Interaction of polymorphism of the interleukin-6 gene with immunological damages and their role in the development of mixed cryoglobulinemia in patients with chronic hepatitis C
DOI:
https://doi.org/10.14739/2310-1237.2019.1.166189Keywords:
chronic hepatitis C, mixed cryoglobulinemia, interleukin-6, genetic polymorphismAbstract
Aim. To determine the role of the relationship of immunological disorders with interleukin-6 gene polymorphism in the formation of HCV-associated mixed cryoglobulinemia.
Materials and methods. The study included 149 patients with chronic hepatitis C. The polymorphism of the IL-6 gene (rs1800795) was determined by the method of polymerase chain reaction, the quantitative content of IL-6, RF IgM and IgG by enzyme immunoassay, cryoglobulins by spectrophotometric method. The patients were divided into groups depending on the polymorphism of the IL-6 gene and the presence of mixed cryoglobulinemia.
Results. The frequency of formation of HCV-associated mixed cryoglobulinemia depended on the polymorphism of the IL-6 gene. In patients with chronic hepatitis C with mixed cryoglobulinemia, the frequency of registration of the CC genotype of the IL-6 gene was lower than in patients without mixed cryoglobulinemia, namely, in 9.7 % versus 28.6 % of patients. The presence of the G-allele, namely the CG/GG genotypes of the IL-6 gene polymorphism, was more often detected in patients with mixed cryoglobulinemia, namely, in 90.3 % of patients against 71.4 % of patients without signs of mixed cryoglobulinemia (χ2 = 8.94, P = 0.003).
In the presence of G-allele, the quantitative content of IL-6 inthe serum of the general group of patients with CHC was higher than in healthy people (P < 0.01), and in the presence of the genotype, the CC did not differ from the control group (P > 0.05). The highest levels of IL-6 were recorded in patients with HCV-associated mixed cryoglobulinemia who had the G-allele. The content of IL-6 in the blood serum of these patients exceeded the indicators of both healthy people (P < 0.001) and the results of patients without mixed cryoglobulinemia (P < 0.01). In patients with chronic hepatitis C with mixed cryoglobulinemia, even in the presence of the CC genotype, the content of IL-6 in serum was higher both in comparison with healthy (P < 0.01) and in comparison with patients without signs of this extrahepatic manifestation (P < 0.01).
In patients with chronic hepatitis C with mixed cryoglobulinemia, the presence of CG/GG genotypes was associated not only with the highest serum IL-6 content, but also with the presence of more pronounced autoimmune disorders due to a higher content of RF IgM (P = 0.04) and mixed cryoglobulins (P = 0.03) in serum, in comparison with patients who had the CC genotype. Moreover, the presence of more pronounced immune disorders in patients with HCV-associated mixed cryoglobulinemia in the presence of CG/GG genotypes was accompanied by more frequent manifestation of severe general weakness (P = 0.003), arthralgia (P = 0.02) and the formation of Meltzer’s triad.
Conclusion. The frequency of detection of the G-allele, namely the CG/GG genotypes of the IL-6 gene polymorphism, is the highest in patients with HCV-associated mixed cryoglobulinemia (90.3 %). The presence of CG/GG genotypes in patients with chronic hepatitis C with mixed cryoglobulinemia contributes to more pronounced immunological disorders due to the highest content of IL-6, mixed cryoglobulins, and RF IgM in serum, which causes the manifestation of the clinical symptoms of this hepatic manifestation.
References
- Lee, M., Yang, H., Lu, S., Jen, C., You, S., Wang, L. et al. (2012). Chronic Hepatitis C Virus Infection Increases Mortality From Hepatic and Extrahepatic Diseases: A Community-Based Long-Term Prospective Study. Journal of Infectious Diseases, 206(4), 469–477. doi: 10.1093/infdis/jis385
- Russi, S., Sansonno, D., Mariggiò, M., Vinella, A., Pavone, F., Lauletta, G., et al. (2014). Assessment of total hepatitis C virus (HCV) core protein in HCV-related mixed cryoglobulinemia. Arthritis Research & Therapy, 16(2), R73. doi: 10.1186/ar4513
- Roccatello, D., Sciascia, S., Rossi, D., Solfietti, L., Fenoglio, R., Menegatti, E., & Baldovino, S. (2017). The challenge of treating hepatitis C virus-associated cryoglobulinemic vasculitis in the era of anti-CD20 monoclonal antibodies and direct antiviral agents. Oncotarget, 8(25). doi: 10.18632/oncotarget.16986
- Mazzaro, C., Monti, G., Saccardo, F., Zignego, A. L., Ferri C., De Vita, S., et al. (2011) Efficacy and safety of peginterferon alfa-2b plus ribavirin for HCV-positive mixed cryoglobulinemia: a multicentre open-label study. Clin Exp Rheumatol., 29(6), 933–41.
- Terrier, B., Semoun, O., Saadoun, D., Sène, D., Resche-Rigon, M., & Cacoub, P. (2011). Prognostic factors in patients with hepatitis C virus infection and systemic vasculitis. Arthritis & Rheumatism, 63(6), 1748–1757. doi: 10.1002/art.30319
- Menegatti, E., Messina, M., Oddone, V., Rubini, E., Sciascia, S., Naretto, C., et al. (2016) Immunogenetics of complement in mixed cryoglobulinaemia. Clin Exp Rheumatol., 34(3 Suppl 97), 12–5.
- Yamagiwa, S., Ishikawa, T., Waguri, N., Sugitani, S., Kamimura, K., Tsuchiya, A., et al. (2017). Increase of Soluble Programmed Cell Death Ligand 1 in Patients with Chronic Hepatitis C. International Journal of Medical Sciences, 14(5), 403–411. doi: 10.7150/ijms.18784
- Holz, L., Yoon, J., Raghuraman, S., Moir, S., Sneller, M., & Rehermann, B. (2012). B cell homeostasis in chronic hepatitis C virus-related mixed cryoglobulinemia is maintained through naïve B cell apoptosis. Hepatology, 56(5), 1602–1610. doi: 10.1002/hep.25821
- Charles, E., Orloff, M., Nishiuchi, E., Marukian, S., Rice, C., & Dustin, L. (2013). Somatic Hypermutations Confer Rheumatoid Factor Activity in Hepatitis C Virus-Associated Mixed Cryoglobulinemia. Arthritis & Rheumatism, 65(9), 2430–2440. doi: 10.1002/art.38041
- Rose-John, S. (2015). The soluble interleukin-6 receptor and related proteins. Best Practice & Research Clinical Endocrinology & Metabolism, 29(5), 787–797. doi: 10.1016/j.beem.2015.07.001
- Naka, T., Nishimoto, N., & Kishimoto, T. (2002). The paradigm of IL-6: from basic science to medicine. Arthritis research, 4 Suppl 3(Suppl 3), S233–42. doi: 10.1186/ar565
- Kishimoto, T. (2005). INTERLEUKIN-6: From Basic Science to Medicine–40 Years in Immunology. Annual Review Of Immunology, 23(1), 1–21. doi: 10.1146/annurev.immunol.23.021704.115806
- O'Reilly, S., Ciechomska, M., Cant, R., & van Laar, J. (2014). Interleukin-6 (IL-6) Trans Signaling Drives a STAT3-dependent Pathway That Leads to Hyperactive Transforming Growth Factor-β (TGF-β) Signaling Promoting SMAD3 Activation and Fibrosis via Gremlin Protein. Journal of Biological Chemistry, 289(14), 9952–9960. doi: 10.1074/jbc.m113.545822
- Li, B., Xiao, Y., Xing, D., Ma, X., & Liu, J. (2016). Circulating interleukin-6 and rheumatoid arthritis. Medicine, 95(23), e3855. doi: 10.1097/md.0000000000003855
- Othman, M., Aref, A., Mohamed, A., & Ibrahim, W. (2013). Serum Levels of Interleukin-6 and Interleukin-10 as Biomarkers for Hepatocellular Carcinoma in Egyptian Patients. ISRN Hepatology, 2013, 412317. doi: 10.1155/2013/412317
- Salter, M., Lau, B., Mehta, S., Go, V., Leng, S., & Kirk, G. (2013). Correlates of Elevated Interleukin-6 and C-Reactive Protein in Persons With or at High Risk for HCV and HIV Infections. JAIDS Journal of Acquired Immune Deficiency Syndromes, 64(5), 488–495. doi: 10.1097/qai.0b013e3182a7ee2e
- Mechie, N. (2014). Predictability of IL-28B-polymorphism on protease-inhibitor-based triple-therapy in chronic HCV-genotype-1 patients: A meta-analysis. World Journal of Hepatology, 6(10), 759. doi: 10.4254/wjh.v6.i10.759
- Shah, S., Ma, Y., Scherzer, R., Huhn, G., French, A., Plankey, M., et al. (2015). Association of HIV, hepatitis C virus and liver fibrosis severity with interleukin-6 and C-reactive protein levels. AIDS, 29(11), 1325–1333. doi: 10.1097/qad.0000000000000654
- Sizovа, L., Koval, T., Kaidashev, I., Ilchenko, V., & Dubinskaya, G. (2016) Rol' geneticheskogo polimorfizma Toll-like receptorov 4 i 7 v razvitii khronicheskogo gepatita C i gendernye osobennosti ikh raspredeleniya [The role of genetic polymorphisms toll-like receptor 4 and 7 in the chronic hepatitis C and gender features of their distribution]. Georgian medical news, 1(250), 51–55. [in Russian].
- Karimifar, M., Pourajam, S., Tahmasebi, A., & Mottaghi, P. (2013). Serum cryoglobulins and disease activity in systematic lupus erythematosus. Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences, 18(3), 234–238.
- Riccio, A., Postiglione, L., Sabatini, P., Linvelli, M., Soriente, I., Sangiolo, M., et al. (2012). Similar Serum Levels of IL-6 and its Soluble Receptors in Patients with HCV-Related Arthritis and Rheumatoid Arthritis: A Pilot Study. International Journal of Immunopathology And Pharmacology, 25(1), 281–285. doi: 10.1177/039463201202500132
- Palazzi, C., Buskila, D., D'Angelo, S., D'Amico, E., & Olivieri, I. (2012). Autoantibodies in patients with chronic hepatitis C virus infection: pitfalls for the diagnosis of rheumatic diseases. Autoimmunity Reviews, 11(9), 659–663. doi: 10.1016/j.autrev.2011.11.011
- Örge, E., Çefle, A., Yazıcı, A., Gürel-Polat, N., & Hulagu, S. (2010). The positivity of rheumatoid factor and anti-cyclic citrullinated peptide antibody in nonarthritic patients with chronic hepatitis c infection. Rheumatology International, 30(4), 485–488. doi: 10.1007/s00296-009-0997-1
- Wu, Y., Hsu, T., Chen, T., Liu, T., Liu, G., Lee, Y., & TSAY, G. (2002). Proteinase 3 and dihydrolipoamide dehydrogenase (E3) are major autoantigens in hepatitis C virus (HCV) infection. Clinical & Experimental Immunology, 128(2), 347–352. doi: 10.1046/j.1365-2249.2002.01827.x
- Lormeau, C., Falgarone, G., Roulot, D., & Boissier, M. (2006). Rheumatologic manifestations of chronic hepatitis C infection. Joint Bone Spine, 73(6), 633–638. doi: 10.1016/j.jbspin.2006.05.005
- Reyes-Avilés, E., Kostadinova, L., Rusterholtz, A., Cruz-Lebrón, A., Falck-Ytter, Y., & Anthony, D. (2015). Presence of Rheumatoid Factor during Chronic HCV Infection Is Associated with Expansion of Mature Activated Memory B-Cells that Are Hypo-Responsive to B-Cell Receptor Stimulation and Persist during the Early Stage of IFN Free Therapy. PLOS ONE, 10(12), e0144629. doi: 10.1371/journal.pone.0144629
- Scott, D., Wolfe, F., & Huizinga, T. (2010). Rheumatoid arthritis. The Lancet, 376(9746), 1094–1108. doi: 10.1016/s0140-6736(10)60826-4
- Marinou, I., Healy, J., Mewar, D., Moore, D., Dickson, M., & Binks, M., et al. (2007). Association of interleukin-6 and interleukin-10 genotypes with radiographic damage in rheumatoid arthritis is dependent on autoantibody status. Arthritis & Rheumatism, 56(8), 2549–2556. doi: 10.1002/art.22814
- Pascual, M., Nieto, A., Matarán, L., Balsa, A., Pascual-Salcedo, D., & Martín, J. (2000). IL-6 promoter polymorphisms in rheumatoid arthritis. Genes & Immunity, 1(5), 338–340. doi: 10.1038/sj.gene.6363677
- Lee, Y., Bae, S., Choi, S., Ji, J., & Song, G. (2012). The association between interleukin-6 polymorphisms and rheumatoid arthritis: a meta-analysis. Inflammation Research, 61(7), 665–671. doi: 10.1007/s00011-012-0459-1
- Ripley, B., Goncalves, B., Isenberg, D. A., Latchman, D. S., & Rahman, A. (2005). Raised levels of interleukin 6 in systemic lupus erythematosus correlate with anaemia. Annals of The Rheumatic Diseases, 64(6), 849–853. doi: 10.1136/ard.2004.022681
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