Summary
The cytokine repertoire of ADP/ATP carrier-specific humoral immune responses and the cytokine-dependent anti-ADP/ATP carrier antibody IgG subclasses were examined in a cohort of ADP/ATP carrier-immunized BALB/c mice treated with anti-CD4 monoclonal antibody. Eighteen male BALB/c mice (6–8 weeks old) were randomized into 3 groups: dilated cardiomyopathy (DCM) group, DCM-tolerance (Tol) group and control group. The mice in DCM group were immunized with the peptides derived from human ADP/ATP carrier protein for 6 months and mice in the control group were sham-immunized, while the mice in DCM-Tol group were immunized with ADP/ATP carrier protein and anti-CD4 McAb simultaneously. Serum autoantibody against ADP/ATP carrier and IgG subclasses were measured by ELISA, intracellular cytokines IFN-γ and IL-4 of Th cells were monitored with flow cytometry, and splenic T cell cytokines IFN-γ, IL-2, IL-4 and IL-6 were detected by using real-time fluorescent quantitative PCR. The results showed that the autoantibody against ADP/ATP carrier was found in all mice in DCM group, and the antibody level, serum IgG1 and IgG2a subclasses, cytokines in T cells and Th cells were all elevated in DCM group, as compared with those in control group (P<0.01). On the other hand, in DCM-Tol group, the autoantibody level and contents of all the cytokines were significantly different from those in DCM group (P<0.01), and were close to those in control group. And the levels of IgG1, IgG2a, IgG2b and IgG3 were influenced, to varying degrees, by anti-CD4 McAb as compared with those in DCM group. All these four types of IgG subclasses were substantially decreased in DCM-Tol group as compared with DCM group. It is concluded that the treatment with anti-CD4 McAb could prevent the activation of T cells, reverse the abnormal secretion of cytokines and the imbalance between Th1/Th2 cell subsets and abnormal production of autoantibody against ADP/ATP carrier, and eventually avoid myocardial injuries.
Similar content being viewed by others
References
Kawai C. From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death: learning from the past for the future. Circulation, 1999,99(8):1091–1100
Sigusch H H, Lehmann M H, Schnittler U et al. Tumour necrosis factor-alpha expression in idiopathic dilated cardiomyopathy: correlation to myocardial inflammatory activity. Cytokine, 2000,12(8):1261–1266
Iwata M, Yoshikawa T, Baba A et al. Autoantibodies against the second extracellular loop of beta1-adrenerrgic receptors predict ventricular tachycardia and sudden death in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol, 2001,37:418–424
Ratcliffe N R, Hutchins J, Barry B et al. Chronic myocar-ditis induced by T cells reactive to a single cardiac my-osin peptide: persistent inflammation, cardiac dilatation, myocardial scarring and continuous myocyte apoptosis. J Autoimmun, 2000,15:359–367
Bozkurt A, Canataroglu A, Cetiner S et al. Lymphocyte subsets in patients with idiopathic dilated cardio-myopathy. Anadolu Kardiyol Derg, 2001,1:98–100
Mozaffari F, Hansson L, Kiaii S et al. Signaling molecules and cytokine production in T cells of multi-ple myeloma increased abnormalities with advancing stage. Br J Haematol, 2004,124:315–324
Fu M, Matsui S. Is cardiomyopathy an autoimmune disease? Keio J Med, 2002,51:208–212
Liao Y H, Fu M. Autoimmunity in the pathogenesis of cardiomyopathy. J Autoimmun, 2000,16:1–2
Fuse K, Kodama M, Ito M et al. Polarity of helper T cell subsets represents disease nature and clinical course of experimental autoimmune myocarditis in rats. Clin Exp Immunol, 2003,134(3):403–408
Himmelrich H, Launois R, Maillard I et al. In BALB/c mice, IL-4 production during the initial phase of infection with Leishmania major is necessary and sufficient to instruct Th2 cell development resulting in progressive disease. J Immuol, 2000,164:4819–4825
Atanasyeva M, Wang Y, Kaya Z et al. Experimental autoimmune myocarditis in A/J mice is an interleukin-4-dependent disease with a Th2 phenotype. Am J Pathol, 2001,159:193–203
Cunningham M W. Cardiac myosin and the TH1/TH2 paradigm in autoimmune myocarditis. Am J Pathol, 2001,159:5–12
Wang Q F, Liao Y H, Gong F L. A study of Th cell subsets in patients with dilated cardiomyopathy. J Clin Cardiol (Chinese), 1999,15:100–102
Staudt A, Bohm M, Knebel F et al. Potential role of autoantibodies belonging to the immunogolbulin G-3 subclass in cardiac dysfunction among patients with dilated cardiomyopathy. Circlulation, 2002,106:2448–2453
Liao Y H, Yuan J, Wang Z H et al. Infectious tolerance to ADP/ATP carrier peptides induced by anti-L3T4 monoclonal antibody in dilated cardiomyopathy. J Clin Immunol, 2005,25:376–384
Schulze K, Becker B F, Schauer R et al. Antibodies to ADP-ATP carrier—an autoantigen in myocarditis and dilated cardiomyopathy—impair cardiac function. Circulation, 1990,81:959–969
Schwimmbeck P L, Bland N K, Schulthesis H P et al. The possible value of synthetic peptides in the diagnosis and therapy of myocarditis and dilated cardiomyopathy. Eur Heart J, 1991,12(Suppl D):76–80
Ulett G C, Ketheesan N, Hirst R G. Cytokine gene expression in innately susceptible BALB/c mice and relatively resistant C57BL/6 mice during infection with virulent Burkholderia pseudomallei. Infect Immun, 2000, 68(4):2034–2042
Liao Y H, Cheng L X, Dai S P et al. Autoantibodies against ADP/ATP carrier from patients with dilated cardiomyopathy increase activity of voltage-dependent Ca channels in isolated cardiac myocytes. Blood Press, 1996, 3(Suppl):41–44
Cao W, Chen Y, Alkan S et al. Human T helper (Th) cell lineage commitment is not directly linked to the secretion of IFN-gamma or IL-4: characterization of Th cells isolated by FACS based on IFN-gamma and IL-4 secretion. Eur J Immunol, 2005,35(9):2709–17
Caforio A L, Goldman J H, Baig M K et al. Cardiac autoantibodies in dilated cardiomyopathy become undetectable with disease progression. Heart, 1997,77(1):62–77
Warraich R S, Dunn M J, Yacoub M H. Subclass specificity of autoantibodies against myosin in patients with idiopathic dilated cardiomyopathy: Pro-inflammatory antibodies in DCM patients. Biochem Biophy Res Commun, 1999,259:255–261
Warraich R S, Noutsias M, Kasac I K et al. Immunoglobulin G3 cardiac myosin autoantibodies correlate with left ventricular dysfunction in patients with dilated cardiomyopathy: Immunoglobulin G3 and clinical correlates. Circulation, 2002,143:1076–1084
DeKruyff R H, Ju S T, Mosmann T et al. Induction of antigen-specific antibody responses in primed and unprimed B cell: functional heterogeneity among Th1 and Th2 T cell clones. J Immunol, 1989,142(8):2575–2582
Molnar I. The balance shift in Th1/Th2 related IL-12/IL-5 cytokines in Graves’ disease during methimazole therapy. Autoimmunity, 2007,40(1):31–37
Author information
Authors and Affiliations
Additional information
Zhaohui WANG, female, born in 1969, M.D., Ph.D
This project was supported by a grant from the National Natural Science Foundation of China (No. 30000070).
Rights and permissions
About this article
Cite this article
Wang, Z., Liao, Y., Yuan, J. et al. Analysis of specific Th1/Th2 helper cell responses and IgG subtype antibodies in anti-CD4 monoclonal antibody treated mice with autoimmune cardiomyopathy. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 28, 409–414 (2008). https://doi.org/10.1007/s11596-008-0408-y
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11596-008-0408-y