Cell-mediated immune cardiocyte injury in viral myocarditis of mice and patients

• Published in: Japanese circulation journal Vol. 53; no. 1; pp. 61 - 77
• Main Authors: DEGUCHI, H, KITAURA, Y, HAYASHI, T, KOTAKA, M, KAWAMURA, K
• Format: Journal Article
• Language: English
• Published: Kyoto Japanese Circulation Society 1989
• Subjects: Adolescent; Adult; Animals; Antigens, Surface - analysis; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Biological and medical sciences; Child; coxsackievirus B3; Coxsackievirus Infections - immunology; Coxsackievirus Infections - pathology; Enterovirus B, Human; Female; Human viral diseases; Humans; Immunity, Cellular; Immunohistochemistry; Infectious diseases; Killer Cells, Natural - immunology; Killer Cells, Natural - pathology; Macrophages - immunology; Macrophages - pathology; Male; Medical sciences; Mice; Mice, Inbred C3H; Microscopy, Electron; Middle Aged; Miscellaneous; Myocarditis - immunology; Myocarditis - pathology; Myocardium - immunology; Myocardium - pathology; Myocardium - ultrastructure; T-Lymphocytes - classification; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Tropical viral diseases; Viral cardiopathies; Viral diseases; Virus Diseases - immunology; Virus Diseases - pathology; Human; Rodentia; Cardiovascular disease; Helper cell; Cytotoxicity; Cellular immunity; Myocyte; Infection; Natural killer cell; B»-Lymphocyte; Myocarditis; Vertebrata; Experimental disease; Mammalia; Mouse; Viral disease; T-Lymphocyte; Suppressive cell; Macrophage
• ISSN: 0047-1828; 1347-4839
• DOI: 10.1253/jcj.53.61

The cellular immune mechanism of cardiocyte injury in viral myocarditis was investigated by observing and analyzing the interactions among cardiocytes, T cells, B cells, natural killer (NK) cells and macrophages in situ in the myocardium of our murine model (C3H/He mice) and of human patients. In murine coxsackie B3 virus myocarditis, lymphocyte subsets were identified by light and electron microscopic immunohistochemical techniques with antibodies against specific antigens of pan T (Thy 1.2), helper/inducer T (Th/i) (Lyt 1+), cytotoxic/suppressor T (Tc/s) (Lyt 2+), B (Ig+) and asialo GM1+ cells in the myocardium. In the acute phase of myocarditis, asialo GM1+ (mostly NK) cells predominated over pan T cells and peaked on day 9. Pan T cells then reached a peak on day 14. The T4/T8 (Lyt 1+/Lyt 2+) ratio was 1.3 +/- 0.5 on day 5 and reached a peak of 9.1 +/- 3.6 with an increase of Lyt 1+ cells on day 14. Thereafter, NK cells and T cells gradually decreased and could still be seen in fibrotic foci even 3 and 12 months later. B cells were so scarce that no quantitative evaluation could be made. Electron microscopy revealed that macrophages were in close contact with Th/i cells, target cardiocytes and less commonly, B cells; Tc/s and NK cells also occasionally conjugated with apparently viable or degenerated cardiocytes. Some lymphocytes were located in widened intercellular spaces of dissociated intercalated discs, and in intracytoplasmic widened confines of some cardiocytes (emperipolesis). These results suggest that in the acute phase of myocarditis, NK cells initiate the reaction, and then sensitized cytotoxic T cells and activated macrophages aggravate cell-mediated injury by their close contacts with target cardiocytes; close contacts among macrophages; Th/i cells and a few B cells, and the increased T4/T8 ratio may facilitate regulation of the complex immune network; in the chronic phase, residual but active NK and cytotoxic T cells may sustain cytotoxicity. In the endomyocardial biopsies obtained from 8 patients with viral or idiopathic myocarditis from 3 to 48 days after the clinical onset, conventional electron microscopy revealed actual contacts among cardiocytes, macrophages and lymphocytes. As in our murine model, some lymphocytes had emperipolesed in cardiocytes or were located in widened spaces of dissociated intercalated discs. In 4 of these 8 patients infiltration of Leu 2a+ Tc/s, Leu 3+ Th/i and Leu 7+ cells was identified immunohistochemically, and T4/T8 ratios varied widely from 0.1 to 3.8 in the endomyocardial biopsides.