Immunopathogenesis of dilated cardiomyopathy. Evidence for the role of TH2-type CD4+T lymphocytes and association with myocardial HLA-DR expression.
BACKGROUND
An immunological pathogenesis underlying dilated cardiomyopathy and myocarditis has been suggested on the basis of the subtype of lymphocyte infiltrates and the degree of HLA expression in cardiac tissue. In the present study, we investigated the relation between the peripheral CD4+T-cell subset and the degree of HLA expression in the heart.


METHODS
Fifty-four patients with heart insufficiency included in the study were biopsied after coronary heart disease had been excluded. Immunohistological staining of the left ventricular tissue were performed employing anti-CD3, -CD4, -CD8, -CD14, and HLA-DR monoclonal antibodies. Intracellular expression of IL-2, IL-4, IL-5, IFN-gamma, and TNF-alpha in peripheral CD4+T lymphocytes was determined using flow cytometry. The severity of heart insufficiency was determined by measurement of brain natriuretic peptide (BNP) and the NYHA class. On the basis of HLA expression in the heart, the patients were divided into three groups: Group I (mild-to-none), Group II (moderate), and Group III (strong-to-very strong).


RESULTS
Of the 54 patients included in this study, 33 (61%) patients were diagnosed as having idiopathic dilated cardiomyopathy and 10 (18.5%) borderline or healing myocarditis according to the Dallas criteria. Both patient groups were found in all three HLA-DR groups. There was no difference in BNP level or NYHA class between the three groups. However, a significant difference in the proportion of CD4+T lymphocytes producing IL-2 (39.2 versus 21.8%), IFN-gamma (19.5 versus 7.8%), and TNF-alpha (35.8 versus 16.1%) between Groups I and III could be detected, whereas the distribution of IL-4 and IL-5 producing CD4+T lymphocytes was similar. The myocardium of Group III patients exhibited a significant higher number of CD3+T cells (11.4 versus 4.3 per mm2) and CD4+T cells (4.7 versus 0.8 per mm2) compared to Group I patients, while no difference existed with respect to CD8+T cells.


CONCLUSIONS
High myocardial expression of the HLA-DR antigen is associated with an increase of peripheral-blood CD4+T lymphocytes expressing cytokines of the TH2 subset. The degree of HLA-DR expression is not associated with the degree of heart insufficiency or underlying diagnosis, but correlates with an increase of activated T cells in the myocardium. The data suggest that CD4+T lymphocytes infiltrating cardiac tissue may play a pathogenic role in dilated cardiomyopathy.
Kuethe
Friedhelm
F
Klinik fuer Innere Medizin I, Friedrich-Schiller-Universitaet Jena, Erlanger Allee 101, Jena, 07740, Germany. Friedhelm.Kuethe@med.uni-jena.de
Braun
Ruedi K
RK
Foerster
Martin
M
Schlenker
Yvonne
Y
Sigusch
Holger H
HH
Kroegel
Claus
C
Figulla
Hans R
HR
D000328:Adult; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D016827:CD8 Antigens / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006684:HLA-DR Antigens / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D015848:Interleukin-5 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D006684:HLA-DR Antigens; D007376:Interleukin-2; D015848:Interleukin-5; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma