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IL-4, IL-10 and TNF-α Polymorphisms in Idiopathic Membranous Nephropathy (IMN)

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DOI: 10.4236/oji.2015.55019    3,722 Downloads   4,230 Views   Citations

ABSTRACT

Idiopathic membranous nephropathy (IMN) is a Th2 nephritogenic immune disorder. It is caused by the accumulation of immune complexes, mainly IgG4, at the basal glomerular membrane that leads to the damage of the glomerular barrier and subsequent injury of podocytes. Our aim was to evaluate the relationship between cytokine polymorphisms and IMN. We investigated the cytokine polymorphisms in forty-five patients and one hundred twenty-four healthy individuals, using polymerase chain reaction-sequence specific primers (PCR-SSP). We showed a significant increase in allelic frequencies of the alleles -590T and -33T of IL-4 gene and -308A of TNF-α gene, in IMN patients. In addition, we observed an increased frequency of allele -1082G in IL-10 gene in a subgroup of patients with CD4/CD8 ratio major than 2, when compared either to control subjects or the subgroup of patients with CD4/CD8 ratio minor than 2. Moreover, analyzing the Th1/Th2 cytokines in serum and urine, we found increased levels of IL-4 in serum and IL-5 in urine of patients. We deduce that the alleles -590T and -33T of IL-4 and -308A of TNF-α may be associated with IMN. In addition, in patients with increased T helper lymphocytes, IL-10 -1082G polymorphism can also play a role in the pathogenesis of the disease. These findings remark the role of Th2 immune response and suggest the association between polymorphic variants of IL-4, IL-10 and TNF-α genes with the development of IMN and therefore giving a better insight in pathogenesis of this disease.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Giacomelli, M. , Kumar, R. , Tampella, G. , Ceffa, S. and Bontempelli, M. (2015) IL-4, IL-10 and TNF-α Polymorphisms in Idiopathic Membranous Nephropathy (IMN). Open Journal of Immunology, 5, 233-243. doi: 10.4236/oji.2015.55019.

References

[1] Nangaku, M., Shankland, S.J. and Couser, W.G. (2005) Cellular Response to Injury in Membranous Nephropathy. Journal of the American Society of Nephrology, 16, 1-9.
http://dx.doi.org/10.1681/ASN.2004121098
[2] Imai, H., Hamai, K., Komatsuda, A., Ohtani, H. and Miura, A.B. (1997) IgG Subclasses in Patients with Membranoproliferative Glomerulonephritis, Membranous Nephrophaty, and Lupus Nephritis. Kidney International, 51, 270-276. http://dx.doi.org/10.1038/ki.1997.32
[3] Kuroki, A., Shibata, T., Honda, H., Totsuka, D., Kobayashi, K. and Sugisaki, T. (2002) Glomerular and Serum IgG Subclasses in Diffuse Proliferative Lupus Nephritis, Membranous Lupus Nephritis, and Idiophatic Membranous Nephrophaty. Internal Medicine, 41, 936-942.
http://dx.doi.org/10.2169/internalmedicine.41.936
[4] Ohtani, H., Wakui, H., Komatsuda, A., Okuyama, S., Masai, R., Maki, N., Kigawa, A., Sawada, K. and Imai, H. (2004) Distribution of Glomerular IgG Sublcass Deposits in Malignancy-Associated Membranous Nephropathy. Nephrology Dialysis Transplantation, 19, 574-579. http://dx.doi.org/10.1093/ndt/gfg616
[5] Aalberse, R.C., Van der Gaag, R. and Van Leeuwen, J. (1983) Serologic Aspects of IgG4 Antibodies. I. Prolonged Immunization Results in an IgG4 Restricted Response. The Journal of Immunology, 130, 722-726.
[6] Iskander, R., Das, P.K. and Aalberse, R.C. (1981) IgG4 Antibodies in Egyptian Patients with Schistosomiasis. 'International Archives of Allergy and Immunology, 66, 200-207.
http://dx.doi.org/10.1159/000232819
[7] Doi, T., Kanatsu, K., Mayumi, M., Hamashima, Y. and Yoshida, H. (1991) Analysis of IgG Immune Complexes in Sera from Patients with Membranous Nephropathy: Role of IgG4 Subclass and Low-Avidity Antibodies. Nephron, 57, 131-136. http://dx.doi.org/10.1159/000186239
[8] van de Zee, J.S., van Swieten, P. and Aalberse, R.C. (1986) Serologic Aspects of IgG4 Antibodies. II. IgG4 Antibodies Form Small, Nonprecipitating Immune Complexes Due to Functional Monovalency. The Journal of Immunology, 137, 3566-3571.
[9] Masutani, K., Taniguchi, M., Nakashima, H., Yotsueda, H., Kudoh, Y., Tsuruya, K., Tokumoto, M., Fukuda, K., Kanai, H., Hirakata, H. and Iida, M. (2004) Up-Regulated Interleukin-4 Production by Peripheral T-Helper Cells in Idiopathic Membranous Nephrophaty. Nephrology Dialysis Transplantation, 19, 580-586. http://dx.doi.org/10.1093/ndt/gfg572
[10] Kuroki, A., Iyoda, M., Shibata, T. and Sugisaki, T. (2005) Th2 Cytokines Increase and Stimulate B Cells to Produce IgG4 in Idiopathic Membranous Nephropathy. Kidney International, 68, 302-310.
http://dx.doi.org/10.1111/j.1523-1755.2005.00415.x
[11] Jeannin, P., Lecoanet, S., Delneste, Y., Gauchat, J.F. and Bonnefoy, J.Y. (1998) IgE versus IgG4 Production Can Be Differentially Regulated by IL-10. Journal of Immunology, 160, 3555-3561.
[12] de Vries, J.E., Punnonen, J., Cocks, B.G. and Aversa, G. (1993) The Role of T/B Cell Interactions and Cytokines in the Regulation of Human IgE Synthesis. Seminars in Immunology, 5, 431-439.
http://dx.doi.org/10.1006/smim.1993.1049
[13] Lecart, S., Morel, F., Noraz, N., Pène, J., Garcia, M., Boniface, K., Lecron, J.C. and Yssel, H. (2002) IL-22, in Contrast to IL-10, Does Not Induce Ig Production, Due to Absence of a Functional IL-22 Receptor on Activated Human B Cells. International Immunology, 14, 1351-1356.
http://dx.doi.org/10.1093/intimm/dxf096
[14] Acharya, B., Shirakawa, T. and Gotoh, A. (2005) Polymorphism of the Interleukin-4, Interleukin-13, and Signal Trasducer and Activator of Transcription 6 Genes in Indonesian Children with Minimal Change Nephrotic Syndrome. American Journal of Nephrology, 25, 30-35. http://dx.doi.org/10.1159/000083729
[15] Ikeuchi, Y., Kobayashi, Y., Arakawa, H., Suzuki, M., Tamra, K. and Morikawa, A. (2009) Polymorphisms in Interleukin-4-Related Genes in Patients with Minimal Change Nephrotic Syndrome. Pediatric Nephrology, 24, 489-495. http://dx.doi.org/10.1007/s00467-008-1003-y
[16] Cohen, C.D., Calvaresi, N. and Kretzler, M. (2005) CD20-Positive Infiltrates in Human Membranous Glomerulonephritis. Journal of Nephrology, 18, 328-333.
[17] Ruggenenti, P., Chiurchiu, C., Abbate, M., Perna, A., Cravedi, P., Bontempelli, M. and Remuzzi, G. (2006) Rituximab for Idiopathic Membranous Nephropathy: Who Can Benefit? Clinical Journal of the American Society of Nephrology, 1, 738-748. http://dx.doi.org/10.2215/CJN.01080905
[18] Remuzzi, G., Chiurchiu, C., Abbate, M., Brusegan, V., Bontempelli, M. and Ruggenenti, P. (2002) Rituximab for Idiopathic Membranous Nephropathy. The Lancet, 360, 923-924.
http://dx.doi.org/10.1016/S0140-6736(02)11042-7
[19] Kawashima, T., Noguchi, E., Arinami, T., Yamakawa-Kobayashi, K., Nakagawa, H., Otsuka, F. and Hamaguchi, H. (1998) Linkage and Association of an Interleukin-4 Gene Polymorphism with Atopic Dermatitis in Japanese Families. Journal of Medical Genetics, 35, 502-504.
http://dx.doi.org/10.1136/jmg.35.6.502
[20] Turner, D.M., Williams, D.M., Sankaran, D., Lazarus, M., Sinnott, P.J. and Hutchinson, I.V. (1997) An Investigation of Polymorphism in the Interleukin-10 Gene Promoter. European Journal of Immunogenetics, 24, 1-8. http://dx.doi.org/10.1111/j.1365-2370.1997.tb00001.x
[21] Kim, J.M., Brannan, C.I., Copeland, N.G., Jenkins, N.A., Khan, T.A. and Moore, K.W. (1992) Structure of the Mouse IL-10 Gene and Chromosomal Localization of the Mouse and Human Genes. Journal of Immunology, 148, 3618-3623.
[22] Louis, E., Franchimont, D., Piron, A., Gevaert, Y., Schaaf-Lafontaine, N., Roland, S., Mahieu, P., Malaise, M., De Groote, D., Louis, R. and Belaiche, J. (1998) Tumour Necrosis Factor (TNF) Gene Polymorphism Influences TNF-α Production in Lipopolysaccharide (LPS)-Stimulated Whole Blood Cell Culture in Healthy Humans. Clinical and Ex- perimental Immunology, 113, 401-406.
http://dx.doi.org/10.1046/j.1365-2249.1998.00662.x
[23] Wilson, A.G., Symons, J.A., McDowell, T.L., McDevitt, H.O. and Duff, G.W. (1997) Effects of a Polymorphisms in the Human Tumour Necrosis Factor α Promoter on Transcriptional Activation. Proceedings of the National Academy of Sciences of the United States of America, 94, 3195-3199. http://dx.doi.org/10.1073/pnas.94.7.3195
[24] Chen, S.Y., Chen, C.H., Huang, Y.C., Chuang, H.M., Lo, M.M. and Tsai, F.J. (2010) Effect of IL-6 C-572G Polymorphism on Idiopathic Membranous Nephropathy Risk in a Han Chinese Population. Renal Failure, 32, 1172-1176. http://dx.doi.org/10.3109/0886022X.2010.516857
[25] Thibaudin, D., Thibaudin, L., Berthoux, P., Mariat, C., Filippis, J.P., Laurent, B., Alamartine, E. and Berthoux, F. (2007) TNFA2 and D2 Alleles of the Tumor Necrosis Factor Alpha Gene Polymorphism Are Associated with Onset/ Occurrence of Idiopathic Membranous Nephropathy. Kidney International, 71, 431-437. http://dx.doi.org/10.1038/sj.ki.5002054
[26] Bantis, C., Heering, P.J., Aker, S., Siekierka, M., Kuhr, N., Grabensee, B. and Ivens, K. (2006) Tumor Necrosis Factor-α Gene G-308A Polymorphism Is a Risk Factor for the Development of Membranous Glomerulonephritis. American Journal of Nephrology, 26, 12-15. http://dx.doi.org/10.1159/000090706
[27] Ricciardolo, F.L., Sorbello, V., Silvestri, M., Giacomelli, M., Debenedetti, V.M., Malerba, M., Ciprandi, G., Rossi, G.A., Rossi, A. and Bontempelli, M. (2013) TNF-α, IL-4R-α and IL-4 Polymorphisms in Mild to Severe Asthma from Italian Caucasians. International Journal of Immunopathology and Pharmacology, 26, 75-84.
[28] Ozaki, T., Tomino, Y., Nakayama, S. and Koide, H. (1992) Two-Color Analysis of Lymphocyte Subpopulations in Patients with Nephrotic Syndrome Due to Membranous Nephropathy. Clinical Nephrology, 38, 75-80.
[29] Zucchelli, P., Ponticelli, C., Cagnoli, L., Aroldi, A. and Beltrandi, E. (1988) Prognostic Value of T Lymphocyte Subset Ratio in Idiopathic Membranous Nephropathy. American Journal of Nephrology, 8, 15-20. http://dx.doi.org/10.1159/000167547
[30] Cagnoli, L., Tabacchi, P., Pasquali, S., Cenci, M., Sasdelli, M. and Zucchelli, P. (1982) T Cell Subset Alterations in Idiopathic Glomerulonephritis. Clinical & Experimental Immunology, 50, 70-76.
[31] Bannister, K.M., Drew, P.A., Clarkson, A.R. and Woodroffe, A.J. (1983) Immunoregulation in Glomerulonephritis, Henoch—Schonlein Purpura and Lupus Nephritis. Clinical & Experimental Immunology, 53, 384-390.
[32] Castro-Santos, P., Suarez, A., López-Rivas, L., Mozo, L. and Gutierrez, C. (2006) TNFα and IL-10 Gene Poly-mor- phisms in Inflammatory Bowel Disease. Association of - 1082 AA Low Producer IL-10 Genotype with Steroid Dependency TNFα and IL-10 Gene Polymorphisms in IBD. American Journal of Gastroenterology, 101, 1039-1047. http://dx.doi.org/10.1111/j.1572-0241.2006.00501.x
[33] Rianthavorn, P., Chokedeemeeboon, C., Deekajorndech, T. and Suphapeetiporn, K. (2013) Interleukin-10 Promoter Polymorphisms and Expression in Thai Children with Juvenile Systemic Lupus Erythematosus. Lupus, 22, 721-726. http://dx.doi.org/10.1177/0961203313486192
[34] Fiorentino, D.F., Zlotnik, A., Mosmann, T.R., Howard, M. and O’Garra, A. (1991) IL-10 Inhibits Cytokine Production by Activated Macrophages. Journal of Immunology, 147, 3815-3822.
[35] de Waal Malefyt, R., Abrams, J., Bennett, B., Figdor, C.G. and de Vries, J.E. (1991) Interleukin 10 (IL-10) Inhibits Cytokine Synthesis by Human Monocytes: An Autoregulatory Role of IL-10 Produced by Monocytes. Journal of Ex- perimental Medicine, 174, 1209-1220.
http://dx.doi.org/10.1084/jem.174.5.1209
[36] de Waal Malefyt, R., Haanen, J., Spits, H., Roncarolo, M.G., te Velde, A., Figdor, C., Johnson, K., Kastelein, R., Yssel, H. and de Vries, J.E. (1991) Interleukin 10 (IL-10) and Viral IL-10 Strongly Reduce Antigen-Specific Human T Cell Proliferation by Diminishing the Antigen-Presenting Capacity of Monocytes via Downregulation of Class II Major Histocompatibility Complex Expression. Journal of Experimental Medicine, 174, 915-924. http://dx.doi.org/10.1084/jem.174.4.915
[37] Neale, T.J., Rüger, B.M., Macaulay, H., Dunbar, P.R., Hasan, Q., Bourke, A., Murray-McIntosh, R.P. and Kitching, A.R. (1995) Tumor Necrosis Factor-α Is Expressed by Glomerular Visceral Epithelial Cells in Human Membranous Nephropathy. American Journal of Pathology, 146, 1444-1454.
[38] Niemir, Z.I., Ondracek, M., Dworacki, G., Stein, H., Waldherr, R., Ritz, E. and Otto, H.F. (1998) In Situ Upregulation of IL-10 Reflects the Activity of Human Glomerulonephritides. American Journal of Kidney Diseases, 32, 80-92. http://dx.doi.org/10.1053/ajkd.1998.v32.pm9669428
[39] Ifuku, M., Miyake, K., Watanebe, M., Ito, K., Abe, Y., Sasatomi, Y., Ogahara, S., Hisano, S., Sato, H., Saito, T. and Nakashima, H. (2013) Various Roles of Th Cytokine mRNA Expression in Different Forms of Glomerulonephritis. American Journal of Nephrology, 38, 115-123. http://dx.doi.org/10.1159/000353102
[40] Honkanen, E., von Willebrand, E., Teppo, A.M., Törnroth, T. and Grönhagen-Riska, C. (1998) Adhesion Molecules and Urinary Tumor Necrosis Factor-α in Idiopathic Membranous Glomerulonephritis. Kidney International, 53, 909- 917. http://dx.doi.org/10.1111/j.1523-1755.1998.00833.x
[41] Kshirsagar, A.V., Nachman, P.H. and Falk, R.J. (2003) Alternative Therapies and Future Intervention for Treatment of Membranous Nephropathy. Seminars in Nephrology, 23, 362-372.
http://dx.doi.org/10.1016/S0270-9295(03)00047-0
[42] Wu, T.H., Tsai, C.Y. and Yang, W.C. (1998) Excessive Expression of the Tumor Necrosis Factor-α Gene in the Kidneys of Patients with Membranous Glomerulonephritis. Chinese Medical Journal (Taipei), 61, 524-530.
[43] Tabibzadeh, S., Kong, Q.F., Kapur, S., Leffers, H., Ridley, A., Aktories, K. and Celis, J.E. (1995) TNF-α Induces Dyscohesion of Epithelial Cells. Association with Disassembly of Actin Filaments. Endocrine, 3, 549-556. http://dx.doi.org/10.1007/BF02953018
[44] Wilson, A.G., de Vries, N., Pociot, F., di Giovine, F.S., van der Putte, L.B. and Duff, G.W. (1993) An Allelic Poly-morphism within the Human Tumor Necrosis Factor Alpha Promoter Region Is Strongly Associated with HLA A1, B8, and DR3 Alleles. Journal of Experimental Medicine, 177, 557-560.
http://dx.doi.org/10.1084/jem.177.2.557
[45] Reichert, L.J., Koene, R.A. and Wetzels, J.F. (1998) Prognostic Factors in Idiopathic Membranous Nephropathy. American Journal of Kidney Diseases, 31, 1-11.
http://dx.doi.org/10.1053/ajkd.1998.v31.pm9428445
[46] Farid, T.M., Abd El Baky, A.M., Khalefa, E.S., Talaat, A.A., Mohamed, A.A., Gheita, T.A. and Abdel-Salam, R.F. (2011) Association of Tumor Necrosis Factor-α Gene Polymorphisms with Juvenile Systemic Lupus Erythematosus Nephritis in a Cohort of Egyptian Patients. Iranian Journal of Kidney Diseases, 5, 392-397.
[47] Tomizawa, S., Maruyama, K., Nagasawa, N., Suzuki, S. and Kuroume, T. (1985) Studies on Vascular Permeability Factor Derived from T Lymphocytes and Inhibitory Effect of Plasma on Its Production in Minimal Change Nephrotic Syndrome. Nephron, 41, 157-160. http://dx.doi.org/10.1159/000183572
[48] Cho, B.S., Yoon, S.R., Jang, J.Y., Pyun, K.H. and Lee, C.E. (1999) Up-Regulation of Interleukin-4 and CD23/ FcepsilonRII in Minimal Change Nephrotic Syndrome. Pediatric Nephrology, 13, 199-204. http://dx.doi.org/10.1007/s004670050592
[49] Neuhaus, T.J., Shah, V., Callard, R.E. and Barratt, T.M. (1995) T-Lymphocyte Activation in Steroid-Sensitive Nephrotic Syndrome in Childhood. Nephrology Dialysis Transplantation, 10, 1348-1352.
[50] Neuhaus, T.J., Wadhwa, M., Callard, R. and Barratt, T.M. (1995) Increased IL-2, IL-4 and Interferon-Gamma (IFN- Gamma) in Steroid-Sensitive Nephrotic Syndrome. Clinical & Experimental Immunology, 100, 475-479. http://dx.doi.org/10.1111/j.1365-2249.1995.tb03725.x
[51] Li, Z.P., Yin, L.L., Wang, H. and Liu, L.S. (2014) Association between Promoter Polymorphisms of Interleukin-4 Gene and Allergic Rhinitis Risk: A Meta-Analysis. Journal of Huazhong University of Science and Technology (Medical Sciences), 34, 306-313. http://dx.doi.org/10.1007/s11596-014-1275-3
[52] Amirzargar, A.A., Movahedi, M., Rezaei, N., Moradi, B., Dorkhosh, S., Mahloji, M. and Mahdaviani, S.A. (2009) Polymorphisms in IL4 and iLARA Confer Susceptibility to Asthma. Journal of Investigational Allergology and Clinical Immunology, 19, 433-438.
[53] Smolnikova, M.V., Smirnova, S.V., Freidin, M.B. and Tyutina, O.S. (2013) Immunological Parameters and Gene Polymorphisms (C-590T IL4, C-597A IL10) in Severe Bronchial Asthma in Children from the Krasnoyarsk Region, West Siberia. International Journal of Circumpolar Health, 72.
http://dx.doi.org/10.3402/ijch.v72i0.21159

  
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