Induction of Systemic Lupus Erythematosus-like Syndrome in BALB/c Mice Leads to Disturbance in Splenic T Cell Subpopulations
-
Parisa Rahimzadeh
,
Sahar Mortezagholi
,
Mojgan Ghayedi
,
Haideh Namdari
,
Mitra Rahimzadeh
,
Roobina Boghozian
,
Maryam Azimi
,
Eisa Salehi
Abstract
Mechanisms underlying the systemic lupus erythematosus (SLE) have not yet been elucidated. In this study, we evaluated the balance of T cell subsets in BALB/c mice model of SLE induced; using Con A and polyamines as DNA immunogenicity modifiers.
BALB/c mice were immunized subcutaneously with 50 µg extracted DNA from cells cultured in different conditions: splenocytes+ polyamines (group P), splenocytes+ Con A (group A), splenocytes+ polyamines+ Con A (group PA) and splenocytes only (control). Anti-double-stranded DNA –(ds-DNA) antibodies, proteinuria, and antinuclear autoantibodies were assessed by enzyme-linked immunosorbent assay, Bradford method, and immunofluorescence respectively. Transcription factors of different T helper subsets were examined by real-time polymerase chain reaction.
The serum level of the anti-dsDNA antibody in group PA was higher than that in the other groups (p>0.05). Antinuclear antibody (ANA) titer increased in groups A and PA. Proteinuria level in group PA was significantly higher than that in the control group (p<0.001). Expression of Foxp3 was decreased in group A (p=0.001). Additionally, the ratios of T-bet/GATA3 and T-bet/Foxp3 were also increased in group A. (p>0.05).
Our results revealed an increased ratio of Th1 to Th2 and decreased expression of Foxp3 in group A, but group PA manifested more obvious signs of the disease. These results suggest that other mechanisms rather than disturbance in T cells' balance may involve the development of disease symptoms.
1. Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus. J Clin Pathol. 2003;56(7):481-90.
2. Su KY, Pisetsky DS. The Role of Extracellular DNA in Autoimmunity in SLE. Scand J Immunol. 2009;70(3):175-83.
3. Herrmann M, Voll RE, Kalden JR. Etiopathogenesis of systemic lupus erythematosus. Immunology today. 2000;21(9):424-6.
4. Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610-5.
5. Chan R-Y, Lai F-M, Li E-M, Tam L-S, Chow K-M, Li P-T, et al. Imbalance of Th1/Th2 transcription factors in patients with lupus nephritis. Rheumatology. 2006;45(8):951-7.
6. Liphaus BL, Kiss MHB. The role of apoptosis proteins and complement components in the etiopathogenesis of systemic lupus erythematosus. Clinics. 2010;65(3):327-33.
7. Ploskonos M, Nikolaev A. Polyamine effect on human peripheral blood lymphocyte apoptosis in vitro. GEMATOL TRANSFUZIOL. 2010;55(4):16-9.
8. Hasan R, Moinuddin, Alam K, Ali R. Polyamine Induced Z-Conformation of Native Calf Thymus DNA. FEBS Lett. 1995;368(1):27-30.
9. Thomas TJ, Thomas T. Polyamine-Induced Z-DNA Conformation in Plasmids Containing (Da-Dc)(N)Center-Dot(Dg-Dt)(N) Inserts and Increased Binding of Lupus Autoantibodies to the Z-DNA Form of Plasmids. Biochem J. 1994;298:485-91.
10. Sciascia SA, Robson K, Zhu L, Garland M. Immunization of nonautoimmune mice with DNA binding domains of the largest subunit of RNA polymerase I results in production of anti-dsDNA and anti-Sm/RNP antibodies. Autoimmunity. 2007;40(1):38-47.
11. Li L, Nukala S, Du Y, Han J, Liu K, Hutcheson J, et al. Murine lupus strains differentially model unique facets of human lupus serology. Clinical and Experimental Immunology.168(2):178-85.
12. Pignatti C, Tantini B, Stefanelli C, Flamigni F. Signal transduction pathways linking polyamines to apoptosis. J Amino Acids. 2004;27(3-4):359-65.
13. Li H, Zhang YY, Sun YN, Huang XY, Jia YF, Li D. Induction of systemic lupus erythematosus syndrome in BALB/c mice by immunization with active chromatin. Acta Pharmacol Sin. 2004;25(6):807-11.
14. Vilar MP, Sato E. Estimating the incidence of systemic lupus erythematosus in a tropical region (Natal, Brazil). Lupus. 2002;11(8):528-32.
15. Lorenz HM, Herrmann M, Winkler T, Kaden JR. Pathogenesis of Systemic Lupus Erythematosus. Aktuelle Rheumatol. 2006;31(1):48-55.
16. Scheinecker C, Bonelli M, Smolen JS. Pathogenetic aspects of systemic lupus erythematosus with an emphasis on regulatory T cells. J Autoimmun. 2010;35(3):269-75.
17. Munoz L, Lauber K, Schiller M, Manfredi A, Schett G, Voll R, et al. [The role of incomplete clearance of apoptotic cells in the etiology and pathogenesis of SLE]. Z Rheumatol. 2010;69(2):152, 4-6.
18. Munoz L, Gaipl U, Franz S, Sheriff A, Voll R, Kalden J, et al. SLE—a disease of clearance deficiency? Rheumatology. 2005;44(9):1101-7.
19. Drake CG, Rozzo SJ, Vyse TJ, Palmer E, Kotzin BL. Genetic Contributions to Lupus-Like Disease in (Nzbxnzw)F-1 Mice. Immunol Rev. 1995;144:51-74.
20. Handwerger BS, Storrer CE, Wasson CS, Movafagh F, Reichlin M. Further characterization of the autoantibody response of Palmerston North mice. J Allergy Clin Immunol. 1999;19(1):45-57.
21. Pathak S, Mohan C. Cellular and molecular pathogenesis of systemic lupus erythematosus: lessons from animal models. Arthritis Res Ther. 2011;13(5):241.
22. Rottman J, Willis C. Mouse models of systemic lupus erythematosus reveal a complex pathogenesis. Veterinary Pathology Online. 2010;47(4):664-76.
23. Khalil M, Inaba K, Steinman R, Ravetch J, Diamond B. T cell studies in a peptide-induced model of systemic lupus erythematosus. J Immunol. 2001;166(3):1667-74.
24. Voynova E, Tchorbanov A, Todorov T, Vassilev T. Breaking of tolerance to native DNA in nonautoimmune mice by immunization with natural protein/DNA complexes. Lupus. 2005;14(7):543-50.
25. Brooks WH. Polyamine involvement in the cell cycle, apoptosis, and autoimmunity. Med Hypotheses. 1995;44(5):331-8.
26. Satoh M, Reeves WH. Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection of pristane. J Exp Med. 1994;180(6):2341-6.
27. Wen ZK, Xu W, Xu L, Cao QH, Wang Y, Chu YW, et al. DNA hypomethylation is crucial for apoptotic DNA to induce systemic lupus erythematosus-like autoimmune disease in SLE-non-susceptible mice. Rheumatology. 2007;46(12):1796-803.
28. Brooks W. Autoimmune Diseases and Polyamines. Clinic Rev Allerg Immunol. 2012;42(1):58-70.
29. Brooks WH. Systemic lupus erythematosus and related autoimmune diseases are antigen-driven, epigenetic diseases. Med Hypotheses. 2002;59(6):736-41.
30. Akahoshi M, Nakashima H, Tanaka Y, Kohsaka T, Nagano S, Ohgami E, et al. Th1/Th2 balance of peripheral T helper cells in systemic lupus erythematosus. Arthritis and Rheumatism. 1999;42(8):1644-8.
31. Barreto M, Ferreira RC, Lourenço L, Moraes-Fontes MF, Santos E, Alves M, et al. Low frequency of CD4+ CD25+ Treg in SLE patients: a heritable trait associated with CTLA4 and TGFβ gene variants. BMC Immunol. 2009;10(1):5.
32. Garrett-Sinha LA, John S, Gaffen SL. IL-17 and the Th17 lineage in systemic lupus erythematosus. Curr Opin Rheumatol. 2008;20(5):519-25.
33. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6(11):1123-32.
34. Kleczynska W, Jakiela B, Plutecka H, Milewski M, Sanak M, Musial J. Imbalance between Th17 and regulatory T-cells in systemic lupus erythematosus. Folia Histochem Cytobiol. 2011;49(4):646-53.
35. Kurasawa K, Hirose K, Sano H, Endo H, Shinkai H, Nawata Y, et al. Increased interleukin‐17 production in patients with systemic sclerosis. Arthritis Rheum. 2000;43(11):2455-63.
36. La Cava A. T-regulatory cells in systemic lupus erythematosus. Lupus. 2008;17(5):421-5.
37. Lee JH, Wang LC, Lin YT, Yang YH, Lin DT, Chiang BL. Inverse correlation between CD4+ regulatory T‐cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus. Immunology. 2006;117(2):280-6.
38. Nalbandian A, Crispin J, Tsokos G. Interleukin‐17 and systemic lupus erythematosus: current concepts. Clin Exp Immunol. 2009;157(2):209-15.
39. Viallard J, Pellegrin J, Ranchin V, Schaeverbeke T, Dehais J, Longy-Boursier M, et al. Th1 (IL-2, interferon-gamma (IFN)) and Th2 (IL-10, IL-4) cytokine production by peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus (SLE). Clin Exp Immunol. 1999;115:189-95.
40. Wong CK, Lit LCW, Tam LS, Li EKM, Wong PTY, Lam CWK. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: Implications for Th17-mediated inflammation in auto-immunity. Clin Immunol. 2008;127(3):385-93.
41. Zhao X-F, Pan H-F, Yuan H, Zhang W-H, Li X-P, Wang G-H, et al. Increased serum interleukin 17 in patients with systemic lupus erythematosus. Mol Biol Rep. 2010;37(1):81-5.
42. Xing Q, Su H, Cui J, Wang B. Role of Treg cells and TGF-β1 in patients with systemic lupus erythematosus: a possible relation with lupus nephritis. Immunol Invest. 2012;41(1):15-27.
43. Ngalamika O, Liang G, Zhao M, Yu X, Yang Y, Yin H, et al. Peripheral whole blood FOXP3 TSDR methylation: a potential marker in severity assessment of autoimmune diseases and chronic infections. Immunol Invest. 2015;44(2):126-36.
44. Chavele K-M, Ehrenstein MR. Regulatory T-cells in systemic lupus erythematosus and rheumatoid arthritis. FEBS Lett. 2011;585(23):3603-10.
45. Tshilela KA, Ikeuchi H, Matsumoto T, Kuroiwa T, Sakurai N, Sakairi T, et al. Glomerular cytokine expression in murine lupus nephritis. Clin Exp Nephrol. 2016;20(1):23-9.
46. Talaat RM, Mohamed SF, Bassyouni IH, Raouf AA. Th1/Th2/Th17/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: Correlation with disease activity. Cytokine. 2015;72(2):146-53.
2. Su KY, Pisetsky DS. The Role of Extracellular DNA in Autoimmunity in SLE. Scand J Immunol. 2009;70(3):175-83.
3. Herrmann M, Voll RE, Kalden JR. Etiopathogenesis of systemic lupus erythematosus. Immunology today. 2000;21(9):424-6.
4. Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610-5.
5. Chan R-Y, Lai F-M, Li E-M, Tam L-S, Chow K-M, Li P-T, et al. Imbalance of Th1/Th2 transcription factors in patients with lupus nephritis. Rheumatology. 2006;45(8):951-7.
6. Liphaus BL, Kiss MHB. The role of apoptosis proteins and complement components in the etiopathogenesis of systemic lupus erythematosus. Clinics. 2010;65(3):327-33.
7. Ploskonos M, Nikolaev A. Polyamine effect on human peripheral blood lymphocyte apoptosis in vitro. GEMATOL TRANSFUZIOL. 2010;55(4):16-9.
8. Hasan R, Moinuddin, Alam K, Ali R. Polyamine Induced Z-Conformation of Native Calf Thymus DNA. FEBS Lett. 1995;368(1):27-30.
9. Thomas TJ, Thomas T. Polyamine-Induced Z-DNA Conformation in Plasmids Containing (Da-Dc)(N)Center-Dot(Dg-Dt)(N) Inserts and Increased Binding of Lupus Autoantibodies to the Z-DNA Form of Plasmids. Biochem J. 1994;298:485-91.
10. Sciascia SA, Robson K, Zhu L, Garland M. Immunization of nonautoimmune mice with DNA binding domains of the largest subunit of RNA polymerase I results in production of anti-dsDNA and anti-Sm/RNP antibodies. Autoimmunity. 2007;40(1):38-47.
11. Li L, Nukala S, Du Y, Han J, Liu K, Hutcheson J, et al. Murine lupus strains differentially model unique facets of human lupus serology. Clinical and Experimental Immunology.168(2):178-85.
12. Pignatti C, Tantini B, Stefanelli C, Flamigni F. Signal transduction pathways linking polyamines to apoptosis. J Amino Acids. 2004;27(3-4):359-65.
13. Li H, Zhang YY, Sun YN, Huang XY, Jia YF, Li D. Induction of systemic lupus erythematosus syndrome in BALB/c mice by immunization with active chromatin. Acta Pharmacol Sin. 2004;25(6):807-11.
14. Vilar MP, Sato E. Estimating the incidence of systemic lupus erythematosus in a tropical region (Natal, Brazil). Lupus. 2002;11(8):528-32.
15. Lorenz HM, Herrmann M, Winkler T, Kaden JR. Pathogenesis of Systemic Lupus Erythematosus. Aktuelle Rheumatol. 2006;31(1):48-55.
16. Scheinecker C, Bonelli M, Smolen JS. Pathogenetic aspects of systemic lupus erythematosus with an emphasis on regulatory T cells. J Autoimmun. 2010;35(3):269-75.
17. Munoz L, Lauber K, Schiller M, Manfredi A, Schett G, Voll R, et al. [The role of incomplete clearance of apoptotic cells in the etiology and pathogenesis of SLE]. Z Rheumatol. 2010;69(2):152, 4-6.
18. Munoz L, Gaipl U, Franz S, Sheriff A, Voll R, Kalden J, et al. SLE—a disease of clearance deficiency? Rheumatology. 2005;44(9):1101-7.
19. Drake CG, Rozzo SJ, Vyse TJ, Palmer E, Kotzin BL. Genetic Contributions to Lupus-Like Disease in (Nzbxnzw)F-1 Mice. Immunol Rev. 1995;144:51-74.
20. Handwerger BS, Storrer CE, Wasson CS, Movafagh F, Reichlin M. Further characterization of the autoantibody response of Palmerston North mice. J Allergy Clin Immunol. 1999;19(1):45-57.
21. Pathak S, Mohan C. Cellular and molecular pathogenesis of systemic lupus erythematosus: lessons from animal models. Arthritis Res Ther. 2011;13(5):241.
22. Rottman J, Willis C. Mouse models of systemic lupus erythematosus reveal a complex pathogenesis. Veterinary Pathology Online. 2010;47(4):664-76.
23. Khalil M, Inaba K, Steinman R, Ravetch J, Diamond B. T cell studies in a peptide-induced model of systemic lupus erythematosus. J Immunol. 2001;166(3):1667-74.
24. Voynova E, Tchorbanov A, Todorov T, Vassilev T. Breaking of tolerance to native DNA in nonautoimmune mice by immunization with natural protein/DNA complexes. Lupus. 2005;14(7):543-50.
25. Brooks WH. Polyamine involvement in the cell cycle, apoptosis, and autoimmunity. Med Hypotheses. 1995;44(5):331-8.
26. Satoh M, Reeves WH. Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection of pristane. J Exp Med. 1994;180(6):2341-6.
27. Wen ZK, Xu W, Xu L, Cao QH, Wang Y, Chu YW, et al. DNA hypomethylation is crucial for apoptotic DNA to induce systemic lupus erythematosus-like autoimmune disease in SLE-non-susceptible mice. Rheumatology. 2007;46(12):1796-803.
28. Brooks W. Autoimmune Diseases and Polyamines. Clinic Rev Allerg Immunol. 2012;42(1):58-70.
29. Brooks WH. Systemic lupus erythematosus and related autoimmune diseases are antigen-driven, epigenetic diseases. Med Hypotheses. 2002;59(6):736-41.
30. Akahoshi M, Nakashima H, Tanaka Y, Kohsaka T, Nagano S, Ohgami E, et al. Th1/Th2 balance of peripheral T helper cells in systemic lupus erythematosus. Arthritis and Rheumatism. 1999;42(8):1644-8.
31. Barreto M, Ferreira RC, Lourenço L, Moraes-Fontes MF, Santos E, Alves M, et al. Low frequency of CD4+ CD25+ Treg in SLE patients: a heritable trait associated with CTLA4 and TGFβ gene variants. BMC Immunol. 2009;10(1):5.
32. Garrett-Sinha LA, John S, Gaffen SL. IL-17 and the Th17 lineage in systemic lupus erythematosus. Curr Opin Rheumatol. 2008;20(5):519-25.
33. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6(11):1123-32.
34. Kleczynska W, Jakiela B, Plutecka H, Milewski M, Sanak M, Musial J. Imbalance between Th17 and regulatory T-cells in systemic lupus erythematosus. Folia Histochem Cytobiol. 2011;49(4):646-53.
35. Kurasawa K, Hirose K, Sano H, Endo H, Shinkai H, Nawata Y, et al. Increased interleukin‐17 production in patients with systemic sclerosis. Arthritis Rheum. 2000;43(11):2455-63.
36. La Cava A. T-regulatory cells in systemic lupus erythematosus. Lupus. 2008;17(5):421-5.
37. Lee JH, Wang LC, Lin YT, Yang YH, Lin DT, Chiang BL. Inverse correlation between CD4+ regulatory T‐cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus. Immunology. 2006;117(2):280-6.
38. Nalbandian A, Crispin J, Tsokos G. Interleukin‐17 and systemic lupus erythematosus: current concepts. Clin Exp Immunol. 2009;157(2):209-15.
39. Viallard J, Pellegrin J, Ranchin V, Schaeverbeke T, Dehais J, Longy-Boursier M, et al. Th1 (IL-2, interferon-gamma (IFN)) and Th2 (IL-10, IL-4) cytokine production by peripheral blood mononuclear cells (PBMC) from patients with systemic lupus erythematosus (SLE). Clin Exp Immunol. 1999;115:189-95.
40. Wong CK, Lit LCW, Tam LS, Li EKM, Wong PTY, Lam CWK. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: Implications for Th17-mediated inflammation in auto-immunity. Clin Immunol. 2008;127(3):385-93.
41. Zhao X-F, Pan H-F, Yuan H, Zhang W-H, Li X-P, Wang G-H, et al. Increased serum interleukin 17 in patients with systemic lupus erythematosus. Mol Biol Rep. 2010;37(1):81-5.
42. Xing Q, Su H, Cui J, Wang B. Role of Treg cells and TGF-β1 in patients with systemic lupus erythematosus: a possible relation with lupus nephritis. Immunol Invest. 2012;41(1):15-27.
43. Ngalamika O, Liang G, Zhao M, Yu X, Yang Y, Yin H, et al. Peripheral whole blood FOXP3 TSDR methylation: a potential marker in severity assessment of autoimmune diseases and chronic infections. Immunol Invest. 2015;44(2):126-36.
44. Chavele K-M, Ehrenstein MR. Regulatory T-cells in systemic lupus erythematosus and rheumatoid arthritis. FEBS Lett. 2011;585(23):3603-10.
45. Tshilela KA, Ikeuchi H, Matsumoto T, Kuroiwa T, Sakurai N, Sakairi T, et al. Glomerular cytokine expression in murine lupus nephritis. Clin Exp Nephrol. 2016;20(1):23-9.
46. Talaat RM, Mohamed SF, Bassyouni IH, Raouf AA. Th1/Th2/Th17/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: Correlation with disease activity. Cytokine. 2015;72(2):146-53.
| Files | ||
| Issue | Vol 20 No 5 (2021) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v20i5.7408 | |
| Keywords | ||
| Animal models Regulatory T-lymphocytes Systemic lupus erythematosus Th1 cells Th2 cells Th17 cells | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Rahimzadeh P, Mortezagholi S, Ghayedi M, Namdari H, Rahimzadeh M, Boghozian R, Azimi M, Salehi E. Induction of Systemic Lupus Erythematosus-like Syndrome in BALB/c Mice Leads to Disturbance in Splenic T Cell Subpopulations. Iran J Allergy Asthma Immunol. 2021;20(5):584-592.
