Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus

Amagai, Masayuki; Tsunoda, Kazuyuki; Suzuki, Harumi; Nishifuji, Koji; Koyasu, Shigeo; Nishikawa, Takeji

doi:10.1172/jci8748

Cited by 239 publications

(295 citation statements)

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“…In contrast, transient but significant T lymphocyte infiltration was observed in our myocarditis model. Although homeostatic proliferation in lymphopenic mice sometimes induces autoimmunity [33,34], we observed little evidence of T-cell infiltration into the liver, lungs, and salivary glands of recipient Rag2 -/-mice in both PV model previously reported [20] and myocarditis model reported here. Adoptive transfer of relatively large number of splenocytes (50 million/mouse) seems sufficient to block homeostatic proliferation of transferred lymphocytes in recipient Rag2 -/-mice.…”

contrasting

confidence: 80%

“…Although animal models have contributed to the elucidation of disease mechanisms, previously reported DCM models required an extensive time period in order to induce the phenotype of cardiomyopathy using repeated immunizations with cardiac components [15,17], presumably due to self-tolerance mechanisms. To overcome the barrier of self-tolerance, in this study we utilized a previously established method, which was successfully applied to develop a PV mouse model with an autoimmune reaction against Dsg3, the target antigen of PV [20]. Our present results prove that the method used to establish the PV model in mice can be applied to other autoimmune disease models.…”

mentioning

confidence: 61%

“…The resting membrane potential, the action potential overshoot, the action potential amplitude, and the APD at 20, 50, and 90% repolarization (APD 20 , APD 50 , and APD 90 ) were measured at 1,000 ms pacing cycle length.…”

Section: Action Potential Recordingmentioning

confidence: 99%

“…However, the progression from myocarditis to DCM has not been investigated in detail. The causes of the initial myocardial damage and subsequent cardiac dysfunction along with the subsequent role of autoimmunity in DCM are still unclear.The pathophysiological role of autoantibodies in disease progression has been established in only some autoimmune diseases such as pemphigus vulgaris (PV), involving anti-desmoglein 3 (Dsg3) antibodies [20], and myasthenia gravis with anti-nicotinic acetylcholine receptor antibodies [21]. 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].…”

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confidence: 99%

“…M 2 R-immunized M 2 R -/-mice produced antibodies in the sera reactive with recombinant M 2 R proteins (A 450 = 1.00 ± 0.44 at 1:10,000 dilution). Immunized splenocytes were then transferred into Rag2 -/-mice in which donor lymphocytes migrate rapidly to secondary lymphoid organs due to the lack of endogenous T and B cells [20].As early as 2 weeks after splenocyte transfer, CD4 + and CD8 + T cells, but not B cells or neutrophils, infiltrated the myocardium of the recipient Rag2 -/-mice (Fig. 1, A-E (N) Heart sections at 13 weeks after splenocyte transfer into Rag2 -/-mice were examined and instances of abnormal swelling of nuclei (over twofold larger in size than healthy nuclei) and multinuclear cardiomyocytes were counted to quantify the morphological changes.…”

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confidence: 99%

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

et al. 2012

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Patients with dilated cardiomyopathy (DCM) often have autoantibodies against cardiac antigens including the M 2 muscarinic acetylcholine receptor (M 2 R). To elucidate the role of autoimmunity against M 2 R in disease development, we induced an immune response against M 2 R by adoptive transfer into Rag2 -/-mice of splenocytes from M 2 R -/-mice immunized with a recombinant M 2 R protein. T lymphocytes transiently infiltrated the heart in recipient mice followed by morphological changes in cardiomyocytes. These mice produced IgG antibodies against M 2 R, which bound to cardiomyocytes in vivo and decreased the amplitude of calcium signals in isolated rat cardiomyocytes in vitro. Recipient mice showed increased heart weights associated with increased intraventricular diameter, decreased systolic function, and increased action potential duration, which are characteristics of DCM. Our results suggest that myocarditis and DCM associated with the presence of anti-M 2 R antibodies are autoimmune diseases with a risk of progressing to the terminal stage. Our mouse model will be useful in the analysis of the molecular mechanisms of disease progression and the development of new therapies for DCM. Keywords IntroductionDilated cardiomyopathy (DCM) causes severe heart failure in young adults including occasional sudden cardiac death. Mutations in genes encoding myocyte structural proteins are found in about 30-40% of DCM, but the etiology of the remaining 60-70% of cases is poorly understood [1][2][3]. Advances in the field of immunology have shed light on the close relationship between immunological disturbances and the progression of heart failure [4][5][6][7]. Adenovirus or enterovirus-specific RNA sequences are often detected in the myocardium of patients with DCM and myocarditis [7][8][9]. Myocardial-reactive antibodies such as those against β 1 adrenergic receptor (β 1 AR), M 2 muscarinic acetylcholine receptor (M 2 R), and cardiac myosin have also been observed in the sera of these patients [10][11][12][13][14]. As a result, it has been hypothesized that prolonged immunological abnormalities after myocarditis, presumably induced by a subclinical viral infection or autoimmunity, could lead to DCM [5,6]. Evidence supporting this hypothesis has accumulated through clinical and experimental studies [15][16][17].For example, immunization of animals with peptides derived from proteins expressed in cardiomyocytes such as β 1 AR [16,17] or cardiac myosin [15] or the transfer of antibodies against cardiac antigens mimics the prolonged immune abnormalities observed after acute myocarditis [18,19]. However, the progression from myocarditis to DCM has not been investigated in detail. The causes of the initial myocardial damage and subsequent cardiac dysfunction along with the subsequent role of autoimmunity in DCM are still unclear.The pathophysiological role of autoantibodies in disease progression has been established in only some autoimmune diseases such as pemphigus vulgaris (PV), involving anti-desmoglein 3 (Dsg3) antibodi...

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confidence: 61%

Section: Action Potential Recordingmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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

et al. 2012

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A Young Patient With Persistent Gingival Bleeding

Yepes

White

2012

JAMA

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Research Advances in Pemphigus

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Díaz²

2001

JAMA

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Pemphigus is an autoimmune disorder, known to be caused by autoantibodies directed against critical adhesion molecules of squamous epithelial cells, the desmogleins. These autoantibodies induce blistering of skin and mucosal surfaces and lead to severe morbidity and, potentially, death. Key factors include associated major histocompatibility complex class II genes, the structure of the desmoglein antigens, and the role of autoantibody in impairing cellular adhesion. This article discusses the precise structure of the major histocompatibility complex class II gene-peptide-T-cell receptor complex involved and of the environmental and genetic factors that induce autoimmunity against desmoglein 1. Discovery of antigen-specific immunotherapy and insight into environmental factors that initiate autoimmunity in genetically susceptible individuals are needed.

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Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus

Cited by 239 publications

References 25 publications

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

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

A Young Patient With Persistent Gingival Bleeding

Research Advances in Pemphigus

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Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus

Cited by 239 publications

References 25 publications

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

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

A Young Patient With Persistent Gingival Bleeding

Research Advances in Pemphigus

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

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