Journal of Translational Medicine | |
Prostaglandin D2-supplemented “functional eicosanoid testing and typing” assay with peripheral blood leukocytes as a new tool in the diagnosis of systemic mast cell activation disease: an explorative diagnostic study | |
Christina Ziemann4  Katrin Jensen1  Gerhard J Molderings5  Norbert-Folke Rath7  Stefan Brettner2  Peter Dreßen3  Dirk Schäfer6  | |
[1] Institute of Medical Biometry and Informatics, University Heidelberg, Heidelberg, Germany;Department of Oncology, Haematology and Palliative Care, District Hospital of Waldbröl, Waldbröl, Germany;Department of Internal Medicine, St. Franziskus Hospital, Eitorf, Germany;Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany;Institute of Human Genetics, University Hospital of Bonn, Bonn, Germany;Medical Clinic III, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany;Oststadt-Heidehaus Hospital Laboratory, Klinikum Region Hannover (clinical centre of the Hannover region), Hannover, Germany | |
关键词: Arachidonic acid; Acetylsalicylic acid; Substance P; Mastocytosis; Functional eicosanoid testing and typing; Peptido-leukotrienes; PGD2; PGE2; Eicosanoids; Systemic mast cell activation disease; | |
Others : 1148478 DOI : 10.1186/s12967-014-0213-2 |
|
received in 2014-03-17, accepted in 2014-07-21, 发布年份 2014 | |
![]() |
【 摘 要 】
Background
Systemic mast cell activation disease (MCAD) is characterized by an enhanced release of mast cell-derived mediators, including eicosanoids, which induce a broad spectrum of clinical symptoms. Accordingly, the diagnostic algorithm of MCAD presupposes the proof of increased mast cell mediator release, but only a few mediators are currently established as routine laboratory parameters. We thus initiated an explorative study to evaluate in vitro typing of individual eicosanoid pattern of peripheral blood leukocytes (PBLs) as a new diagnostic tool in MCAD.
Methods
Using the “functional eicosanoid testing and typing” (FET) assay, we investigated the balance (i.e. the complex pattern of formation, release and mutual interaction) of prostaglandin E2 (PGE2) and peptido-leukotrienes (pLT) release from PBLs of 22 MCAD patients and 20 healthy individuals. FET algorithms thereby consider both basal and arachidonic acid (AA)-, acetylsalicylic acid (ASA)-, and substance P (SP)-triggered release of PGE2 and pLT. The FET assay was further supplemented by analyzing prostaglandin D2 (PGD2), as mast cell-specific eicosanoid.
Results
We observed marked PGE2-pLT imbalances for PBLs of MCAD patients, as indicated by a markedly enhanced mean FET value of 1.75 ± 0.356 (range: 1.14–2.36), compared to 0.53 ± 0.119 (range: 0.36-0.75) for healthy individuals. In addition, mean PGD2 release from PBLs of MCAD patients was significantly, 6.6-fold higher than from PBLs of healthy individuals (946 ± 302.2 pg/ml versus 142 ± 47.8 pg/ml; P < 0.001). In contrast to healthy individuals, PGD2 release from PBLs of MCAD patients was markedly triggered by SP (mean: 1896 ± 389.7 pg/ml; P < 0.001), whereas AA and ASA caused individually varying effects on both PGD2 and pLT release.
Conclusions
The new in-vitro FET assay, supplemented with analysis of PGD2, demonstrated that the individual patterns of eicosanoid release from PBLs can unambiguously distinguish MCAD patients from healthy individuals. Notably, in our analyses, the FET value and both basal and triggered PGD2 levels were not significantly affected by MCAD-specific medication. Thus, this approach may serve as an in-vitro diagnostic tool to estimate mast cell activity and to support individualized therapeutic decision processes for patients suffering from MCAD.
【 授权许可】
2014 Schäfer et al.; licensee BioMed Central Ltd.
【 预 览 】
Files | Size | Format | View |
---|---|---|---|
20150404153233273.pdf | 923KB | ![]() |
|
Figure 5. | 41KB | Image | ![]() |
Figure 4. | 51KB | Image | ![]() |
Figure 3. | 46KB | Image | ![]() |
Figure 2. | 40KB | Image | ![]() |
Figure 1. | 43KB | Image | ![]() |
【 图 表 】
Figure 1.
Figure 2.
Figure 3.
Figure 4.
Figure 5.
【 参考文献 】
- [1]Molderings GJ, Brettner S, Homann J, Afrin LB: Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol 2011, 4:10. BioMed Central Full Text
- [2]Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, Castells M, Escribano L, Hartmann K, Lieberman P, Nedoszytko B, Orfao A, Schwartz LB, Sotlar K, Sperr WR, Triggiani M, Valenta R, Horny HP, Metcalfe DD: Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 2012, 157:215-225.
- [3]Hamilton MJ, Hornick JL, Akin C, Castells MC, Greenberger NJ: Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol 2011, 128:147-152.
- [4]Valent P, Akin C, Escribano L, Födinger M, Hartmann K, Brockow K, Castells M, Sperr WR, Kluin-Nelemans HC, Hamdy NA, Lortholary O, Robyn J, van Doormaal J, Sotlar K, Hauswirth AW, Arock M, Hermine O, Hellmann A, Triggiani M, Niedoszytko M, Schwartz LB, Orfao A, Horny HP, Metcalfe DD: Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest 2007, 37:435-453.
- [5]Akin C, Valent P, Metcalfe DD: Mast cell activation syndrome: Proposed diagnostic criteria. J Allergy Clin Immunol 2010, 126:1099-1104.
- [6]Alvarez-Twose I, González de Olano D, Sánchez-Muñoz L, Matito A, Esteban-López MI, Vega A, Mateo MB, Alonso Díaz de Durana MD, de la Hoz B, Del Pozo Gil MD, Caballero T, Rosado A, Sánchez Matas I, Teodósio C, Jara-Acevedo M, Mollejo M, García-Montero A, Orfao A, Escribano L: Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms. J Allergy Clin Immunol 2010, 125:1269-1278.
- [7]Cardet JC, Castells MC, Hamilton MJ: Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep 2013, 13:10-18.
- [8]Frieri M, Patel R, Celestin J: Mast cell activation syndrome: a review. Curr Allergy Asthma Rep 2013, 13:27-32.
- [9]Boyce JA: Eicosanoid mediators of mast cells: receptors, regulation of synthesis, and pathobiologic implications. Chem Immunol Allergy 2005, 87:59-79.
- [10]Lundström SL, Saluja R, Adner M, Haeggström JZ, Nilsson G, Wheelock CE: Lipid mediator metabolic profiling demonstrates differences in eicosanoid patterns in two phenotypically distinct mast cell populations. J Lipid Res 2013, 54:116-126.
- [11]O’Sullivan S: On the role of PGD2 metabolites as markers of mast cell activation in asthma. Acta Physiol Scand Suppl 1999, 644:1-74.
- [12]Dahlén SE, Kumlin M: Monitoring mast cell activation by prostaglandin D2 in vivo. Thorax 2004, 59:453-455.
- [13]Schäfer D, Maune S: Pathogenic mechanisms and in-vitro diagnosis of AERD. J Allergy (Cairo) 2012, 2012:789232.
- [14]Molderings GJ, Kolck U, Scheurlen C, Brüss M, Frieling T, Raithel M, Homann J: Systemic mast cell disease with gastrointestinal symptoms–a diagnostic questionnaire. Dtsch Med Wochenschr 2006, 131:2095-2100.
- [15]Molderings GJ, Haenisch B, Bogdanow M, Fimmers R, Nöthen MM: Familial occurrence of systemic mast cell activation disease. PLoS One 2013, 8:e76241.
- [16]Alfter K, von Kügelgen I, Haenisch B, Frieling T, Hülsdonk A, Haars U, Rolfs A, Noe G, Kolck UW, Homann J, Molderings GJ: New aspects of liver abnormalities as part of the systemic mast cell activation syndrome. Liver Int 2009, 29:181-186.
- [17]Schäfer D, Schmid M, Göde UC, Baenkler HW: Dynamics of eicosanoids in peripheral blood cells during bronchial provocation in aspirin-intolerant asthmatics. Eur Respir J 1999, 13:638-646.
- [18]Schäfer D, Baenkler HW: Functional eicosanoid test and typing (FET) of peripheral blood cells in eicosanoids related diseases. J Physiol Pharmacol 2005, 56(Suppl 5):103-118.
- [19]Schäfer D: Testing and typing of eicosanoid-patterns. J Physiol Pharmacol 2006, 57(Suppl 12):47-64.
- [20]Brune K, Reinke M, Lanz R, Peskar BA: Monoclonal antibodies against E- and F-type prostaglandins. FEBS Lett 1985, 186:46-50.
- [21]Reinke M, Hoppe H, Röder T, Bestmann HJ, Molenhauer J, Brune K: A monoclonal antibody against the sulfidopeptide leukotrienes LTC4, LTD4 and LTE4. Biochim Biophys Acta 1991, 1081:274-278.
- [22]Schäfer D, Lindenthal U, Wagner M, Bölcskei PL, Baenkler HW: Effect of prostaglandin E2 on eicosanoid release by human bronchial biopsy specimens from normal and inflamed mucosa. Thorax 1996, 51:919-923.
- [23]Abel U: Die Bewertung diagnostischer Tests. Hippokrates, Stuttgart; 1993.
- [24]Butterfield JH: Survey of aspirin administration in systemic mastocytosis. Prostaglandins Other Lipid Mediat 2009, 88:122-124.
- [25]Butterfield JH, Weiler CR: Prevention of mast cell activation disorder-associated clinical sequelae of excessive prostaglandin D2production.Int Arch Allergy Immunol 2008, 147:338–343.
- [26]Maintz L, Wardelmann E, Walgenbach K, Fimmers R, Bieber T, Raap U, Novak N: Neuropeptide blood levels correlate with mast cell load in patients with mastocytosis. Allergy 2011, 66:862-869.
- [27]Katsanos GS, Anogeianaki A, Orso C, Tetè S, Salini V, Antinolfi PL, Sabatino G: Mast cells and chemokines. J Biol Regul Homeost Agents 2008, 22:145-151.
- [28]Krishnaswamy G, Ajitawi O, Chi DS: The human mast cell: an overview. Methods Mol Biol 2006, 315:13-34.
- [29]Baenkler HW, Schäfer D: Abnormal eicosanoid-pattern of peripheral white-blood-cells in gastro-intestinal cancer. J Physiol Pharmacol 2005, 56:119-128.
- [30]Baenkler HW, Zeus J, Schenk J, Schäfer D: Abnormal eicosanoid pattern by blood leukocytes in gastroduodenal ulcer. Med Sci Monit 2004, 10:CR557-CR562.
- [31]Schmid M, Göde U, Schäfer D, Wigand ME: Arachidonic acid metabolism in nasal tissue and peripheral blood cells in aspirin intolerant asthmatics. Acta Otolaryngol 1999, 119:277-280.
- [32]Velten FW, Bayerl C, Baenkler HW, Schaefer D: Functional eicosanoid test and typing (FET) in acetylsalicylic acid intolerant patients with urticaria. J Physiol Pharmacol 2006, 57(Suppl 12):35-46.
- [33]Förster U, Strahtmann S, Schäfer D, Szczepek AJ, Olze H: Eicosanoid imbalance correlates in-vitro with the pattern of clinical symptoms of Samter’s triad. Rhinology 2013, 51:61-69.
- [34]Lewis RA, Soter NA, Diamond PT, Austen KF, Oates JA, Roberts LJ II: Prostaglandin D2generation after activation of rat and human mast cells with anti IgE.J Immunol 1982, 129:1627–1631.
- [35]Sismanopoulos N, Delivanis DA, Alysandratos KD, Angelidou A, Therianou A, Kalogeromitros D, Theoharides TC: Mast cells in allergic and inflammatory diseases. Curr Pharm Des 2012, 18:2261-2277.
- [36]Roberts LJ, Oates JA: Biochemical diagnosis of systemic mast cell disorders. J Invest Dermatol 1991, 96(Suppl 3):19S-24S. discussion 24S-25S; 60S-65S
- [37]Awad JA, Morrow JD, Roberts LJ II: Detection of the major urinary metabolite of prostaglandin D2 in the circulation: Demonstration of elevated levels in patients with disorders of mast cell activation. J Allergy Clin Immunol 1994, 93:817-824.
- [38]Morrow JD, Guzzo C, Lazarus G, Oates JA, Roberts LJ 2nd: Improved diagnosis of mastocytosis by measurement of the major urinary metabolite of prostaglandin D2.J Invest Dermatol 1995, 104:937–940.
- [39]Kolck UW: Investigations on the pathogenesis of the systemic mast cell activation syndrome and its impact on heart function. In Medical Thesis. Institute for Pharmacology and Toxioclogy, University of Bonn; 2009. [in German]
- [40]Molderings GJ, Meis K, Kolck UW, Homann J, Frieling T: Comparative analysis of mutation of tyrosine kinase kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects. Immunogenetics 2010, 62:721-727.
- [41]Torrey E, Simpson K, Wilbur S, Munoz P, Skikne B: Malignant mastocytosis with circulating mast cells. Am J Hematol 1990, 34:283-286.
- [42]Georgin-Lavialle S, Lhermitte L, Baude C, Barete S, Bruneau J, Launay JM, Chandesris MO, Hanssens K, de Gennes C, Damaj G, Lanternier F, Hamidou M, Lortholary O, Dubreuil P, Feger F, Lepelletier Y, Hermine O: Blood CD34-c-Kit + cell rate correlates with aggressive forms of systemic mastocytosis and behaves like a mast cell precursor. Blood 2011, 118:5246-5249.
- [43]Tanaka K, Ogawa K, Sugamura K, Nakamura M, Takano S, Nagata K: Cutting edge: differential production of prostaglandin D2 by human helper T cell subsets. J Immunol 2000, 164:2277-2280.
- [44]Luna-Gomes T, Magalhães KG, Mesquita-Santos FP, Bakker-Abreu I, Samico RF, Molinaro R, Calheiros AS, Diaz BL, Bozza PT, Weller PF, Bandeira-Melo C: Eosinophils as a novel cell source of prostaglandin D2: autocrine role in allergic inflammation. J Immunol 2011, 187:6518-6526.
- [45]Ugajin T, Satoh T, Kanamori T, Aritake K, Urade Y, Yokozeki H: FcεRI, but not FcγR, signals induce prostaglandin D2 and E2 production from basophils. Am J Pathol 2011, 179:775-782.
- [46]Horny HP, Ruck M, Wehrmann M, Kaiserling E: Blood findings in generalized mastocytosis: evidence of frequent simultaneous occurrence of myeloproliferative disorders. Br J Haematol 1990, 76:186-193.
- [47]Böhm A, Födinger M, Wimazal F, Haas OA, Mayerhofer M, Sperr WR, Esterbauer H, Valent P: Eosinophilia in systemic mastocytosis: clinical and molecular correlates and prognostic significance. J Allergy Clin Immunol 2007, 120:192-199.
- [48]Butterfield JH: Increased leukotriene E4 excretion in systemic mastocytosis. Prostaglandins Other Lipid Mediat 2010, 92:73-76.
- [49]Raithel M, Zopf Y, Kimpel S, Naegel A, Molderings GJ, Buchwald F, Schultis HW, Kressel J, Hahn EG, Konturek P: The measurement of leukotrienes in urine as diagnostic option in systemic mastocytosis. J Physiol Pharmacol 2011, 62:469-472.
- [50]Galli SJ, Costa JJ: Mast-cell-leukocyte cytokine cascades in allergic inflammation. Allergy 1995, 50:851-862.
- [51]Mellor EA, Frank N, Soler D, Hodge MR, Lora JM, Austen KF, Boyce JA: Expression of the type 2 receptor for cysteinyl leukotrienes (CysLT2R) by human mast cells: functional distinction from CysLT1R. PNAS 2003, 100:11589-11593.
- [52]Kaneko I, Suzuki K, Matsuo K, Kumagai H, Owada Y, Noguchi N, Hishinuma T, Ono M: Cysteinyl leukotrienes enhance the degranulation of bone marrow-derived mast cells through the autocrine mechanism. Tohoku J Med 2009, 217:185-191.
- [53]Tolar J, Tope WD, Neglia JP: Leukotriene- receptor inhibition for the treatment of systemic mastocytosis. N Engl J Med 2004, 350:735-736.
- [54]Riccioni G, Bucciarelli T, Mancini B, Di Ilio C, D'Orazio N: Antileukotriene drugs: clinical application, effectiveness and safety. Curr Med Chem 2007, 14:1966-1977.
- [55]Turner PJ, Kemp AS, Rogers M, Mehr S: Refractory symptoms successfully treated with leukotriene inhibition in a child with systemic mastocytosis. Pediatr Dermatol 2012, 29:222-223.
- [56]Ramires R, Caiaffa MF, Tursi A, Haeggström JZ, Macchia L: Novel inhibitory effect on 5-lipoxygenase activity by the anti-asthma drug montelukast. Biochem Biophys Res Commun 2004, 324:815-821.
- [57]Woszczek G, Chen LY, Alsaaty S, Nagineni S, Shelhamer JH: Concentration-dependent noncysteinyl leukotriene type 1 receptor-mediated inhibitory activity of leukotriene receptor antagonists. J Immunol 2010, 184:2219-2225.
- [58]Butterfield JH, Kao PC, Klee GC, Yocum MW: Aspirin idiosyncrasy in systemic mast cell disease: a new look at mediator release during aspirin desensitization. Mayo Clin Proc 1995, 70:481-487.
- [59]Benyon RC, Robinson C, Church MK: Differential release of histamine and eicosanoids from human skin mast cells activated by IgE-dependent and non-immunological stimuli. Br J Pharmacol 1989, 97:898-904.
- [60]Karimi K, Kool M, Nijkamp FP, Redegeld FA: Substance P can stimulate prostaglandin D2 and leukotriene C4 generation without granule exocytosis in murine mast cells. Eur J Pharmacol 2004, 489:49-54.
- [61]Nordlind K, Theodorsson E: Plasma concentrations and urinary excretion of regulatory peptides in patients with urticaria pigmentosa. Ups J Med Sci 1993, 98:169-178.
- [62]Brzezińska-Błaszczyk E, Zalewska A: In vitro reactivity of mast cells in urticaria pigmentosa skin. Arch Dermatol Res 1998, 290:14-17.
- [63]Cooke HJ, Fox P, Alferes L, Fox CC, Wolfe SA Jr: Presence of NK1 receptors on a mucosal-like mast cell line, RBL-2H3 cells. Can J Physiol Pharmacol 1998, 76:188-193.
- [64]Krumins SA, Broomfield CA: Evidence of NK1 and NK2 tachykinin receptors and their involvement in histamine release in a murine mast cell line. Neuropeptides 1992, 21:65-72.
- [65]van der Kleij HPM, Ma D, Redegeld FAM, Kraneveld AD, Nijkamp FP, Bienenstock J: Functional expression of neurokinin 1 receptors on mast cells induced by IL-4 and stem cell factor. J Immunol 2003, 171:2074-2079.
- [66]Karimi K, Redegeld FA, Blom R, Nijkamp FP: Stem cell factor and interleukin-4 increase responsiveness of mast cells to substance P. Exp Hematol 2000, 28:626-634.
- [67]Kulka M, Sheen CH, Tancowny BP, Grammer LC, Schleimer RP: Neuropeptides activate human mast cell degranulation and chemokine production. Immunology 2008, 123:398-410.
- [68]Tatemoto K, Nozaki Y, Tsuda R, Konno S, Tomura K, Furuno M, Ogasawara H, Edamura K, Takagi H, Iwamura H, Noguchi M, Naito T: Immunoglobulin E-independent activation of mast cell is mediated by Mrg receptors. Biochem Biophys Res Commun 2006, 4:1322-1328.