Research Report 2000 - MDC

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Immunology of Cardiovascular Diseases Gerd Wallukat Our laboratory is engaged in clinical and basic research mainly focused on immunological processes in cardiovascular diseases. We have observed autoantibodies against adrenergic receptors and AT1-receptors in the sera of patients with myocarditis, dilated cardiomyopathy, and hypertension. These autoantibodies recognize epitopes on the first or second extracellular loop of the receptors and act like the corresponding pharmacological agonists. In patients with myocarditis and dilated cardiomyopathy, but also in Chagas’ disease, the autoantibodies recognize the β1-adrenoceptor and muscarinic M2 receptor as an antigen. In patients with hypertension, the autoantibodies are directed against the α1-adrenergic receptor and/or AT1-receptor. In recent years, we have investigated in more detail the effects of β1adrenoceptor autoantibodies. These human autoantibodies cross-react with the rat β1-adrenoceptor and exhibit their effects via the ß-adrenoceptor - adenylate cyclase - protein kinase A - cascade. Long-term treatment of cultured rat cardiomyocytes with this antibody leads to a subtype specific reduction of the expression of the β1-adrenoceptor on mRNA and protein levels and to upregulation of the inhibitory G-protein Giα. 114 Autoantibodies in myocarditis and dilated cardiomyopathy The suggestion that the anti-β1adrenoceptor autoantibody might play a role in the pathogenesis of DCM is supported by similar findings in patients with myocarditis, a disease widely held to be a precursor of DCM. It is, therefore, also of interest in the present context that, in a patient with acute myocarditis, the healing process, as reflected by a normalization of the ejection fraction and the heart rate, correlates with disappearance of the anti-β1-adrenoceptor autoantibodies from the blood. Based on our autoimmune hypothesis, we have proposed new therapeutic possibilities to treat patients with endstage dilated cardiomyopathy. One of them is immunoadsorption using Therasorb columns to remove immunoglobulins from the patient’s plasma. After this treatment, a marked improvement in cardiac function is observed. This improvement is not only observed immediately after treatment, but for a long period thereafter. In these patients treated with standard therapy plus β-blocking agents, after immunoadsorption, autoantibodies were not detectable and the ejection fraction (EF) increased from 22.3 % before treatment to 37.0 % after a period of 12 months. The strong correlation observed between the reduction in the amount of circulating autoantibodies to the β1-adrenoceptor and the improvement in the function of the heart just described can be interpreted as supporting the hypothesis that the anti-β1-adrenoceptor antibodies play a part in the pathophysiology of myocarditis and DCM. To confirm this hypothesis, we have now developed an immunoadsorption column that selectively removes only the anti-β1-adrenoceptor autoantibodies. Autoantibodies in hypertension Furthermore, we have investigated the role of autoantibodies in essential and malignant hypertension. In some sera of patients with this disease we have detected autoantibodies directed against the α1-adrenergic receptor. These autoantibodies and anti-peptide antibodies generated against peptides corresponding to the first or second extracellular loop of the α1-adrenergic receptor recognize both these extracellular loops and act like an α-adrenergic agonist. In a special type of hypertension – preeclampsia – we have observed autoantibodies against the angiotensin II AT1-receptor. This antibody is detectable after the 20th week of pregnancy and disappears after delivery. The anti-AT1-receptor antibodies act like the agonist angiotensin II and induce the formation of the AP1- complex. These functional autoantibodies are found in all preeclamptic women investigated and may play a role in elevating vascular resistance and promoting hypertension and cardiac hypertrophy in these patients. Role of mast cells in the heart Another of our research topics is cardiac mast cells. Because the heart of patients with dilated cardiomyopathy contain four times more mast cells and more histamine than controls, we wish to discover the role of these cells. Using a monoclonal antibody against surface determinants of rat connective tissue mast cells, we have been able to identify a great number of, mostly undifferentiated, mast cells in the neonatal rat heart and in cell cultures prepared from this organ. In cell culture, we have been able to differentiate the mast cells. These differentiated mast cells, mostly located in intimate contact with cardiomyocytes, synthesize the mediators histamine, serotonin and tumor necrosis factor α (TNFα). In heart tissue of DCM patients, we have investigated the degranulation of TNFα and tryptase from mast cells. Both mediators may be involved in the development of fibrosis in the failing heart.
Selected Publications Schneider, G., Schrödel, W., Wallukat, G., Müller, J., Nissen, E., Rönspeck, W., Wrede, P., and Kunze, R. (1998) Peptide design by artifical neural networks and computer-based evolutionary search. Proc. Natl. Acad. Sci. USA 95, 12179-12184. Podlowski, S., Luther, H.P., Morwinski, R., Müller, J., and Wallukat, G. (1998) Agonistic anti-β1adrenergic receptor autoantibodies from cardiomyopathy patients reduce the β1-adrenergic receptor expression in neonatal rat cardiomyocytes. Circulation 98, 2470-2476. Wallukat, G., Fu, H.M., Matsui, S., Hjalmarson, Å., and Fu, M.L. (1999) Autoantibodies against M2 muscarinic receptors in patients with cardiomyopathy display nondesensitizing agonist-like effects. Life Sci. 64, 465-469. Wallukat, G., Homuth, V., Fischer, T., Lindschau, C., Horstkamp, B., Jüpner, A., Baur, E., Nissen, E., Vetter, K., Neichel, D., Dudenhausen, J.W., Haller, H., and Luft, F.C. (1999) Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J. Clin. Invest. 103, 945-952. Müller, J., Wallukat, G., Dandel, M., Bieda, H., Brandes, K., Spiegelsberger, S., Nissen, E., Kunze, R., and Hetzer, R. (<strong>2000</strong>) Immunoglobulin adsorption in patients with idiopathic dilated cardiomyopathy. Circulation 101, in press. Structure of the Group Group leader Dr. Gerd Wallukat Scientists Dr. Rosemarie Morwinski* Dr. Eberhard Nissen** Graduate and undergraduate students Dajana Neichel Technical assistants Karin Karczewski Holle Schmidt Monika Wegener Secretariat Verona Kuhle * supported by BBB ** supported by Affina GmbH 115
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Research Report 2000 Covers the Per
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Molecular Therapy Molecular and Dev
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The quantum theory, that provided a
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Introduction Clinical Research The
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Genome Research in Berlin- Brandenb
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External Evaluation Over the period
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Congresses In the years reported, t
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Awards A number of prestigious priz
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Genetics, Bioinformatics and Struct
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disorders. Various MDC groups have
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Steen R.G., Kwitek-Black A.E., Glen
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Selected Publications Binas, B., Da
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Technology transfer Based on the fu
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Selected Publications Müller, D.N.
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Selected Publications Hennies, H.C.
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Somatic genetic alterations in brea
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Clinical and Molecular Genetics of
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Selected Publications Toka, H.R., B
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Lbx1, c-met and the control of cell
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Selected Publications Moore, A., Mc
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Selected Publications Herz, J., Wil
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We aim to study the genetic epidemi
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Nucleation Nucleation as a pre-requ
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Selected Publications Damaschun, G.
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Selected Publications Yuan, T., Wal
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stability. By determining the struc
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Role of Protein Dynamics in Enzyme
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Modeling Nucleic Acid Structure and
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Conformation, Stability and Interac
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Protein Structure Analysis and Prot
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Cell Growth and Differentiation 61
Page 63 and 64: dendritic cells (DC). Adoptive tran
Page 65 and 66: developmental pathway that may invo
Page 67 and 68: Regulation of Transcription in Mamm
Page 69 and 70: Differentiation and Growth Control
Page 71 and 72: Cell cycle-dependent transcriptiona
Page 73 and 74: Cell Cycle Regulation Hans-Dieter R
Page 75 and 76: Epithelial Differentiation, Invasio
Page 77 and 78: Selected Publications Hartmann, G.,
Page 79 and 80: Selected Publications Behrens, J.,
Page 81 and 82: Selected Publications Karsten, U.,
Page 83 and 84: Depressed contractility in human he
Page 85 and 86: Understanding calcium handling prot
Page 87 and 88: VSMCs. We have cloned and character
Page 89 and 90: Surgical Oncology Peter M. Schlag T
Page 91 and 92: Ubiquitin System and Endoplasmic Re
Page 93 and 94: P450 Cytochromes and the Endoplasmi
Page 95 and 96: Vascular Biology Hermann Haller Thi
Page 97 and 98: Selected Publications Gollasch, M.,
Page 99 and 100: Electron Microscopy Members of the
Page 101 and 102: Molecular Therapy 101
Page 103 and 104: Hematology, Oncology and Tumor Immu
Page 105 and 106: Selected Publications Sturm, I., K
Page 107 and 108: Selected Publications Westermann, J
Page 109 and 110: fractions. The hematopoietic potent
Page 111 and 112: Interaction of pharmacologically ac
Page 113: Molecular Basis of Congestive Heart
Page 117 and 118: different murine and human tumor ce
Page 119 and 120: Molecular and Cell Biology of Hemat
Page 121 and 122: Phospholipids Dietrich Arndt Cytoto
Page 123 and 124: Regulation and Deregulation of Cell
Page 125 and 126: Evolution, Regulation and Genetic A
Page 127 and 128: Molecular and Developmental Neurosc
Page 129 and 130: Cellular Neurosciences Helmut Kette
Page 131 and 132: Growth Factor and Regeneration Gary
Page 133 and 134: Synapse Formation and Function Fran
Page 135 and 136: Developmental Neurobiology Fritz G.
Page 137 and 138: Selected Publications Volkmer, H.,
Page 139 and 140: Structure and Organization 139
Page 141 and 142: Prof. Dr. Hans Meyer President of t
Page 143 and 144: Supporting Divisions Safety The div
Page 145 and 146: Press and Public Relations Research
Page 147 and 148: Purchasing and Materials Management
Page 149 and 150: Computing The computing group of th
Page 151 and 152: Awards Thomas Biederer Boehringer-M
Page 153 and 154: Index A Abdul, Yetunde 90 Aguirre-A
Page 155 and 156: H Haase, Hannelore 85, 97, 100, 142
Page 157 and 158: Q Qin, Zhihai 107, 117 Quass, Petra
Page 159: Board of Trustees Chair Wolf-Michae
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Research Report 2000 - MDC

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