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Mastzellerkrankungen

Clinical presentation and genetics

Systemic mast cell activation disease (MCAD) denotes a group of primary mast cell disorders characterized by aberrant release of variable subsets of mast cell mediators and/or accumulation of pathological mast cells in potentially any or all organs and tissues. The clinical presentation of MCAD is very diverse, since due to both the widespread distribution of mast cells and the great heterogeneity of aberrant mediator expression patterns, symptoms can occur in virtually all organs and tissues. According to the current classification of MCAD the traditionally recognized rare variant termed systemic mastocytosis (SM) is characterized by specific pathological somatic mutations in exon 17 of the tyrosine kinase KIT (for which KITD816V accounts for the great majority) and immunohistochemical findings (known as the

World  Health Organization (WHO) criteria) caused by these mutations. The other variant, only recently recognized, is termed mast cell activation syndrome (MCAS; seemingly borne of a large collection of mutations in various genes) and presents a complex clinical picture of multiple proven mast cell mediator-induced symptoms (relevant differential diagnoses exluded) and failure to meet the WHO criteria for diagnosis of SM. Recent findings suggest that MCAS is a fairly common disorder in contrast to SM. According to recent findings, the variants and clinical subtypes of MCAD do not represent distinct disease entities but should be more accurately regarded as varying compositions of a common process of mast cell dysfunction. Although almost all mutations causing MCAD were somatic rather than germline, evidence was provided for common familial occurrence of MCAD. Irrespective of systemic MCAD variant and gender, around 75% of the index patients had at least one first-degree relative with MCAD. The molecular processes which result in familial aggregation of MCAD remain speculative. The detection of differing systemic MCAD-associated somatic mutations within given families suggests that the disease arises secondary to a dysfunction of as yet unidentified operator and/or regulator genes.

 

Research topics


Molecular, genetical and clinical investigations on mast cell activation disease (mastocytosis). Relevance of agmatine in the pathogenesis of intestinal cancer, leukemic and liver diseases. The research projects are supported by grants of the Monika-Kutzner-StiftungB. Braun-Stiftung
Förderclub Mastzellforschung e.V. (Homepage)


Research staff

Gerhard J. Molderings
Funktion: Projektleiter
Associate Professor of Pharmacology and Toxicology
Guest researcher at the Institute of Human Genetics, University Hospital of Bonn
Chief scientist of the Bonn Interdisciplinary Research Group for Systemic Mast Cell Diseases

Tel.: 0228 - 287 - 51060

Email: molderings@uni-bonn.de

 

Publications

2014

  1. D. Pöhlau, M. Raithel, B. Haenisch, S. Harzer, G. J. Molderings (2014) Die neurolo¬gi¬schen und psychiatrischen Symptome der systemischen Mastzellaktivierungser¬krankung vermutlich oft gesehen, aber nur selten diagnostiziert -. NeuroTransmitter, im Druck.
  2. G. J. Molderings (2014) The genetic basis of mast cell activation disease - looking through a glass darkly. Crit Rev Oncol Hematol doi: 0.1016/j.critrevonc.2014.09.001. [Epub ahead of print]
  3. D. Schäfer, P. Dreßen, S. Brettner, N.-F. Rath, G. J. Molderings, K. Jensen, C. Ziemann (2014) Prostaglandin D2-supplemented „functional eicosanoid testing and typing“ assay with peripheral blood leukocytes as a new tool in the diagnosis of systenic mast cell activation disease: an explorative diagnostic study. J Transl Med 12:213.
  4. G. J. Molderings, J. Homann, S. Brettner, M. Raithel, T. Frieling (2013) Systemische Mastzellaktivierungserkrankung: Ein praxisorientierter Leitfaden zu Diagnostik und Therapie. Dtsch Med Wochenschr 139: 1-16.
  5. B. Haenisch, H. Fröhlich, S. Herms, G. J. Molderings (2014) Evidence for contribu¬tion of epigenetic mechanisms in the pathogenesis of systemic mast cell activation disease. Immunogenetics 66: 287-297.
  6. L. B. Afrin, G. J. Molderings (2014) A concise, practical guide to diagnostic assess¬ment for mast cell activation disease. World J Hematol 6: 1-17.
  7. B. Sido, F.L. Dumpulin, J. Homann, H.-J. Hertfelder, M. Bollmann, G. J. Molderings (2014) Chirurgische Eingriffe an Patienten mit Mastzellüberaktivitätserkrankung. Chirurg 85: 327-333.

2013

  1. G. J. Molderings, B. Haenisch, M. Bogdanow, R. Fimmers, M. M. Nöthen (2013) Familial occurrence of systemic mast cell activation disease. PLoS ONE 8: e76241.
  2. J.E. Piletz, F. Aricioglu, J.-T. Cheng, C.A. Fairbanks, V.H. Gilad, B. Haenisch, A. Halaris, S. Hong, J.E. Lee, J. Li, P. Liu, G.J. Molderings, A.L.S. Rodrigues, J. Satriano, G.J. Seong, G. Wilcox, N. Wu, G.M. Gilad (2013) Agmatine: clinical applications after 100 years in translation, Drug Discovery Today 18: 880-893.
  3. A.F. Hagel, C.M. Layritz, W.H. Hagel, H.-J. Hagel, E. Hagel, W. Dauth, J. Kressel, T. Regnet , A. Rosenberg, M.F. Neurath, G.J. Molderings, M. Raithel (2013) Intravenous infusion of ascorbic acid decreases serum histamine concentrations in patients with allergic and non-allergic diseases. Naunyn-Schmiedebrg´s Arch Pharmacol 386: 789-793.
  4. B. Haenisch, S. Herms, G.J. Molderings (2013) The transcriptome of the human mast cell leukemia cells HMC-1.2 - An approach to identify specific changes in the gene expression profile in KitD816V systemic mastocytosis. Immunologic Research 56: 155-162
  5. O. S. Yousefi, T. Wilhelm, K. Maschke-Neuß, M. Kuhny, C. Martin, G. J. Molderings, F. Kratz, B. Hildenbrand, M. Huber (2013) The 1,4-benzodiazepine Ro5-4864 (4-chlorodiazepam) suppresses multiple pro-inflammatory mast cell effector functions. Cell Communication and Signaling 11: 13
  6. B. Haenisch, M. Huber, T. Wilhelm, M. Steffens, G.J. Molderings (2013) Investigations into mechanisms mediating the inhibitory effect of 1,4-benzodiazepines on mast cells by gene expression profiling. Life Sci 92: 345-351
  7. K. Hoffmann, R. Altarcheh Xifro, J.L. Hartweg, P. Spitzlei, K. Meis, G.J. Molderings, I. von Kügelgen (2013). Inhibitory effects of benzodiazepines on the adenosine A2B receptor mediated secretion of interleukin-8 in human mast cells. Eur J Pharmacol 700: 152-158

2012

  1. B. Haenisch, M. M. Nöthen, G. J. Molderings (2012) Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology 137: 197-205.
  2. G.J. Molderings (2012) Physiological, pathophysiological and therapeutic impact of the enteric serotonergic system. Arzneimittelforsch/Drug Res 62: 157-166.
  3. B. Haenisch, M. Huber, T. Wilhelm, G.J. Molderings (2012) Moleculargenetic investigations on the mechanisms mediating the inhibitory effect of benzodiazepines on mast cells. Naunyn-Schmiedeberg´s Arch Pharamcol 385, Suppl. 1: S60
  4. G.J. Molderings, B. Haenisch (2012) Agmatine (decarboxylated L-arginine): Physiological role and therapeutic potential. Pharmacol Ther 133: 351-365

2011

  1. Y. Zopf, S. Kimpel, A. Naegel, G.J. Molderings, O. Konturek, F. Buchwald, H.W. Schultis, J. Kressel, E.G. Hahn, M. Raithel (2011) The measurement of leukotrienes in urine as diagnostic option in systemic mastocytosis. J Physiol Pharmacol 62: 469-472
  2. H. Seidel, G.J. Molderings, J. Oldenburg , K. Meis, U.W. Kolck, J. Homann, H.-J. Hertfelder (2011) Bleeding diathesis in patients with mast cell activation disease. Thrombosis Haemostasis 106: 987-989
  3. G. J. Molderings, S. Brettner, J. Homann, L. B. Afrin (2011) Mast cell activation disease: A concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol 4: 10
  4. B. Haenisch, H. Bönisch, S. Cichon, J-P Allam, N, Novak, G.J. Molderings (2011) Effects of exogenous agmatine in human leukemia HMC-1 and HL-60 cells on proliferation, polyamine metabolism and cell cycle. Leukemia Res 35: 1248-1253
  5. G. J. Molderings, M. Raithel, F. Kratz, M. Azemar, B. Haenisch, S. Harzer, J. Homann (2011) Omalizumab treatment of systemic mast cell activation disease: experiences from four cases. Internal Medicine 50: 611-615
  6. T. Frieling, K. Meis, U.W. Kolck, J. Homann, A. Hülsdonk, U. Haars, H.-J. Hertfelder, J. Oldenburg, H. Seidel, G.J. Molderings (2011) Evidence for mast cell activation in patients with therapy-resistant irritable bowel syndrome. Z Gastroenterol 49: 191-194
  7. The poster presentation of the data at the 21. Kongress der Mitteldeutschen Gesellschaft für Gastroenterologie (2012 in Jena, Germany) was awarded as the best poster presented.

2010

  1. G.J. Molderings, K. Meis, U.W. Kolck, J. Homann, T. Frieling (2010) Comparative analysis of mutation of tyrosine kinase Kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects. Immunogenetics 62: 721-727
  2. G.J. Molderings (2010) Mast cell function in physiology and pathophysiology. BIOTREND Rev 5: 1-9 (pdf-file)
  3. C. Breuer , J. Oh, G.J. Molderings, M. Schemann, B. Kuch, E. Mayatepek, R. Adam (2010) Therapy-refractory gastrointestinal motility disorder and alterations in interstitial cells of Cajal (ICC) in a patient with c-kit mutation. World J Gastroenterol 16: 4363-4366
  4. J. Homann, U.W, Kolck, A. Ehnes, T. Frieling, M. Raithel, G.J. Molderings (2010) Die systemische Mastozytose - Standortbestimmung einer internistischen Erkrankung. Med Klinik 105: 544-553
  5. J. Homann, S. Homann, G.J. Molderings (2010) Bemerkungen zur Begutachtung von systemischen Mastzellerkrankungen. Der medizinische Sachverständige 05-2010: 194ff
  6. R. A. Xifro, K. Hoffmann, K. Meis, P. Spitzlei, G.J. Molderings, I. von Kügelgen (2010) Evidence for the involvement of peripheral-type benzodiazepine receptors in the inhibitory effcet of diazepam, flunitrazepam and 4-chlorodiazepam on the interleukin-8 production in human mast cells. Naunyn-Schmiedeberg´s Arch Pharmacol 381 (Suppl. 1): R40

2009

  1. G.J. Molderings, G. Solleder, U.W. Kolck, J. Homann, D. Schröder, I. von Kügelgen, R. Vorreuther (2009) Ureteral stones due to systemic mastocytosis: diagnostic and therapeutic characteristics. Urol Res 37: 227-229
  2. I. von Kügelgen, K. Meis, P. Spitzlei, G.J. Molderings (2009) Adenosine A2B-receptor-mediated activation of the transcription factors NFkappaB and AP-1 in human mast cells. Naunyn-Schmiedeberg´s Arch Pharmacol 379 (Suppl. 1): R17
  3. K. Meis, P. Spitzlei, I. von Kügelgen, G.J. Molderings (2009) Investigation on the molecular mechanisms mediating the inhibitory effect of benzodiazepines on mast cells. Naunyn-Schmiedeberg´s Arch Pharmacol 379 (Suppl. 1): R43
  4. G.J. Molderings (2009) Commentary [Systemic mastocytosis]: Condition is often overlooked. BMJ 338:b799. doi: 10.1136/bmj.b799
  5. K. Alfter, I. von Kügelgen, B. Haenisch, T. Frieling, A. Hülsdonk, U. Haars, A. Rolfs, G. Noe, U.W. Kolck, J. Homann, G.J. Molderings (2009) New aspects of liver abnormalities as part of the systemic mast cell activation syndrome. Liver International 29: 181-186

2008

  1. B. Haenisch, I. von Kügelgen, H. Bönisch, M. Göthert, T. Sauerbruch, M. Schepke, G. Marklein, K. Höfling, D. Schröder, G.J. Molderings (2008) Regulatory mechanisms underlying agmatine homeostasis in human. Am J Physiol Gastrointest Liver Physiol 295: G1104-G1110
  2. Pasternack SM, I.v. Kügelgen, K.A. Aboud, Y.A. Lee, F. Rüschendorf, K. Voss, A.M. Hillmer, G.J. Molderings, T. Franz, A. Ramirez, P. Nurnberg, M.M. Nöthen, R.C. Betz (2008) G-protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth. Nat. Genet. 40: 329-334

2007

  1. K. Alfter, I. von Kügelgen, U.W. Kolck, G. Noe, T. Frieling, H.-J. Hertfelder, J. Oldenburg, J. Homann, G.J. Molderings (2007) Diagnostics and therapy of systemic mastocytosis. Med Welt 58: 621-631
  2. G.J. Molderings, M. Göthert, I. v. Kügelgen (2007) Characterization of an antiproliferative effect of imidazoline receptor ligands on PC12 cells. Pharmacol. Reports 59: 789-794
  3. G.J. Molderings, H. Bönisch, M. Brüss, C. Wolf, O. von Kügelgen, M. Göthert (2007) S1P-receptors in PC12 and transfected HEK293 cells: Molecular targets of hypotensive imidazoline I1 receptor ligands. Neurochem Int 51: 476-485
  4. K. Alfter, I. von Kügelgen, U.W. Kolck, G. Noe, T. Frieling, H.-J. Hertfelder, J. Oldenburg, J. Homann, G.J. Molderings (2007) Diagnostics and therapy of systemic mastocytosis. Med Welt 58: 621-631
  5. G.J. Molderings, H. Bönisch, M. Brüss, C. Wolf, O. von Kügelgen, M. Göthert (2007) Identification of S1P receptors as molecular targets for the blood pressure-lowering imidazoline drugs clonidine and moxonidine. Neurochem Int, 51: 476-485
  6. G.J. Molderings, U.W. Kolck, C. Scheurlen, M. Brüss, J. Homann, I. von Kügelgen (2007) Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder. Scand J Gastroenterol, 42: 1045-1053
  7. U.W. Kolck, K. Alfter, J. Homann, I. von Kügelgen, G.J. Molderings (2007) Letter to the editor: Cardiac mast cells: implications for heart failure. J Am Coll Cardiol, 49: 1107

2006

  1. G.J. Molderings, U. Kolck, C. Scheurlen, M. Brüss, T. Frieling, M. Raithel, J. Homann (2006) Systemic mast cell disease with gastrointestinal symptoms - a diagnostic questionnaire. Dtsch Med Wochenschr, 131: 2095-2100

2005

  1. G.J. Molderings, M. Brüss, M. Raithel, V. Wilken, K. Hartman, K. Brockow, E. Wardelmann, Ch. Scheurlen, J. Homann (2005) Systemische Mastozytose als Grund für chronische gastrointestinale Beschwerden. Dtsch. Arztebl., 102: A1744-A1749

2004

  1. G.J. Molderings, B. Kribben, A. Heinen, D. Schröder, M. Brüss, M. Göthert (2004) Intestinal tumor and agmatine (decarboxylated arginine). Low content in colon carcinoma tissue specimens and inhibitory effect on tumor cell proliferation in vitro. Cancer, 101: 858-868
  2. M. Brüss, J. Homann, G.J. Molderings (2004) Dysferlinopathie als extrahepatische Ursache von Transaminasenerhöhungen. Med. Klinik, 99: 326-329
  3. B. Kribben, J. Heller, J. Trebicka, T. Sauerbruch, M. Brüss, M. Göthert, G.J. Molderings (2004) Agmatine (decarboxylated arginine) a modulator of liver cell homeostasis and proliferation. Naunyn-Schmiedeberg´s Arch. Pharmacol., 369: 160-165

2003 - 1997

  1. A. Heinen, M. Brüss, H. Bönisch, M. Göthert, G.J. Molderings (2003) Pharmacological characteristics of the specific transporter for the endogenous cell growth inhibitor agmatine in six tumor cell lines. Int. J. Colorectal Dis., 18: 314-319
  2. M. Brüss, H. Bönisch, M. Göthert, G.J. Molderings (2003) Molecular structure of the rabbit alpha2A-adrenoceptor. A contribution to the alpha2A-adrenoceptor versus I1 imidazoline receptor controversy. Naunyn-Schmiedeberg´s Arch. Pharmacol., 367: 328-331
  3. Molderings GJ, Homann J, Brüss M (2002) Systemische Mastozytose. Med Welt 7-8: 255-260
  4. Molderings GJ, Heinen A, Menzel S, Göthert M (2002) Exposure of rat isolated stomach and rats in vivo to [14C]agmatine: accumulation in the stomach wall and distribution in various tissues. Fund Clin Pharmacol 16: 219-225
  5. Molderings GJ, Bönisch H, Göthert M, Brüss M (2001) Agmatine and putrescine uptake in the human glioma cell line SK-MG-1. Naunyn-Schmiedeberg&s Arch Pharmacol 363: 671-679
  6. Molderings GJ, Menzel S, Kathmann M, Schlicker E, Göthert M (2000) Dual interaction of agmatine with the rat alpha2D-adrenoceptor: competitive antagonism and allosteric activation. Br J Pharmacol 130: 1706-1712
  7. Molderings GJ, Homann J (2000) Agmatin - klinische Perspektiven eines neuen Botenstoffs. Med Welt 11: 356-361
  8. G.J. Molderings, J. Likungu, M. Göthert (1999) Presynaptic cannabinoid and imidazoline receptors in the human heart and their potential relationship. Naunyn-Schmiedeberg's Arch. Pharmacol. 360: 157-164
  9. G.J. Molderings, K. Donecker, M. Burian, W.A. Simon, D.W. Schröder, M. Göthert (1998) Characterization of I2 imidazoline and sigma-binding sites in the rat and human stomach. J. Pharmacol. Exp. Ther. 285: 170-177
  10. G.J. Molderings, J. Likungu, J. Jakschik, M. Göthert (1997) Presynaptic imidazoline receptors and non-adrenoceptor [3H]-idazoxan binding sites in human cardiovascular tissue. Br. J. Pharmacol., 122: 43-50

 

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