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

Authors

  • K. V. Kalashnyk Zaporizhzhia State Medical University, Ukraine,
  • Yu. Yu. Riabokon Zaporizhzhia State Medical University, Ukraine,
  • O. V. Riabokon Zaporizhzhia State Medical University, Ukraine,

DOI:

https://doi.org/10.14739/2310-1237.2019.1.166189

Keywords:

chronic hepatitis C, mixed cryoglobulinemia, interleukin-6, genetic polymorphism

Abstract

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

Downloads

How to Cite

1.
Kalashnyk KV, Riabokon YY, Riabokon OV. 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. Pathologia [Internet]. 2019May13 [cited 2024Nov.13];(1). Available from: http://pat.zsmu.edu.ua/article/view/166189

Issue

Section

Original research