Autoimmune cardiomyopathy and heart block develop spontaneously in HLA-DQ8 transgenic IAβ knockout NOD mice

Abstract

A line of nonobese diabetic (NOD) mice expressing the human diabetes-associated HLA-DQ8 transgene in the absence of mouse IA␤ failed to show spontaneous insulitis or diabetes, but rather developed dilated cardiomyopathy, leading to early death from heart failure. Pathology in these animals results from an organ-and cell-specific autoimmune response against normal cardiomyoctes in the atrial and ventricular walls, as well as against very similar myocytes present in the outermost muscle layer surrounding the pulmonary veins. Progression of the autoimmune process could be followed by serial ECG measurements; irradiation of young animals significantly delayed disease progression, and this effect could be reversed by adoptive transfer of splenocytes taken from older animals with complete heart block. Disease progression could also be blocked by cyclosporin A treatment, but was accelerated by injection of complete Fruend's adjuvant. The constellation of findings of spontaneously arising destructive focal lymphocytic infiltrates within the myocardium, rising titers of circulating anticardiac autoantibodies, dilation of the cardiac chambers, and gradual progression to end-stage heart failure bears a striking resemblance to what is seen in humans with idiopathic dilated cardiomyopathy, a serious and often life-threatening medical condition. This transgenic strain provides a highly relevant animal model for human autoimmune myocarditis and postinflammatory dilated cardiomyopathy.I diopathic dilated cardiomyopathy (IDCM) describes a condition whereby previously healthy individuals develop lifethreatening heart failure associated with enlargement of the heart, but with no apparent underlying cause (1, 2). The cardiac pathology seen in the majority of IDCM patients indicates a recent or more long-standing immune-mediated inflammatory process within the muscle tissue of the heart (i.e., myocarditis) (3,4). IDCM patients often demonstrate circulating anticardiac autoantibodies, and the myocarditis is generally thought to arise from an autoimmune response against cardiac tissues (5). Research on IDCM has been hampered by the lack of an appropriate animal model, that is, a model where animals develop disease spontaneously, show severe life-threatening pathology, and display an immunological and histological picture similar to that seen in humans with IDCM.The human MHC class II molecule DQ8 (i.e., haplotype DQA1*0301, DQB1*0302) is known to be associated with type 1 diabetes (T1D). To map DQ8-restricted T cell epitopes for T1D autoantigens we crossed DQ8 transgenic nonobese diabetic (NOD) mice with a NOD MHC class II ␤-chain knockout line (6). Because the resulting animals express the human MHC class II molecule but not the mouse, any CD4 ϩ T cells arising would be restricted to the human MHC molecule. We chose the NOD strain because it is known to have defects in self-tolerance, which we hypothesized would aid our efforts to induce immune responses against self-antigens such as GAD65. Although replacement of the murine T1D-asso...

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

“…The data presented here confirms previous findings [40,41]. In addition our data show gender-bias in susceptibility, presence of Ttg antibodies and role of MHC polymorphism and background genes in spontaneous autoimmunity.…”

Genetic Control of Autoimmunity: Protection from Diabetes, but Spontaneous Autoimmune Biliary Disease in a Nonobese Diabetic Congenic Strain

“…The concept of the NOD genetic background providing a pan-autoimmune diathesis that is focused by specific modification is consistent with the observation that the B7-2 knockout placed on the NOD background develops an autoimmune demyelinating disease, and that HLA-DQ8 placed on the NOD background produces autoimmune myocarditis (38,39). The development of biliary tract disease, Sjogren's syndrome (40), thyroiditis (41), and autoimmune diabetes in a set of genetically similar NOD and NOD congenic strains serves as a model for human pedigrees containing multiple autoimmune diseases, including diabetes and primary biliary cirrhosis.…”

A Spontaneous Model for Autoimmune Myocarditis Using the Human MHC Molecule HLA-DQ8

“…While this manuscript was under consideration, an article describing the development of autoimmune myocarditis in double-transgenic human CD4/HLA-DQ8mII Ϫ/Ϫ NOD mice appeared (38). However, only one transgenic NOD line was described, raising the possibility that this phenotype may have been caused by founder effects, e.g., due to the transgene insertion site (38). In addition, the expression of the HLA-DQ8 transgene was examined on only a single genetic background.…”