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Introdução: O Lupus Eritematoso Sistemico (LES), Esclerodermia e Artite de inicio tardio sao doencas inflamatorias autoimunes caracterizadas por producao de autoanticorpos e presenca de celulas T anormais as quais geram resposta imune defeituosa. A expressao anormal de moléculas chave em sinalizacao e a funcao defeituosa dos linfocitos T cumprem um papel significativo na patogenese da doenca autoimune. As celulas T mostram numerosas anormalidades na sinalizacao do Complexo Receptor de celula T cadeia zeta (TCRζ)1, estas aberracoes resultam na alteracao da expressao de citocinas e alguns eventos bioquimicos envolvidos na expressao de moleculas de superficie. Os defeitos no complexo TCRζ podem estar associados ao uso de corticoides, utilizados em pacientes com doenca autoimune devido a seu potente atividade auto-inflamatoria e propiedades imunossupressoras. Os corticoides sinteticos como a dexametasona inibem a atividade transcricional de alguns fatores como NFkB e AP-1 os quais regulam a sintese de algumas citocinas e poderiam estar envolvidas na sintese de TCRζ2, 3. Objetivos: Avaliar a associacao dos defeitos da expressao de cadeia zeta (ζ), em celulas T de pacientes com doenca autoimune sem tratamento com corticoides. Os defeitos na expressao defeituosa de zeta, proteina associada ao receptor TCR altera a ativacao normal do linfocito T. Materiais e métodos: Estudo analitico de casos e controles, com uma relacao 1:1 (13:13). Os casos foram pacientes com doenca autoimune ativa (6 pacientes com LES, 5 pacientes com esclerodermia e 2 pacientes com artrite de inicio tardio), e que nao tenham iniciado tratamento com corticoides e os controles foram pacientes sem diagnostico de doenca autoimune. O diagnostico se fez atraves dos criterios estabelecidos pelo Colegio Americano de Reumatologia para pacientes com LES, esclerodermia e artrite de inicio tardio. Se realizou venopuncao extraindo 10mls de sangue total, se extraiu RNA total e se fez RT PCR, se amplificou utilizando um jogo de primers que flanqueiam uma regiao de 138 pares de bases que envolviam os exoes 2, 3 e 4 de cadeia ζ. Resultados: Nos valores de amplificacao de cadeia Z se encontraram diferencas significativas em pacientes com doenca autoimune (0.8214}0.1787, med=0.7368) comparada com o grupo controle (0.9225}0.1272, med=0.9830) (p=0.045, Teste nao parametrico, exato de Mann Whitney) Conclusão: A expressao de cadeia Z encontrou-se diminuida em celulas T de pacientes com doenca autoimune, sem uso de corticoides, a diminuicao ou uma falta de expressao da cadeia Z pode causar alteracoes na resposta imune.

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). Defeitos na expressão de cadeia zeta (ζ) em um grupo de pacientes com Lúpus, Esclerodermia e artrite de início tardio, Colômbia 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.

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