. 16, no. 1, pp. 44-51.Ahmed M.S., Bae Y.S. Dendritic cell-based immunotherapy for rheumatoid arthritis: from bench to bedside. Immune Netw., 2016, Vol. 16, no. 1, pp. 44-51.Blanco P., Palucka A.K., Gill M., Pascual V., Banchereau J. Induction of dendritic cell differentiation by IFNalpha in systemic lupus erythematosus. Science, 2001, Vol. 294, no. 5546, pp. 1540-1543.Blanco P., Palucka A.K., Gill M., Pascual V., Banchereau J. Induction of dendritic cell differentiation by IFNalpha in systemic lupus erythematosus. Science, 2001, Vol. 294, no. 5546, pp. 1540-1543.Chamorro S. TLR triggering on tolerogenic dendritic cells results in TLR2 up-regulation and a reduced proinflammatory immune program. J. Immunol., 2009, Vol. 183, no. 5, pp. 2984-2994.Chamorro S. TLR triggering on tolerogenic dendritic cells results in TLR2 up-regulation and a reduced proinflammatory immune program. J. Immunol., 2009, Vol. 183, no. 5, pp. 2984-2994.Chen K., Wang J.M., Yuan R., Yi X., Li L., Gong W., Yang T., Li L., Su S. Tissue-resident dendritic cells and diseases involving dendritic cell malfunction. Int. Immunopharmacol., 2016, Vol. 34, pp.1-15.Chen K., Wang J.M., Yuan R., Yi X., Li L., Gong W., Yang T., Li L., Su S. Tissue-resident dendritic cells and diseases involving dendritic cell malfunction. Int. Immunopharmacol., 2016, Vol. 34, pp.1-15.Chen E., Keystone E.C., Fish E.N. Restricted cytokine expression in rheumatoid arthritis. Arthritis Rheum., 1993, Vol. 36, no. 7, pp. 901-910.Chen E., Keystone E.C., Fish E.N. Restricted cytokine expression in rheumatoid arthritis. Arthritis Rheum., 1993, Vol. 36, no. 7, pp. 901-910.Coutinho A.E., Chapman K.E. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol. Cell. Endocrinol., 2011, Vol. 335, no. 1, pp. 2-13.Coutinho A.E., Chapman K.E. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol. Cell. Endocrinol., 2011, Vol. 335, no. 1, pp. 2-13.Estrada-Capetillo L., Hernandez-Castro B., Monsivais-Urenda A., Alvarez-Quiroga C., LaysecaEspinosa E., Abud-Mendoza C., Baranda L., Urzainqui А.,Sanchez-Madrid F., Gonzalez-Amaro R. Induction of Th17 lymphocytes and Treg cells by monocyte-derived dendritic cells in patients with rheumatoid arthritis and systemic lupus erythematosus. Clin. Dev. Immunol., 2013, Vol. 2013, Article ID 584303, 9 p.Estrada-Capetillo L., Hernandez-Castro B., Monsivais-Urenda A., Alvarez-Quiroga C., LaysecaEspinosa E., Abud-Mendoza C., Baranda L., Urzainqui А.,Sanchez-Madrid F., Gonzalez-Amaro R. Induction of Th17 lymphocytes and Treg cells by monocyte-derived dendritic cells in patients with rheumatoid arthritis and systemic lupus erythematosus. Clin. Dev. Immunol., 2013, Vol. 2013, Article ID 584303, 9 p.Gessani S., Conti L., Del Cornò M., Belardelli F. Type I interferons as regulators of human antigen presenting cell functions. Toxins (Basel), 2014, Vol. 6, no. 6, pp. 1696-1723.Gessani S., Conti L., Del Cornò M., Belardelli F. Type I interferons as regulators of human antigen presenting cell functions. Toxins (Basel), 2014, Vol. 6, no. 6, pp. 1696-1723.Gottenberg J.E., Chiocchia G. Dendritic cells and interferon-mediated autoimmunity. Biochimie, 2007, Vol. 89, no. 6-7, pp. 856-871.Gottenberg J.E., Chiocchia G. Dendritic cells and interferon-mediated autoimmunity. Biochimie, 2007, Vol. 89, no. 6-7, pp. 856-871.Harry R.A., Anderson A.E., Isaacs J.D., Hilkens C.M. Generation and characterization of therapeutic tolerogenic dendritic cells for rheumatoid arthritis. Ann. Rheum. Dis., 2010, Vol. 69, no. 11, pp. 2042-2050.Harry R.A., Anderson A.E., Isaacs J.D., Hilkens C.M. Generation and characterization of therapeutic tolerogenic dendritic cells for rheumatoid arthritis. Ann. Rheum. Dis., 2010, Vol. 69, no. 11, pp. 2042-2050.Hilkens C.M.U., Isaacs J.D. Tolerogenic dendritic cells in clinical practice. Open Arthritis Journal, 2010, Vol. 3, pp. 8-12.Hilkens C.M.U., Isaacs J.D. Tolerogenic dendritic cells in clinical practice. Open Arthritis Journal, 2010, Vol. 3, pp. 8-12.van Roon J.A.G., Hartgring S.A.Y., van der Wurff-Jacobs K.M.G., Bijlsma J.W.J., Lafeber F.P.J.G. Numbers of CD25+Foxp3+ T cells that lack the IL-7 receptor are increased intra-articularly and have impaired suppressive function in RA patients. Rheumatology, 2010, Vol. 49, no. 6, pp. 2084-2089.van Roon J.A.G., Hartgring S.A.Y., van der Wurff-Jacobs K.M.G., Bijlsma J.W.J., Lafeber F.P.J.G. Numbers of CD25+Foxp3+ T cells that lack the IL-7 receptor are increased intra-articularly and have impaired suppressive function in RA patients. Rheumatology, 2010, Vol. 49, no. 6, pp. 2084-2089.Khan S., Greenberg J.D., Bhardwaj N. Dendritic cells as targets for therapy in rheumatoid arthritis. Nat. Rev. Rheumatol., 2009, Vol. 5, no. 10, pp. 566-571.Khan S., Greenberg J.D., Bhardwaj N. Dendritic cells as targets for therapy in rheumatoid arthritis. Nat. Rev. Rheumatol., 2009, Vol. 5, no. 10, pp. 566-571.Leplina O.Yu., Tyrinova T.V., Tikhonova M.A., Ostanin A.A., Chernykh E.R. Interferon alpha induces generation of semi-mature dendritic cells with high pro-inflammatory and cytotoxic potential. Cytokine, 2015, Vol. 71, no. 1, pp. 1-7.Leplina O.Yu., Tyrinova T.V., Tikhonova M.A., Ostanin A.A., Chernykh E.R. Interferon alpha induces generation of semi-mature dendritic cells with high pro-inflammatory and cytotoxic potential. Cytokine, 2015, Vol. 71, no. 1, pp. 1-7.Liu J., Cao X. Regulatory dendritic cells in autoimmunity: a comprehensive review. J. Autoimmun., 2015, Vol. 63, pp. 1-12.Liu J., Cao X. Regulatory dendritic cells in autoimmunity: a comprehensive review. J. Autoimmun., 2015, Vol. 63, pp. 1-12.Manicassamy S., Ravindran R., Deng J., Oluoch H., Denning T.L., Kasturi S.P., Rosenthal K.M., Evavold B.D., Pulendran B. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat. Med., 2009, Vol. 15, no. 4, pp. 401-409.Manicassamy S., Ravindran R., Deng J., Oluoch H., Denning T.L., Kasturi S.P., Rosenthal K.M., Evavold B.D., Pulendran B. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity. Nat. Med., 2009, Vol. 15, no. 4, pp. 401-409.Martin C.A, Carsons S.E., Kowalewski R., Bernstein D., Valentino M., Santiago-Schwarz F. Aberrant extracellular and dendritic cell (DC) surface expression of heat shock protein (hsp)70 in the rheumatoid joint: possible mechanisms of hsp/DC-mediated cross-priming. J. Immunol., 2003, Vol. 171, no. 11, pp. 5736-5742.Martin C.A, Carsons S.E., Kowalewski R., Bernstein D., Valentino M., Santiago-Schwarz F. Aberrant extracellular and dendritic cell (DC) surface expression of heat shock protein (hsp)70 in the rheumatoid joint: possible mechanisms of hsp/DC-mediated cross-priming. J. Immunol., 2003, Vol. 171, no. 11, pp. 5736-5742.Matasic R., Dietz A.B., Vuk-Pavlovic S. Dexamethasone inhibits dendritic cell maturation by redirecting differentiation of a subset of cells. J. Leukoc. Biol., 1999, Vol. 66, no. 6, pp. 909-914.Matasic R., Dietz A.B., Vuk-Pavlovic S. Dexamethasone inhibits dendritic cell maturation by redirecting differentiation of a subset of cells. J. Leukoc. Biol., 1999, Vol. 66, no. 6, pp. 909-914.Miossec P., Naviliat A., Duput-dAngeac A., Sany J., Banchereau J. Low levels of interleukin-4 and high levels of transforming growth factor beta in rheumatoid synovitis. Arthr. Rheum., 1999, Vol. 33, pp. 1180-1187.Miossec P., Naviliat A., Duput-dAngeac A., Sany J., Banchereau J. Low levels of interleukin-4 and high levels of transforming growth factor beta in rheumatoid synovitis. Arthr. Rheum., 1999, Vol. 33, pp. 1180-1187.Aerts N.E., De Knop K.J., Leysen J., Ebo D.G., Bridts C.H., Weyler J.J., Stevens W.J., De Clerck L.S. Increased IL-17 production by peripheral T helper cells after tumour necrosis factor blockade in rheumatoid arthritis is accompanied by inhibition of migration associated chemokine receptor expression. Rheumatology (Oxford), 2010, Vol. 49, no. 12, pp. 2264-2272.Aerts N.E., De Knop K.J., Leysen J., Ebo D.G., Bridts C.H., Weyler J.J., Stevens W.J., De Clerck L.S. Increased IL-17 production by peripheral T helper cells after tumour necrosis factor blockade in rheumatoid arthritis is accompanied by inhibition of migration associated chemokine receptor expression. Rheumatology (Oxford), 2010, Vol. 49, no. 12, pp. 2264-2272.Ning B., Wei J., Zhang A., Gong W., Fu J., Jia T., Yang S.Y. Antigen-specific tolerogenic dendritic cells ameliorate the severity of murine collagen-induced arthritis. PLoS One, 2015, Vol. 10. doi: 10.1371/journal. pone.0131152Ning B., Wei J., Zhang A., Gong W., Fu J., Jia T., Yang S.Y. Antigen-specific tolerogenic dendritic cells ameliorate the severity of murine collagen-induced arthritis. PLoS One, 2015, Vol. 10. doi: 10.1371/journal. pone.0131152Parlato S., Santini S.M., Lapenta C., Di Pucchio T., Logozzi M., Spada M., Giammarioli A.M., Malorni W., Fais S., Belardelli F. Expression of CCR-7, MIP-3beta, and Th-1 chemokines in type I IFN-induced monocytederived dendritic cells: importance for the rapid acquisition of potent migratory and functional activities. Blood, 2001, Vol. 98, no. 10, pp. 3022-3029.Parlato S., Santini S.M., Lapenta C., Di Pucchio T., Logozzi M., Spada M., Giammarioli A.M., Malorni W., Fais S., Belardelli F. Expression of CCR-7, MIP-3beta, and Th-1 chemokines in type I IFN-induced monocytederived dendritic cells: importance for the rapid acquisition of potent migratory and functional activities. Blood, 2001, Vol. 98, no. 10, pp. 3022-3029.Pettit A.R., Thomas R. Dendritic cells: the driving force behind autoimmunity in rheumatoid arthritis? Immunol. Cell. Biol., 1999, Vol. 77, no. 5, pp. 420-427.Pettit A.R., Thomas R. Dendritic cells: the driving force behind autoimmunity in rheumatoid arthritis? Immunol. Cell. Biol., 1999, Vol. 77, no. 5, pp. 420-427.Qu C., Brinck-Jensen N.S., Zang M., Chen K. Monocyte-derived dendritic cells: targets as potent antigenpresenting cells for the design of vaccines against infectious diseases. Int. J. Infect. Dis., 2014, Vol. 19, pp. 1-5.Qu C., Brinck-Jensen N.S., Zang M., Chen K. Monocyte-derived dendritic cells: targets as potent antigenpresenting cells for the design of vaccines against infectious diseases. Int. J. Infect. Dis., 2014, Vol. 19, pp. 1-5.Radstake T.R., Nabbe K.C., Wenink M.H., Roelofs M.F., Oosterlaar A., van Lieshout A.W., Barrera P., van Lent P.L., van den Berg W.B. Dendritic cells from patients with rheumatoid arthritis lack the interleukin 13 mediated increase of FcRII expression, which has clear functional consequences. Ann. Rheum. Dis., 2005, Vol. 64, pp. 1737- 1743.Radstake T.R., Nabbe K.C., Wenink M.H., Roelofs M.F., Oosterlaar A., van Lieshout A.W., Barrera P., van Lent P.L., van den Berg W.B. Dendritic cells from patients with rheumatoid arthritis lack the interleukin 13 mediated increase of FcRII expression, which has clear functional consequences. Ann. Rheum. Dis., 2005, Vol. 64, pp. 1737- 1743.Radstake T.R., van der Voort R., ten Brummelhuis M., de Waal Malefijt M., Looman M., Figdor C.G., van den Berg W.B., Barrera P., Adema G.J. Increased expression of CCL18, CCL19, and CCL17 by dendritic cells from patients with rheumatoid arthritis, and regulation by Fc gamma receptors. Ann. Rheum. Dis., 2005, Vol. 64, no. 3, pp. 359-367.Radstake T.R., van der Voort R., ten Brummelhuis M., de Waal Malefijt M., Looman M., Figdor C.G., van den Berg W.B., Barrera P., Adema G.J. Increased expression of CCL18, CCL19, and CCL17 by dendritic cells from patients with rheumatoid arthritis, and regulation by Fc gamma receptors. Ann. Rheum. Dis., 2005, Vol. 64, no. 3, pp. 359-367.Radstake T.R., van Lent P.L., Pesman G.J., Blom A.B., Sweep F.G., Ronnelid J., Adema G.J., Barrera P., van den Berg W.B. High production of proinflammatory and Th1 cytokines by dendritic cells from patients with rheumatoid arthritis, and down regulation upon Fc gamma triggering. Ann. Rheum. Dis., 2004, Vol. 63, no. 6, pp. 696-702.Radstake T.R., van Lent P.L., Pesman G.J., Blom A.B., Sweep F.G., Ronnelid J., Adema G.J., Barrera P., van den Berg W.B. High production of proinflammatory and Th1 cytokines by dendritic cells from patients with rheumatoid arthritis, and down regulation upon Fc gamma triggering. Ann. Rheum. Dis., 2004, Vol. 63, no. 6, pp. 696-702.Rodriguez-Carrio J., de Paz B., Lуpez P., Prado C., Alperi-Lуpez M., Ballina-Garcнa F.J., Suarez A. IFNα serum levels are associated with endothelial progenitor cells imbalance and disease features in rheumatoid arthritis patients. PLoS One., 2014, Vol. 9, no. 1, doi: 10.1371/journal.pone.0086069.Rodriguez-Carrio J., de Paz B., Lуpez P., Prado C., Alperi-Lуpez M., Ballina-Garcнa F.J., Suarez A. IFNα serum levels are associated with endothelial progenitor cells imbalance and disease features in rheumatoid arthritis patients. PLoS One., 2014, Vol. 9, no. 1, doi: 10.1371/journal.pone.0086069.Ronnblom L., Eloranta M.L. The interferon signature in autoimmune diseases. Curr. Opin. Rheumatol., 2013, Vol. 25, no. 2, pp. 248-253.Ronnblom L., Eloranta M.L. The interferon signature in autoimmune diseases. Curr. Opin. Rheumatol., 2013, Vol. 25, no. 2, pp. 248-253.Santiago-Schwarz F., Anand P., Liu S., Carsons S.E. Dendritic cells (DCs) in rheumatoid arthritis (RA): progenitor cells and soluble factors contained in RA synovial fluid yield a subset of myeloid DCs that preferentially activate Th1 inflammatory-type responses. J. Immunol., 2001, Vol. 167, no. 3, pp. 1758-1768.Santiago-Schwarz F., Anand P., Liu S., Carsons S.E. Dendritic cells (DCs) in rheumatoid arthritis (RA): progenitor cells and soluble factors contained in RA synovial fluid yield a subset of myeloid DCs that preferentially activate Th1 inflammatory-type responses. J. Immunol., 2001, Vol. 167, no. 3, pp. 1758-1768.Schinnerling K., Soto L., Garcia-Gonzalez P., Catalan D., Aguillуn J.C. Skewing dendritic cell differentiation towards a tolerogenic state for recovery of tolerance in rheumatoid arthritis. Autoimmun. Rev., 2015, Vol. 14, no. 6, pp. 517-527.Schinnerling K., Soto L., Garcia-Gonzalez P., Catalan D., Aguillуn J.C. Skewing dendritic cell differentiation towards a tolerogenic state for recovery of tolerance in rheumatoid arthritis. Autoimmun. Rev., 2015, Vol. 14, no. 6, pp. 517-527.Schultz H.S., Guo L., Keller P., Fleetwood A.J., Sun M., Guo W., Ma C., Hamilton J.A., Bjørkdahl O., Berchtold M.W., Panina S. OSCAR-collagen signaling in monocytes plays a proinflammatory role and may contribute to the pathogenesis of rheumatoid arthritis. Eur. J. Immunol., 2016, Vol. 46, no. 4, pp. 952-963.Schultz H.S., Guo L., Keller P., Fleetwood A.J., Sun M., Guo W., Ma C., Hamilton J.A., Bjørkdahl O., Berchtold M.W., Panina S. OSCAR-collagen signaling in monocytes plays a proinflammatory role and may contribute to the pathogenesis of rheumatoid arthritis. Eur. J. Immunol., 2016, Vol. 46, no. 4, pp. 952-963.Selenko-Gebauer N., Majdichttp J., Szekeres A., Höfler G., Guthann E., Korthäuer U., Zlabinger G., Steinberger P., Pickl W.F., Stockinger H., Knapp W., Stöckl J. B7-H1 (Programmed Death-1 Ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy. J. Immunol., 2003, Vol. 170, no. 7, pp. 3637-3644.Selenko-Gebauer N., Majdichttp J., Szekeres A., Höfler G., Guthann E., Korthäuer U., Zlabinger G., Steinberger P., Pickl W.F., Stockinger H., Knapp W., Stöckl J. B7-H1 (Programmed Death-1 Ligand) on dendritic cells is involved in the induction and maintenance of T cell anergy. J. Immunol., 2003, Vol. 170, no. 7, pp. 3637-3644.Thomas R., MacDonald K.P., Pettit A.R., Cavanagh L.L., Padmanabha J., Zehntner S. Dendritic cells and the pathogenesis of rheumatoid arthritis. J. Leukoc. Biol., 1999, Vol. 66, no. 2, pp. 286-292.Thomas R., MacDonald K.P., Pettit A.R., Cavanagh L.L., Padmanabha J., Zehntner S. Dendritic cells and the pathogenesis of rheumatoid arthritis. J. Leukoc. Biol., 1999, Vol. 66, no. 2, pp. 286-292.Torres-Aguilar H., Aguilar-Ruiz S.R., Gonzalez-Perez G., Munguia R., Bajaсa S., Meraz-Rios M.A., SanchezTorres C. Tolerogenic dendritic cells generated with different immunosuppressive cytokines induce antigen-specific anergy and regulatory properties in memory CD4+ T cells. J. Immunol., 2010, Vol. 184, no. 4, pp. 1765-1775.Torres-Aguilar H., Aguilar-Ruiz S.R., Gonzalez-Perez G., Munguia R., Bajaсa S., Meraz-Rios M.A., SanchezTorres C. Tolerogenic dendritic cells generated with different immunosuppressive cytokines induce antigen-specific anergy and regulatory properties in memory CD4+ T cells. J. Immunol., 2010, Vol. 184, no. 4, pp. 1765-1775.Tsark E.C., Wang W., Teng Y.C., Arkfeld D., Dodge G.R., Kovats S. Differential MHC class II-mediated presentation of rheumatoid arthritis autoantigens by human dendritic cells and macrophages. J. Immunol., 2002, Vol. 169, no. 11, pp. 6625-6633.Tsark E.C., Wang W., Teng Y.C., Arkfeld D., Dodge G.R., Kovats S. Differential MHC class II-mediated presentation of rheumatoid arthritis autoantigens by human dendritic cells and macrophages. J. Immunol., 2002, Vol. 169, no. 11, pp. 6625-6633.Wenink M.H., Han W., Toes R.E., Radstake T.R. Dendritic cells and their potential implication in pathology and treatment of rheumatoid arthritis. Handb. Exp. Pharmacol., 2009, Vol. 188, pp. 81-98.Wenink M.H., Han W., Toes R.E., Radstake T.R. Dendritic cells and their potential implication in pathology and treatment of rheumatoid arthritis. Handb. Exp. Pharmacol., 2009, Vol. 188, pp. 81-98.Zhao Y., Zhang A., Du H., Guo S., Ning B., Yang S. Tolerogenic dendritic cells and rheumatoid arthritis: current status and perspectives. Rheumatol. Int., 2012, Vol. 32, no. 4, pp. 837-844.Zhao Y., Zhang A., Du H., Guo S., Ning B., Yang S. Tolerogenic dendritic cells and rheumatoid arthritis: current status and perspectives. Rheumatol. Int., 2012, Vol. 32, no. 4, pp. 837-844.

The authors declare that there are no conflicts of interest present.