Main Article Content

Authors

Introduction: Systemic Lupus Erythematosus (SLE), Scleroderma and late-onset arthritis are autoimmune inflammatory diseases (EIA) characterized by autoantibody production and presence of abnormal T cells which generate defective immune response. The abnormal expression of key signaling molecules in the defective function of T-lymphocytes plays a significant role in the pathogenesis of autoimmune disease. The T-cells exhibit numerous abnormalities TCRζ1 signaling complex, these aberrations result in altered expression of cytokines and some biochemical events involved in the expression of surface molecules. Defects in the complex may be associated TCRζ to steroids used in autoimmune disease patients due to their powerful anti-inflammatory activity and immunosuppressive properties. The synthetic corticosteroids such as examethasone inhibit the transcriptional activity of some factors such as NFKB and AP-1, which regulate the synthesis of certain cytokines and could be involved in the TCRζ synthesis. Material and Methods: A case-control study, with a 1:1 ratio of cases and controls (13:13). Cases were patients with active autoimmune disease (6 patients with SLE, 5 patients with scleroderma and 2 patients with lateonset arthritis), who have not started treatment with corticosteroids. Controls were patients with no autoimmune disease. The diagnosis was made by the criteria established by the American College of Rheumatology for patients with SLE, scleroderma and late-onset arthritis. A 10 mL sample was obtained by venipuncture whole blood. Total RNA was extracted and RT-PCR was performed using a set of primers flanking a region of 138 base pairs involving exons 2, 3 and 4 of the ζ chain. Results: The values of Z chain amplification showed significant differences in patients with autoimmune disease (0.8214 } 0.1787, med = 0.7368) compared with the control group (0.9225 } 0.1272, med = 0.9830) (p = 0.045, Mann-Withney non-parametric one tailed exact test). Conclusion: We observed a reduced level of in the zeta chain expression in T cells in patients with autoimmune disease without use of corticosteroids.

Heber Siachoque-Montañez

Coordinador de la Unidad de Inmunología, Facultad de Medicina, Universidad del Rosario, Bogotá D. C., Colombia.

Milcíades Ibáñez-Pinilla

Profesor titular, Facultad de Medicina, Universidad Nacional de Colombia.

Antonio Iglesias-Gamarra

Profesor titular, Facultad de Medicina, Universidad Nacional de Colombia.
Siachoque-Montañez, H., Ibáñez-Pinilla, M., & Iglesias-Gamarra, A. (2014). Defects in the Zeta Chain Expression (ζ) in a Group of Patients with SLE, Scleroderma and Late-onset Arthritis, Colombia 2014. Revista Ciencias De La Salud, 12(3), 303–318. https://doi.org/10.12804/revsalud12.03.2014.01

Juang CM, Hung CF,Yeh JY, Horng HC,Twu NF, Cheng MH, et al. Regulatory T cells: potential target

in anticancer immunotherapy. Taiwan J Obstet Gynecol. 2007; 46(3):215-21.

Akbari O, Stock P, DeKruyff R, Umetsu D. Role of regulatory T cells in allergy and asthma. Curr Opin

Immunol. 2003;15(6):627-33.

Siachoque H, Rondón F, Restrepo JF, Pérez R, Iglesias A. Defectos en la síntesis de cadena ζ en el linfocito

T, generando señales intracelulares equivocadas, responsables de lupus eritematoso sistémico.

Rev Colomb Reumatol. 2010; 17(4):219-30.

Tsokos CG, Liossis SN. Immune cell signaling defects in lupus: activation, anergy and death. Immunol.

Today. 1999; 20:119-24.

Jensen JP, HouD, Ramsburg M, Taylor A, Dean M, Weissman AM. Organization of the human T cell

receptor zeta/eta gene and its genetic linkage to the Fc gamma RII-Fc gamma RIII gene cluster. J Immunol.

; 148(8):2563-71.

Takeuchi T, TsuzakaK, Pang M, Amano K, Koide J, Abe T. TCR zeta chain lacking exon 7 in two patients

with systemic lupus erythematosus. IntImmunol.1998; 10(7):911-21.

Nambiar MP, Enyedy EJ, Fisher CU, Krishnan S, Warke VG, Guilliland WR, et al. Abnormal expression

of various molecular forms and distribution of T cell receptor zeta chain in patients with systemic

lupus erythematosus. Arthritis Rheum. 2002;46(1):163-74.

Vassilopoulos D, Kovacs B, Tsokos GC. TCR/CD3complex-mediated signal transduction pathway in T

cells and T cell lines from patients with systemic lupus erythematosus. J Immunol.1995;155(4):2269-81.

Krishnan S, Nambiar MP, Warke VG, Fisher CU, Mitchell J, Delaney N, et al. Alterations in lipid raft

composition and dynamics contribute to abnormal T cell responses in systemic lupus erythematosus.

JImmunol. 2004;172(12):7821-31.

Spies CM, Strehl C, Van der Goes MC, Bijlsma J, Buttgereit F. Glucocorticoids. Best Practice & Research

Clinical Rheumatology. 2011;25:891-900.

Hoffman GS. Immunosuppressive therapy for autoimmune diseases. Ann Allergy. 1993;70(4):263-74.

Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids,

recent developments and mechanistic insights. Mol Cell Endocrinol. 2011;335(1):2-13.

Clark AR. Anti-inflammatory functions of glucocorticoid-induced genes. Mol Cell Endocrinol.

;275(1-2):79-97.

Alessandri AL, Sousa LP, Lucas CD, Rossi AG, PinhoV. Teixeira M. Resolution of inflammation: mechanisms

and opportunity for drug development. Pharmacol Ther. 2013;139(2):189-212.

Nambiar MP, Enyedy EJ, Fisher CU, Warke VG, Juang Y, Tsokos GC. Dexamethasone modulates TCR

zeta chain expression and antigen receptor-mediated early signaling events in human T lymphocytes.

Cell Immunol. 2001;208(1):62-71.

Liberman AC, Druker J, Perone MJ, Arzt E. Glucocorticoids in the regulation of transcription factors

that control cytokine synthesis. Cytokine Growth Factor Rev 2007;18(1-2):45-56.

Flammer JR, Rogatsky I. Minireview: Glucocorticoids in autoimmunity: unexpected targets and

mechanisms. Mol Endocrinol. 2011;25(7):1075-86.

Fahey AJ, Robins RA, Kindle KB, Heery DM, Constantinescu CS. Effects of glucocorticoids on STAT4

activation in human T cells are stimulus-dependent. J Leukoc Biol. 2006;80(1):133-44.

Luther C, Adamopoulou E, Stoeckle C, Brucklacher-Waldert V, Rosenkranz D, Stoltze L, et al. Prednisolone

treatment induces tolerogenic dendritic cells and a regulatory milieu in myasthenia gravis

patients. J Immunol. 2009;183(2):841-8.

Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, et al. IL-6 programs Th-17 cell differentiation

by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007;8(9):967-74.

Flammer JR, Dobrovolna J, Kennedy MA, Chinenov Y, Glass CK, Ivashkiv LB, Rogatsky I. Type I interferon

signaling pathway is a target for glucocorticoid inhibition. Mol Cell Biol. 2010;30(19):4564-74.

Velten FW, Duperrier K, Bohlender J, Metharom P, Goerdt S. A gene signature of inhibitory MHC

receptors identifies a BDCA3(+) subset of IL-10-induced dendritic cells with reduced allostimulatory

capacity in vitro. Eur J Immunol. 2004;34(10):280011.

Buttgereit F, Straub RH, Wehling M, Burmester GR. Glucocorticoids in the treatment of rheumatic

diseases: an update on the mechanisms of action. Arthritis Rheum. 2004;50(11):3408-17.

Buttgereit F, Wehling M, Burmester GR. A new hypothesis of modular glucocorticoid actions: steroid

treatment of rheumatic diseases revisited. Arthritis Rheum. 1998;41:761-7.

Croxtall JD, Choudhury Q, Flower RJ. Glucocorticoids act within minutes to inhibit recruitment of

signalling factors to activated EGF receptors through a receptor-dependent, transcription-independent

mechanism. Br J Pharmacol. 2000;130(2):289-98.

Rhen T, Cidlowski JA. Anti-inflammatory action of glucocorticoids-new mechanisms for old drugs. N

Engl J Med. 2005;353(16):1711-23.

Stahn C, Buttgereit F. Genomic and nongenomic effects of glucocorticoids. Nat Clin Pract Rheumatol.

;4(10):525-33.

Hoffman H, Rosengren S, Boyle DL, Cho JY, Nayar J, et al. Prevention of cold-associated acute inflammation

in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet.

;364:1779-1785.

Buttgereit F, Burmester GR, Straub RH, Seibel MJ, Zhou H. Exogenous and endogenous glucocorticoids

in rheumatic diseases. Arthritis Rheum. 2011;63(1):1-9.

Sakai A, Han J, Cato AC, Akira S, Li JD. Glucocorticoids synergize with IL-1beta to induce TLR2 expression

via MAP kinase phosphatase 1- dependent dual Inhibition of MAPK JNK and p38 in epithelial

cells. BMC Mol Biol. 2004;5:2

Beaulieu E, Morand EF. Role of GILZ in immune regulation, glucocorticoid actions and rheumatoid

arthritis. Nat Rev Rheumatol. 2011;7(6):340-8.

Nambiar MP, Fisher CU, Warke VG, Krishnan S, Mitchell JP, Delaney N, et al. Reconstitution of deficient

T cell receptor chain restores T cell signaling and augments T cell receptor/CD3-induced interleukin-2

production in patients with systemic lupus erythematosus. Arthritis Rheum. 2003;48(7):1948-55.

Tenbrock K, Juang T, Kyttaris VC, Tsokos GC. Altered signal transduction in SLE T cells. Rheumatology.

;46(10):1525-30.

Franchimont D, Galon J, Gadina M, Visconti R, Zhou Y, Aringer M, et al. Inhibition of Th1 immune

response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat-4 phosphorylation

in T lymphocytes. J Immunol. 2000;164:1768-74.

Li R, Yang W, Zhang J, Hirankarn N, Pan HF, Mok CC, et. al. Association of CD247 with systemic lupus

erythematosus in Asian populations. Lupus. 2012;21(1):75-83.

Yoshimoto K, Setoyama Y, Tsuzaka K, Abe T, Takeuchi T. Reduced Expression of TCR zeta is involved

in the abnormal production of cytokines by peripheral T cells of patients with systemic lupus erythematosus.

J Biomed-Biotechnol. 2010;10:1-6.

Irving BA, Chan AC, Weiss A. Functional characterization of a signal transducing motif present in the

T cell antigen receptor z chain. J Exp Med. 1993;177(4):1093-103.

Zenner G, Vorherr T, Mustelin T, Burn P. Differential and multiple binding of signal transducing

molecules to the ITAMs of the TCR zeta chain. J. Cell Biochem. 1996;63(1):94-103.

Wange RL, Samelson LE. Complex complexes: signalingat the TCR. Immunity. 1996;5(3):197-205.

Kersh EN, Shaw AS, Allen PM. Fidelity of T cell activation through multistep T cell receptor zeta

phosphorylation. Science. 1988;281(5376):572-5.

Kersh EN, Kersh GJ, Allen PM. Partially phosphorylated T cell receptor zeta molecules can inhibit T

cell activation. J Exp Med. 1999;190(11):1627-36.

Migliorati G, Bartoli A, Nocentini G, Ronchetti R, Moraca R, Riccardi C. Effect of dexamethasone on

T-cell receptor/CD3 expression. Mol Cell Biochem.1997;167(1-2):135-44.

Boumpas DT, Anastassiou ED, Older SA, Tsokos GC, Nelson DL, Balow JE. Dexamethasone inhibits

human interleukin 2 but not interleukin 2 receptor gene expression invitro at the level of nuclear

transcription. J. Clin. Invest. 1991;87(5):1739-47.

Barnes PJ, Adckock I. Anti-inflammatory actions of steroids: molecular mechanisms. Trends Pharmacol

Sci. 1993;14(12):436-41.

Giunchi L, Nocentini G, Ronchetti S, Bartoli A, Riccardi C, Migliorati G. TCR kappa, a new splicing

of the murine TCR zeta gene locus, is modulated by glucocorticoid treatment. Mol Cell Biochem.

;195(1-2):47-53.

Boldizsar F, Szabo M, Kvell K, Czompoly T, Talaber G, Bjorkan J, et al. ZAP-70 tyrosines 315 and 492

transmit non-genomic glucocorticoid (GC) effects in T cells. Mol Immunol. 2013;53(1-2):111-7.

Ronchetti S, Nocentini G, Giunchi L, Bartoli A, Moraca R, Riccardi C, Migliorati G. Short term dexamethasone

treatment modulates the expression of the murine TCR zeta gene locus. Cell Immunol.

;178(2):124-31.

Downloads

Download data is not yet available.