Cytokines and neopterin in antiphospholipid syndrome

Objective. To study clinical significance of proinflammatory cytokines (tumor necrosis factor α – TNFα, interleukine 6 – IL6, IL18), soluble receptors of TNFα (sTNF-R), anti- inflammatory cytokines (IL10) and integral marker of cytokine-dependent cell immune response activation neopterin in antiphospholipid syndrome (APS).Material and methods. Serum concentration of cytokines and neopterin was evaluated by immunoenzyme assay with commercial kits “BioSource International, Inc.” (USA), “Bender MedSystems” (Austria) and “IBL” (Germany) in 39 pts with primary APS (PAPS), 53 pts with secondary APS (SAPS) associated with systemic lupus erythematosus (SLE), 164 pts with SLE and 54 healthy donors.Results. Level of Th1 cytokines (TNFα, IL18), sTNF-R and neopterin in PAPS, SAPS and SLE as well as Th2 cytokines (IL6, IL10) in SAPS and SLE were significantly higher than in donors (p<0,05). TNFα elevation in PAPS was associated with damage of cardiac valves (p<0,05) and CNS (p<0,01), IL18 elevation – with chronic leg ulcers (p<0,001). Most prominent sTNFα-R elevation in SAPS was revealed in pts with thrombocytopenia (p<0,05). Neopterin hyperproduction in APS was associated with cardiac valve damage16 (p<0,001). IL10 level elevation in APS correlated with decreased thrombosis history (r=- 0,4; p<0,02), in SLE with APS – with decrease of damage score SLICC (r=-0,7; p<0,001) what proves protective significance of IL10 in relation to thrombosis development and disease progression. Increased concentration of IL 18 was associated with atherogenic disturbances presented as hypertrigliceridemia (r=0,6; p<0,01) and decrease of HDLP cholesterol (r—0,4; p<0,01). Positive correlation between TNFα, IL6 and neopterin level, IgM anticardiolipine antibodies and IgG/IgM antiprothrombin antibodies (p<0,05) was revealed. Cytokine, sTNFα-R and neopterin level elevation in SLE with APS was associated with increase of SLEDAI and ECLAM activity indices (p<0,05). Conclusion. Cytokine and neopterin hyperproduction reflecting cell immunity activation and inflammation is an important factor of APS pathogenesis.

antiphospholipid syndrome, tumor necrosis factor α, soluble TNFα receptors, IL6, IL10, IL18, neopterin, antiphospholipid antibodies, cell immune response activation, inflammation

1. <div><p>Алекперов Р.Т., Тимченко А.В., Самсонов М.Ю. и соавт. Уровень растворимых рецепторов 1 типа фактора некроза опухоли у больных системной склеродермией. Тер.архив, 2004, 5, 11-5.</p><p>Александрова Е.Н., Насонов Е.Л., Ковалев В.Ю. Количественный иммуноферментный метод определения антител к кардиолипину в сыворотке крови. Клинич. ревматол., 1995, 4, 35-9.</p><p>Бородин А.Г., Баранов А.А., Клюквина Н.Г. и соавт. Клинико-патогенетическое значение фактора некроза опухоли альфа при системной красной волчанке. Тер.архив, 2002, 5, 32-4.</p><p>Ильина А.Е., Клюквина Н.Г., Александрова Е.Н. и соавт. Растворимые рецепторы α-фактора некроза опухолей: связь с атеросклеротическим поражением сосудов при системной красной волчанке у мужчин. Тер.архив, 2006, 6, 20-4.</p><p>Кричевская О.А., Клюквина Н.Г., Александрова Е.Н. и соавт. Фактор некроза опухоли α и его растворимые рецепторы при ревматических заболеваниях: клиническое и патогенетическое значение. Научно-практич. ревматол., 2005, 2, 43-6.</p><p>Насонов Е.Л., Баранов А.А., Шилкина Н.П. Васкулиты и васкулопатии. Ярославль, Верхняя Волга, 1999, 616 с.</p><p>Насонов Е.Л., Самсонов М.Ю., Тилз Г., Фукс Д. Неоптерин: новый иммунологический маркер аутоиммунных ревматических заболеваний. Клин. мед., 2000, 8, 43-6.</p><p>Насонов Е.Л. Современные направления иммуно- логических исследований при хронических воспалительных и аутоиммунных заболеваниях человека. Тер.архив, 2001, 8, 43-6.</p><p>Панафидина Т.А., Попкова Т.В., Алекберова З.С. и соавт. Интерлейкин-18 при системной красной волчанке: связь с клиническими проявлениями заболевания и атеросклеротическим поражением сосудов. Тер.архив, 2008, 5, 41-6.</p><p>Свиридов Е.А., Телегина Т.А. Неоптерин и его восстановленные формы: биологическая роль и участие в клеточном иммунитете. Успехи биологич. химии, 2005, 45, 355-90.</p><p>Ярилин А.А. Система цитокинов и принципы ее функционирования в норме и патологии. Иммунология, 1997, 5, 7-14.</p><p>Aringer M., Smolen J.C. Complex cytokine effect in a complex autoimmune disease: tumor necrosis factor in systemic lupus erythematosus. Arthr. Res. Ther., 2003, 5, 172-7.</p><p>Asanuma Yu., Chung C.P., Oeser A. et al. Increased concentration of proatherogenic inflammatory cytokines in systemic lupus erythematosus: relationship to cardiovascular risk factors. J. Rheumatol., 2006, 33, 539-45.</p><p>Berman J., Girardi G., Salmon J.E. TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J. Immunol., 2005, 174, 485-90.</p><p>Bertolaccini M.L., Atsumi T., Lanchbury J.C. et al. Plasma tumor necrosis factor alpha level and 238* promoter polymorphism in patients with antiphospholipid syndrome. Thromb. Haemost., 2001, 85, 193-4.</p><p>Blank M., Krause I., Lanir N. et al. Transfer of experimental antiphpspholipid syndrome by bone marrow cell transplantation: the importance of the T cell. Arthritis. Rheum., 1995, Vol. 38, 115-22.</p><p>Davas E.M., Tsirogianni A., Kappou I. et al. Serum IL-6, TNF alpha, p55 srTNF alpha, p75 srTNF alpha, srIL-2 alpha levels and disease activity in systemic lupus erythematosus. Clin. Rheum., 1999, 18, 17-22.</p><p>Dayer E., Dayer J.-M., Roux-Lombard P. Primer: the practical use of biological markers of rheumatic and systemic inflammatory diseases. Nature Clin. Pract. Rheumatology, 2007, 3, 512-20.</p><p>Espersen G.T., Vestergard M., Erust E. et al. Tumor necrosis factor alpha and interleukin-2 in plasma from rheumatoid arthritis patients in relation with disease activity. Clin. Rheumatol., 1991, 10, 374-76.</p><p>Forastiero R.R., Martinuzzo M.E., de Larranga G.F. Circulating levels of tissue factor and proinflammatory cytokines in patients with primary antiphospholipid syndrome or leprosy related antiphospholipid antibodies. Lupus, 2005, 14, 129-36.</p><p>Gabay C., Cakir N., Moral F. et al. Circulating levels of tumor necrosis factor soluble receptor in systemic lupus erythematosus are significantly higher than in other rheumatic disease and correlate with disease activity. J. Rheumatol., 1997, 24, 303-8.</p><p>Garcia-Moll X., Cole D., Zouridakis E., Kaski J.C. Increased serum neopterin: a marker of coronary artery disease activity in women. Heart, 2000, 83, 346-50.</p><p>Girardi G., Berman J., Redecha P. et al. Complement C5a receptors and neutrophil mediated fetal injury in the antiphospholipid syndrome. J. Clin. Invest., 2003, 112, 1644-54.</p><p>Grondal G., Gunnarson I., Ronnelid J. et al. Cytokine production, serum levels and disease activity in systemic lupus erythematosus. Clin. Exp. Rheumatol., 2000, 18, 565-70.</p><p>Hamid C., Norgate K., D′Cruz D.P. Anti – β2GPI – antibody – induced endothelial cell gene expression profiling reveals induction of novel pro-inflammatory genes potentially involved in primary antiphospholipid syndrome. Ann. Rheum. Dis., 2007, 66, 1000-7.</p><p>Heilig B., Fiehn C., Brockhaus M. et al. Evaluation of soluble tumor necrosis factor (TNF) receptors and TNF receptor antibodies in patients with systemic lupus erythematosus, progressive systemic sclerosis and mixed connective tissue diseases. J. Clin. Immunol., 1993, 13, 321-8.</p><p>Hochberg M.C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum., 1997, 40, 1725-34.</p><p>Hossiau F.A. Serum interleukin 10 titers in systemic lupus erythematosus reflect disease activity. Lupus, 1995, 4, 393-5.</p><p>Karakantza M., Theodorou G.L., Meimaris N. et al. Type 1 and type 2 cytokine-producing CD4+ and CD8+ T cells in primary antiphospholipid syndrome. Ann. Hematol., 2004, 83, 704-11.</p><p>Kuwana M., Matsuura E., Kobayashi K. et al. Binding of beta 2-glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells. Blood, 2005, 105, 1552-7.</p><p>Lacki J.K., Leszczynski P., Kelemen J. et al. Cytokine concentration in serum of lupus erythematosus patients: the effect on acute phase response. J. Med., 1997, 28, 99-107.</p><p>Linker-Israeli M., Deans R.J., Wallace D.J. et al. Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis. J. Immunol.,1991, 147, 117-23.</p><p>Llorente L., Richaud-Patin Y., Wijdenes J. et al. Spontaneous production of interleukin-10 by B lymphocytes and monocytes in systemic lupus erythematosus. Eur. Cytokine Netw., 1993, 4, 421-7.</p><p>Mahmoud R.A., El-Gendi H.I., Ahmed H.H. Serum neopterin, tumor necrosis factor-alpha and soluble tumor necrosis factor receptor II (p75) levels and disease activity in Egyptian female patients with systemic lupus erythematosus. Clin. Biochem., 2005, 38, 134- 41.</p><p>Nassonov E.L., Samsonov M.Y., Tilz G.P. et al. Serum concentrations of neopterin, soluble interleukin 2 receptor, and soluble tumor necrosis factor receptor in Wegener’s granulomatosis. J. Rheumatol., 1997, 24, 666-70.</p><p>Nochy D., Daugas E., Droz D. et al. The intrarenal vascular lesions associated with primary antiphospholipid syndrome. J. Am. Soc. Nephrol., 1999, 10, 507.</p><p>Papo T., Piette J.-C., Legao E. et al. T lymphocytes subsets in primary antiphospholipid syndrome. J. Rheumatol., 1994, 21, 2242-45.</p><p>Park M.C., Park Y.B., Lee S.K. Elevated interleukin-18 levels correlated with disease activity in systemic lupus erythematosus. Clin. Rheumatol., 2004, 23, 225-9.</p><p>Pierangeli S.S., Colden-Stanfield M., Liu X. et al. Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo. Circulation, 1999, 99, 1997-2.</p><p>Raines E.W., Ferri N. Thematic review series: The immune system and atherogenesis. Cytokines affecting endothelial and smooth muscle cells in vascular disease. Lipid Res., 2005, 46, 108-92.</p><p>Samsonov M.Y., Tilz G.P. Egorova O. et al. Serum soluble markers of immune activation and disease activity in systemic lupus erythematosus. Lupus, 1995, 4, 29-32.</p><p>Segal R., Bermas B.L. Dayan M. et al. Kinetics of cytokine production in experimental systemic lupus erythematosus: involvement of T helper cell 1/T helper cell 2-type cytokines in disease. J. Immunol., 1997, 158, 3009-16.</p><p>Shimizu T., Tomita Y., Son K. et al. Elevation of serum soluble tumour necrosis factor receptors in patients with polymyositis and dermatomyositis. Clin. Rheumatol., 2000, 19, 352-9.</p><p>Shoenfeld Y., Meroni P.L., Cervera R. Antifosfolipid syndrome dilemmas still be to solved: 2008 status. Ann. Rheum. Dis., 2008, 67, 438-42.</p><p>Studnicka-Benke A., Steiner G., Petera P., Smolen J.S. Tumour necrosis factor alpha and its soluble receptors parallel clinical disease and autoimmune activity in systemic lupus erythematosus. Br. J. Rheumatol., 1996, 35, 1067-74.</p><p>Svenungsson E., Fei G.Z., Jensen-Urstad K. et al. TNF-alpha: a link between hypertriglyceridaemia and inflammation in SLE patients with cardiovascular disease. Lupus, 2003, 12, 454-61.</p><p>Svenungsson E., Gunnarsson I., Fei G.Z. et al. Elevated triglycerides and low levels of high-density lipoprotein as markers of disease activity in association with upregulation of the tumor necrosis factor alpha/tumor necrosis factor receptor system in systemic lupus erythematosus. Arthritis Rheum., 2003, 48, 2533-40.</p><p>Tan E.M., Cohen A.S., Fries J.F. et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum., 1982, 25, 1271-7.</p><p>Tso T.K., Huang W.N., Huang H.Y., Chang C.K. Relationship of plasma interleukin-18 concentrations to traditional and non-traditional cardiovascular risk factors in patients with systemic lupus erythematosus. Rheumatology, 2006, 45, 1148-53.</p><p>Visvanathan S., McNeil H.P. Cellular immunity to β2-glycoprotein I in patients with antiphospholipid syndrome. J. Immunol., 1999, 162, 6919-25.</p><p>Westerweel P.E., Luyten R.K., Koomans H.A. et al. Premature atherosclerotic cardiovascular disease in systemic lupus erythematosus. Arthritis Rheum., 2007, 56, 1384-96.</p><p>Wilson W. A., Azzudin E. Gharavi A.E. et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Arthritis Rheum, 1999, 42, 1309-11.</p><p>Wong C.K., Ho C.Y., Li E.K., et al. Elevated production of interleukin – 18 is associated with renal disease in patients with systemic lupus erythematosus. Clin. Exp. Immunol., 2002, 130, 345-51.</p><p>Woods A., Brull D.J., Humphries S.E., Montgomery H.E. Genetics of inflammation and risk of coronary artery disease: the central role of interleukin-6. Eur. Heart J., 2000, 21, 1574-83.</p><p>Yoshida K., Arai T., Kaburaki J. et al. Restricted T-cell receptor beta-chain usage by T cells autoreactive to beta(2)-glycoprotein I in patients with antiphospholipid syndrome. Blood, 2002, 99, 2499-04.</p></div><br />