Fc Receptor–Mediated Inhibitory Effect of Immunoglobulin Therapy on Autoimmune Giant Cell Myocarditis

Abstract

Abstract-In the present study, the mechanisms and importance of the Fc portion of immunoglobulin in experimental giant cell myocarditis were examined. Giant cell myocarditis was induced in rats by immunization of porcine cardiac myosin.were administered intraperitoneally daily on days 1 to 21. Intact immunoglobulin administration significantly ameliorated myocarditis, but F(abЈ) 2 fragments did not. The ribonuclease protection assay revealed that therapy with intact immunoglobulin, but not F(abЈ) 2 fragments, suppressed the mRNA expressions of inflammatory and proinflammatory cytokines. Immunohistochemical analysis showed that therapy with intact immunoglobulin, but not F(abЈ) 2 fragments, suppressed dendritic cell (DC) expression during both the early and the subsequent fulminant phases. Moreover, the early treatment of intact immunoglobulin until the 11th day or 14th day, when the expression of DCs was completely suppressed, ameliorated myocarditis. However, the late treatment of intact immunoglobulin beginning on day 15, when the expression of DCs had already been completed, failed to ameliorate the condition. An in vitro study showed that intact immunoglobulin, but not F(abЈ) 2 fragments, suppressed the lipopolysaccharide-induced interleukin-1␤ production associated with the downregulation of CD32 antigen (Fc␥ receptor II) expression. Thus, intact immunoglobulin therapy markedly suppressed myocarditis as a result of Fc receptor-mediated anti-inflammatory action, and the suppression of the disease was associated with the suppression of DCs, ie, the suppression of the initial antigen-priming process in experimental giant cell myocarditis.

Effects of Late Administration of Immunoglobulin on Experimental Atherosclerosis in Apolipoprotein E-Deficient Mice

“…shown in previous studies, immunoglobulin antigenecity between different species does not appear to be a problem, 10,11,13 and furthermore both agents have the same chemical structure as the Fab portion of immunoglobulin.…”

“…The therapy was first demonstrated to be effective for an autoimmune disorder (idiopathic thrombocytopenic purpura) 8 and since then, it has been established as effective in the treatment of Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, dermatomyositis and Kawasaki's syndrome, and in the prevention of graft-vs-host disease in recipients of allogenic bone marrow transplants. [8][9][10][11][12][13][14][15][16][17] Benefits have been reported for many other autoimmune and systemic inflammatory conditions, but controlled trials are often lacking.…”

The Role of Fcγ Receptors in Myocardial Diseases and Atherosclerosis

“…At first glance their results appear to be contradictory to previous reports by our own group [15,16] by Gill et al [70] In our study, not only FcγRIIB-mediated inhibitory effect on experimental autoimmune myocarditis in rats [15] but FcγRIIB-mediated antiatherosclerotic effect in apolipoprotein E-deficient mice [16] were demonstrated, using immunoglobulin preparations. Gill et al [70] demonstrated the targeting effect of immunoglobulin on adhesion molecules using ischemia reperfusion model in cats, suggesting the down regulation of adhesion molecules via Fc receptors.…”

“…An in vitro study showed that intact immunoglobulin, but not F(ab') 2 Fragments, suppressed the lipopolysaccharide-induced interleukin-1β production associated with the down regulation of CD32 antigen (Fcγ receptor II) expression. Thus, intact immunoglobulin therapy markedly suppressed myocarditis as a result of Fc receptormediated anti-inflammatory action, and the suppression of the disease was associated with the suppression of DCs, ie, the suppression of the initial antigen-priming process in experimental giant cell myocarditis [15]. Altogether, FcγRIIB-mediated inhibitory action is highly involved [16].…”

Successful Immunoglobulin Treatment for Fulminant Myocarditis and Serial Analysis of Serum Thioredoxin. A Case Report.

“…14,15 Moreover, immunoglobulin therapy suppressed experimental giant cell myocarditis in rats associated with the suppression of the expression of dendritic cell via inhibitory Fc receptor. 16 Because the leukocyte count was immediately decreased by the treatment, anti-inflammatory effects of immunoglobulin were shown in this study and, moreover, it may be because of the immunomodulatory effects of immunoglobulin that the patient's condition rapidly recovered, as spontaneous recovery of cardiac functions is in general slow in patients with acute myocarditis. 1,17 Increasing evidence supports the role of local and systemic oxidative stresses in the development and severity of myocarditis and cardiomyopathy.…”