Localization of a functional autoimmune epitope on the muscarinic acetylcholine receptor-2 in patients with idiopathic dilated cardiomyopathy.

Abstract

A peptide corresponding to the sequence 169-193 of the second extracellular loop of the human muscarinic acetylcholine receptor-2 was used as an antigen to screen sera from patients with idiopathic dilated cardiomyopathy (DCM, n = 36) and healthy blood donors (HBD, n = 40). The sera from 14 patients with DCM (38.8%) and 3 HBD (7.5%) recognized the muscarinic receptor peptide at dilutions varying from 1:20 to 1:160 in ELISA. A highly significant correlation (P = 0.006) was found between the presence of antimuscarinic receptor-2 autoantibodies and anti-fl-adrenoceptor-1 autoantibodies in the patients' sera. Affinity-purified autoantibodies from positive sera of patients with DCM recognized on the electrotransferred protein of rat ventricular membrane a major band of about 80 kD. Incubation of autoantibodies with membrane resulted not only in a decrease in the maximal binding sites (B..) but also in an increase in Kd of radioligand binding in a concentration-dependent manner. This suggests a mixed-type of inhibition. Moreover, preincubation with atropine abolished the inhibitory effect of autoantibodies on the receptor binding whereas carbachol appeared to have no effect on the activity of the autoantibodies.These data define a subgroup of patients with idiopathic DCM who have in their sera functionally active autoantibodies against muscarinic receptor-2. (J. Clin. Invest. 1993Invest. .91:1964Invest. -1968

Autoimmunity against M2 muscarinic acetylcholine receptor induces myocarditis and leads to a dilated cardiomyopathy‐like phenotype

“…Certain types of antibodies may affect cardiomyocyte functions by binding membrane receptors on heart cells in DCM patients [10][11][12][13][14] and in animal models [15][16][17]. For example, agonistic anti-β 1 AR autoantibodies induce cardiomyocyte apoptosis in vitro [22] and the passive transfer of β 1 AR-specific antisera induced a DCM-like phenotype in recipient rodents in vivo [17].…”

Immunoadsorption and subsequent immunoglobulin substitution decreases myocardial gene expression of desmin in dilated cardiomyopathy

“…Disturbances in humoral immunity play an important role in cardiac dysfunction of DCM patients. A number of autoantibodies against cardiac cell proteins have been identified in DCM: e.g., antibodies against the cardiac beta-1 adrenergic receptor, contractile proteins, mitochondrial proteins and the muscarinic acetylcholine receptor-2 [2][3][4][5][6][7]. Experimental and clinical data indicate that cardiac antibodies play an active role in the pathogenesis of DCM and may contribute to cardiac dysfunction.…”

Foreword to special issue on “Myocarditis”

“…Meanwhile, the first experimental observations were made by several investigators, suggesting a possible involvement of autoimmune mechanisms to cardiac autoantigens; in particular, a mouse model for myosin-induced autoimmune myocarditis was described by the Neu et al [5]. In addition, various groups in the late 80s and early 90s reported the presence of circulating anti-heart autoantibodies against myosin as well as other autoantigens in acute and chronic myocarditis or dilated cardiomyopathy, in keeping with the hypothesis of autoimmunity being involved in a subset of patients [6][7][8][9][10][11][12][13][14]. A retrospective multicenter registry from the USA coordinated by Cooper et al [15] reported the efficacy of immunosuppressive therapy in a rare but lethal form of myocarditis, e.g., giant cell myocarditis.…”