Abstract
Hemorrhagic fever with renal syndrome (HFRS) is an acute viral infection caused by Hantavirus (HTV). Capillary leakage is one of the hallmarks of HTV infection. The mechanisms underlying the pathogenesis of HFRS are not completely understood. However, it has been suggested that immune mechanisms, including cytokines, might have an important role in HFRS pathogenesis. In this study, we investigated the potential role of interleukin-21 (IL-21) which is a newly discovered cytokine that stimulates T-cell and B-cell responses in the pathogenesis of HFRS. Serum samples were collected from 58 patients hospitalized with laboratory-verified HTV infection and 20 healthy controls. Serum IL-21 concentration was measured using an enzyme-linked immunosorbent assay. Serum IL-21 levels began to increase in the fever phase when renal damage appeared. The highest serum IL-21 level was detected in oliguric phase along with the peak degree of urinary renal impairment. When entering the polyuric phase, with gradual increase in urine and recovered renal function, the serum IL-21 level was observed to fall, returning to normal level after the renal function recovered in the convalescent phase. The serum IL-21 level was positively correlated with blood urea nitrogen (BUN) and creatinine (Cr), suggesting that the serum IL-21 level is associated with the disease severity of HFRS. This study indicated that IL-21 may act as an important inflammatory mediator in the immunopathogenesis of HFRS. The strategy to control IL-21 may hamper the immune response in patients with HFRS.
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Settergren, B., C. Ahlm, O. Alexeyev, J. Billheden, and B. Steamayr. 1997. Pathogenetic and clinical aspects of the renal involvement in hemorrhagic fever with renal syndrome. Renal Failure 19(1): 1–14.
Schmaljohn, C., and B. Hjelle. 1997. Hantaviruses: a global disease problem. Emerging Infectious Diseases 3(2): 95–104.
Jonsson, C.B., L.T. Figueiredo, and O. Vapalahti. 2010. A global perspective on Hantavirus ecology, epidemiology, and disease. Clinical Microbiology Reviews 23(2): 412–441.
Ruo, S.L., Y.L. Li, Z. Tong, Q.R. Ma, Z.L. Liu, Y.W. Tang, et al. 1994. Retrospective and prospective studies of hemorrhagic fever with renal syndrome in rural China. Journal of Infectious Diseases 170(3): 527–534.
Markotić, A. 2003. Immunopathogenesis of hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Acta Medica Croatica 57(5): 407–414.
Zeng, R., R. Spolski, E. Casas, W. Zhu, D.E. Levy, and W.J. Leonard. 2007. The molecular basis of IL-21-mediated proliferation. Blood 109(10): 4135–4142.
Parrish-Novak, J., D.C. Foster, R.D. Holly, and C.H. Clegg. 2002. Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses. Journal of Leukocyte Biology 72(5): 856–863.
Jüngel, A., J.H. Distler, M. Kurowska-Stolarska, C.A. Seemayer, R. Seibl, A. Forster, et al. 2004. Expression of interleukin-21 receptor, but not interleukin-21, in synovial fibroblasts and synovial macrophages of patients with rheumatoid arthritis. Arthritis and Rheumatism 50(5): 1468–1476.
Monteleone, G., I. Monteleone, D. Fina, P. Vavassori, Blanco G. Del Vecchio, R. Caruso, et al. 2005. Interluein-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn’s disease. Gastroenterology 128(3): 687–694.
Bubier, J.A., T.J. Sproule, O. Foreman, R. Spolski, D.J. Shaffer, H.C. Morse 3rd, et al. 2009. A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. Proceedings of the National Academy of Sciences of the United States of America 106(5): 1518–1523.
Liu, R., Q. Wu, D. Su, N. Che, H. Chen, L. Geng, et al. 2012. A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis. Arthritis Research and Therapy 14(6): R255.
Liu, R., L. Van Kaer, A. La Cava, M. Price, D.I. Campagnolo, M. Collins, et al. 2006. Autoreactive T cells mediate NK cell degeneration in autoimmune disease. Journal of Immunology 176(9): 5247–5254.
Elsaesser, H., K. Sauer, and D.G. Brooks. 2009. IL-21 is required to control chronic viral infection. Science 324(5934): 1569–1572.
Yi, J.S., M. Du, and A.J. Zajac. 2009. A vital role for interleukin-21 in the control of a chronic viral infection. Science 324(5934): 1572–1576.
Fröhlich, A., J. Kisielow, I. Schmitz, S. Freigang, A.T. Shamshiev, J. Weber, et al. 2009. IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science 324(5934): 1576–1580.
Leonard, W.J., R. Zeng, and R. Spolski. 2008. Interleukin 21: A cytokine/cytokine receptor system that has come of age. Journal of Leukocyte Biology 84(2): 348–356.
Brandt, K., P.B. Singh, S. Bulfone-Paus, and R. Rückert. 2007. Interleukin-21: A new modulator of immunity, infection, and cancer. Cytokine and Growth Factor Reviews 18(3–4): 223–232.
Hu, X., S. Ma, X. Huang, X. Jiang, X. Zhu, H. Gao, et al. 2011. Interleukin-21 is upregulated in hepatitis B-related acute-on-chronic liver failure and associated with severity of liver disease. Journal of Viral Hepatitis 18(7): 458–467.
Iannello, A., S. Samarani, and A. Ahmad. 2010. Comment on “HIV-specific IL-21 producing CD4+ T cells are induced in acute and chronic progressive HIV infection and are associated with relative viral control”. Journal of Immunology 185(10): 5675. author reply 5675.
Pallikkuth, S., A. Parmigiani, and S. Pahwa. 2012. Role of IL-21 and IL-21 receptor on B cells in HIV infection. Critical Reviews in Immunology 32(2): 173–195.
Chen, H.X., F.X. Qiu, B.J. Dong, S.Z. Ji, Y.T. Li, Y. Wang, H.M. Wang, G.F. Zuo, X.X. Tao, and S.Y. Gao. 1986. Epidemiological studies on hemorrhagic fever with renal syndrome in China. Journal of Infectious Diseases 154: 394–398.
Liang, M., D. Li, S.Y. Xiao, C. Hang, C.A. Rossi, and C.S. Schmaljohn. 1994. Antigenic and molecular characterization of hantavirus isolates from China. Virus Research 31: 219–233.
Wang, M., J. Wang, Y. Zhu, Z. Xu, K. Yang, A. Yang, et al. 2009. Cellular immune response to hantaan virus nucleocapsid protein in the acute phase of hemorrhagic fever with renal syndrome: correlation with disease severity. Journal of Infectious Diseases 199(2): 188–195.
Sadeghi, M., I. Eckerle, V. Daniel, U. Burkhardt, G. Opelz, and P. Schnitzler. 2011. Cytokine expression during early and late phase of acute Puumala hantavirus infection. BMC Immunology 12: 65.
Saksida, A., B. Wraber, and T. Avšič-Županc. 2011. Serum levels of inflammatory and regulatory cytokines in patients with hemorrhagic fever with renal syndrome. BMC Infectious Diseases 11: 142.
Li, M., Y. Ji, Y. Dong, Y. Zhou, H. Ren, and M. Xie. 2013. The detection of vascular endothelial growth factor in serum of patients with hemorrhagic fever with renal syndrome. Inflammation 36(4): 962–967.
Fan, W., X. Liu, and J. Yue. 2012. Determination of urine tumor necrosis factor, IL-6, IL-8, and serum IL-6 in patients with hemorrhagic fever with renal syndrome. Brazilian Journal of Infectious Diseases 16(6): 527–530.
Acknowledgments
This project was support by the National Grant Program on Key Infectious Disease of China (Grant no. 2012ZX10002007-002-007) and the Shaanxi province Natural Foundation of China (Grant no. 19100047 and 08140009). The authors would like to extend their appreciations to Dr. Li Guangyu and Dr. Zhang Xiuzhen for manuscript revision.
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None of the authors have any financial, professional or personal conflicts of interests with the manuscript.
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Chen, H., Liu, H., Wang, Y. et al. Elevated Serum IL-21 Levels in Hantavirus-Infected Patients Correlate with the Severity of the Disease. Inflammation 37, 1078–1083 (2014). https://doi.org/10.1007/s10753-014-9831-3
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DOI: https://doi.org/10.1007/s10753-014-9831-3