Recent advances in our understanding of mast cell activation – or should it be mast cell mediator disorders?

References

• Chen CC, Grimbaldeston MA, Tsai M, et al. Identification of mast cell progenitors in adult mice. Proc Natl Acad Sci U S A. 2005;102:11408–11413.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Valent P, Akin C. Mast cells, mastocytosis, and related disorders. N Engl J Med. 2015;373:163–172.
   PubMed Web of Science ®Google Scholar
• Theoharides TC. Neuroendocrinology of mast cells: challenges and controversies. Exp Dermatol. 2017;26:751–759.
   PubMed Web of Science ®Google Scholar
• Cheng LE, Hartmann K, Roers A, et al. Perivascular mast cells dynamically probe cutaneous blood vessels to capture immunoglobulin E. Immunity. 2013;38(1):166–175.
   PubMed Web of Science ®Google Scholar
• Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature. 2008;454:445–454.
   PubMed Web of Science ®Google Scholar
• Toniato E, Frydas I, Robuffo I, et al. Activation and inhibition of adaptive immune response mediated by mast cells. J Biol Regul Homeost Agents. 2017;31:543–548.
   PubMed Web of Science ®Google Scholar
• Avila M, Gonzalez-Espinosa C. Signaling through Toll-like receptor 4 and mast cell-dependent innate immunity responses. IUBMB Life. 2011;63:873–880.
   PubMed Web of Science ®Google Scholar
• Cardamone C, Parente R, Feo GD, et al. Mast cells as effector cells of innate immunity and regulators of adaptive immunity. Immunol Lett. 2016;178:10–14.
   PubMed Web of Science ®Google Scholar
• Forsythe P. Microbes taming mast cells: implications for allergic inflammation and beyond. Eur J Pharmacol. 2016;778:169–175.
   PubMed Web of Science ®Google Scholar
• Gong J, Yang NS, Croft M, et al. The antigen presentation function of bone marrow-derived mast cells is spatiotemporally restricted to a subset expressing high levels of cell surface FcepsilonRI and MHC II. BMC Immunol. 2010;11:34.
   PubMed Web of Science ®Google Scholar
• Carroll-Portillo A, Cannon JL, Te RJ, et al. Mast cells and dendritic cells form synapses that facilitate antigen transfer for T cell activation. J Cell Biol. 2015;210:851–864.
   PubMed Web of Science ®Google Scholar
• Bulfone-Paus S, Bahri R. Mast cells as regulators of T cell responses. Front Immunol. 2015;6:394.
   PubMed Web of Science ®Google Scholar
• Ishii T, Wang J, Zhang W, et al. Pivotal role of mast cells in pruritogenesis in patients with myeloproliferative disorders. Blood. 2009;113:5942–5950.
   PubMed Web of Science ®Google Scholar
• Mekori YA, Hershko AY, Frossi B, et al. Integrating innate and adaptive immune cells: mast cells as crossroads between regulatory and effector B and T cells. Eur J Pharmacol. 2016;5:84–89.
   PubMed Web of Science ®Google Scholar
• Rodriguez Cetina Biefer H, Heinbokel T, Uehara H, et al. Mast cells regulate CD4(+) T-cell differentiation in the absence of antigen presentation. J Allergy Clin Immunol. 2018;142:1894–1908.
   Web of Science ®Google Scholar
• Christy AL, Brown MA. The multitasking mast cell: positive and negative roles in the progression of autoimmunity. J Immunol. 2007;179:2673–2679.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Alysandratos KD, Angelidou A, et al. Mast cells and inflammation. Biochim Biophys Acta. 2012;1822:21–33.
   PubMed Web of Science ®Google Scholar
• Sismanopoulos N, Delivanis DA, Mavrommati D, et al. Do mast cells link obesity and asthma? Allergy. 2013;68:8–15.
   PubMed Web of Science ®Google Scholar
• Mukai K, Tsai M, Saito H, et al. Mast cells as sources of cytokines, chemokines, and growth factors. Immunol Rev. 2018;282:121–150.
   PubMed Web of Science ®Google Scholar
• Galli SJ, Grimbaldeston M, Tsai M. Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol. 2008;8:478–486.
   PubMed Web of Science ®Google Scholar
• Cao J, Papadopoulou N, Kempuraj D, et al. Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. J Immunol. 2005;174:7665–7675.
   PubMed Web of Science ®Google Scholar
• Lazarus LH, Perrin MH, Brown MR, et al. Verification of both the sequence and confromational specificity of neurotensin in binding to mast cells. Biochem Biophys Res Commun. 1977;76:1079–1085.
   PubMed Web of Science ®Google Scholar
• Donelan J, Boucher W, Papadopoulou N, et al. Corticotropin-releasing hormone induces skin vascular permeability through a neurotensin-dependent process. Proc Natl Acad Sci USA. 2006;103:7759–7764.
   PubMed Web of Science ®Google Scholar
• Mustain WC, Rychahou PG, Evers BM. The role of neurotensin in physiologic and pathologic processes. Curr Opin Endocrinol Diabetes Obes. 2011;18:75–82.
   PubMed Web of Science ®Google Scholar
• Caceda R, Kinkead B, Nemeroff CB. Neurotensin: role in psychiatric and neurological diseases. Peptides. 2006;27:2385–2404.
   PubMed Web of Science ®Google Scholar
• Mashaghi A, Marmalidou A, Tehrani M, et al. Neuropeptide substance P and the immune response. Cell Mol Life Sci. 2016;73:4249–4264.
   PubMed Web of Science ®Google Scholar
• O’Connor TM, O’Connell J, O’Brien DI, et al. The role of substance P in inflammatory disease. J Cell Physiol. 2004;201:167–180.
   PubMed Web of Science ®Google Scholar
• Hokfelt T, Pernow B, Wahren J. Substance P: a pioneer amongst neuropeptides. J Intern Med. 2001;249:27–40.
   PubMed Web of Science ®Google Scholar
• Douglas SD, Leeman SE. Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation. Ann N Y Acad Sci. 2011;1217:83–95.
   PubMed Web of Science ®Google Scholar
• McNeil BD, Pundir P, Meeker S, et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature. 2015;519:237–241.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Kempuraj D, Tagen M, et al. Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev. 2007;217:65–78.
   PubMed Web of Science ®Google Scholar
• Zhang B, Weng Z, Sismanopoulos N, et al. Mitochondria distinguish granule-stored from de novo synthesized tumor necrosis factor secretion in human mast cells. Int Arch Allergy Immunol. 2012;159:23–32.
   PubMed Web of Science ®Google Scholar
• Askenase PW. Mast cells and the mediation of T-cell recruitment in arthritis. N Engl J Med. 2005;349:1294.
   Web of Science ®Google Scholar
• Zhang B, Alysandratos KD, Angelidou A, et al. Human mast cell degranulation and preformed TNF secretion require mitochondrial translocation to exocytosis sites: relevance to atopic dermatitis. J Allergy Clin Immunol. 2011;127:1522–1531.
   PubMed Web of Science ®Google Scholar
• Gordon JR, Galli SJ. Mast cells as a source of both preformed and immunologically inducible TNF-α/cachectin. Nature. 1990;346:274–276.
   PubMed Web of Science ®Google Scholar
• Picard M, Giavina-Bianchi P, Mezzano V, et al. Expanding spectrum of mast cell activation disorders: monoclonal and idiopathic mast cell activation syndromes. Clin Ther. 2013;35:548–562.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Bondy PK, Tsakalos ND, et al. Differential release of serotonin and histamine from mast cells. Nature. 1982;297:229–231.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Cochrane DE. Critical role of mast cells in inflammatory diseases and the effect of acute stress. J Neuroimmunol. 2004;146:1–12.
   PubMed Web of Science ®Google Scholar
• Caraffa A, Conti C, Ovidio D, et al. New concepts in neuroinflammation: mast cells pro-inflammatory and anti-inflammatory cytokine mediators. J Biol Regul Homeost Agents. 2018;32:449–454.
   PubMed Web of Science ®Google Scholar
• Conti P, Caraffa A, Kritas SK, et al. Mast cell, pro-inflammatory and anti-inflammatory: jekyll and Hyde, the story continues. J Biol Regul Homeost Agents. 2017;31:263–267.
   PubMed Web of Science ®Google Scholar
• Salamon P, Shoham NG, Gavrieli R, et al. Human mast cells release interleukin-8 and induce neutrophil chemotaxis on contact with activated T cells. Allergy. 2005;60:1316–1319.
   PubMed Web of Science ®Google Scholar
• Kempuraj D, Papadopoulou NG, Lytinas M, et al. Corticotropin-releasing hormone and its structurally related urocortin are synthesized and secreted by human mast cells. Endocrinology. 2004;145:43–48.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Donelan JM, Papadopoulou N, et al. Mast cells as targets of corticotropin-releasing factor and related peptides. Trends Pharmacol Sci. 2004;25:563–568.
   PubMed Web of Science ®Google Scholar
• Petra AI, Tsilioni I, Taracanova A, et al. Interleukin 33 and interleukin 4 regulate interleukin 31 gene expression and secretion from human laboratory of allergic diseases 2 mast cells stimulated by substance P and/or immunoglobulin E. Allergy Asthma Proc. 2018;39(2):153–160.
   PubMed Web of Science ®Google Scholar
• Theoharides TC. Danger signals and inflammation. Clin Ther. 2016;38:996–999.
   PubMed Web of Science ®Google Scholar
• Zhang B, Asadi S, Weng Z, et al. Stimulated human mast cells secrete mitochondrial components that have autocrine and paracrine inflammatory actions. PloS One. 2012;7:e49767.
   PubMed Web of Science ®Google Scholar
• Collins LV, Hajizadeh S, Holme E, et al. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J Leukoc Biol. 2004;75:995–1000.
   PubMed Web of Science ®Google Scholar
• Marques PE, Amaral SS, Pires DA, et al. Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure. Hepatology. 2012;56:1971–1982.
   PubMed Web of Science ®Google Scholar
• Sun S, Sursal T, Adibnia Y, et al. Mitochondrial DAMPs increase endothelial permeability through neutrophil dependent and independent pathways. PloS One. 2013;8:e59989.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Asadi S, Panagiotidou S, et al. The “missing link” in autoimmunity and autism: extracellular mitochondrial components secreted from activated live mast cells. Autoimmun Rev. 2013;12:1136–1142.
   PubMed Web of Science ®Google Scholar
• Asadi S, Theoharides TC. Corticotropin-releasing hormone and extracellular mitochondria augment IgE-stimulated human mast-cell vascular endothelial growth factor release, which is inhibited by luteolin. J Neuroinflam. 2012;9:85.
   PubMed Web of Science ®Google Scholar
• Lauritzen KH, Moldestad O, Eide L, et al. Mitochondrial DNA toxicity in forebrain neurons causes apoptosis, neurodegeneration, and impaired behavior. Mol Cell Biol. 2010;30:1357–1367.
   PubMed Web of Science ®Google Scholar
• Zhang B, Angelidou A, Alysandratos KD, et al. Mitochondrial DNA and anti-mitochondrial antibodies in serum of autistic children. J Neuroinflammation. 2010;7:80.
   PubMed Web of Science ®Google Scholar
• Moulin D, Donze O, Talabot-Ayer D, et al. Interleukin (IL)-33 induces the release of pro-inflammatory mediators by mast cells. Cytokine. 2007;40:216–225.
   PubMed Web of Science ®Google Scholar
• Saluja R, Ketelaar ME, Hawro T, et al. The role of the IL-33/IL-1RL1 axis in mast cell and basophil activation in allergic disorders. Mol Immunol. 2015;63:80–85.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Petra AI, Taracanova A, et al. Targeting IL-33 in autoimmunity and inflammation. J Pharmacol Exp Ther. 2015;354:24–31.
   PubMed Web of Science ®Google Scholar
• Silver MR, Margulis A, Wood N, et al. IL-33 synergizes with IgE-dependent and IgE-independent agents to promote mast cell and basophil activation. Inflamm Res. 2010;59:207–218.
   PubMed Web of Science ®Google Scholar
• Kumar S, Khodoun M, Kettleson EM, et al. Glyphosate-rich air samples induce IL-33, TSLP and generate IL-13 dependent airway inflammation. Toxicology. 2014;325:42–51.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Zhang B, Kempuraj D, et al. IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proc Natl Acad Sci USA. 2010;107:4448–4453.
   PubMed Web of Science ®Google Scholar
• Taracanova A, Alevizos M, Karagkouni A, et al. SP and IL-33 together markedly enhance TNF synthesis and secretion from human mast cells mediated by the interaction of their receptors. Proc Natl Acad Sci U S A. 2017;114:E4002–E4009.
   PubMed Web of Science ®Google Scholar
• Taracanova A, Tsilioni I, Conti P, et al. Substance P and IL-33 administered together stimulate a marked secretion of IL-1beta from human mast cells, inhibited by methoxyluteolin. Proc Natl Acad Sci U S A. 2018.
   PubMed Web of Science ®Google Scholar
• Hsu CL, Neilsen CV, Bryce PJ. IL-33 is produced by mast cells and regulates IgE-dependent inflammation. PLoS ONE. 2010;5:e11944.
   PubMed Web of Science ®Google Scholar
• Tung HY, Plunkett B, Huang SK, et al. Murine mast cells secrete and respond to interleukin-33. J Interferon Cytokine Res. 2014;34:141–147.
   PubMed Web of Science ®Google Scholar
• Sumpter TL, Ho CH, Pleet AR, et al. Autocrine hemokinin-1 functions as an endogenous adjuvant for IgE-mediated mast cell inflammatory responses. J Allergy Clin Immunol. 2015;135:1019–1030.
   PubMed Web of Science ®Google Scholar
• Morita H, Nakae S, Saito H, et al. IL-33 in clinical practice: size matters? J Allergy Clin Immunol. 2017;140:381–383.
   PubMed Web of Science ®Google Scholar
• Kandere-Grzybowska K, Letourneau R, Kempuraj D, et al. IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells. J Immunol. 2003;171:4830–4836.
   PubMed Web of Science ®Google Scholar
• Noordenbos T, Blijdorp I, Chen S, et al. Human mast cells capture, store, and release bioactive, exogenous IL-17A. J Leukoc Biol. 2016;100:453–462.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Kalogeromitros D. The critical role of mast cells in allergy and inflammation. Ann N Y Acad Sci. 2006;1088:78–99.
   PubMed Web of Science ®Google Scholar
• Wernersson S, Pejler G. Mast cell secretory granules: armed for battle. Nat Rev Immunol. 2014;14:478–494.
   PubMed Web of Science ®Google Scholar
• Xu H, Bin NR, Sugita S. Diverse exocytic pathways for mast cell mediators. Biochem Soc Trans. 2018;46:235–247.
   PubMed Web of Science ®Google Scholar
• Gilfillan AM, Tkaczyk C. Integrated signalling pathways for mast-cell activation. Nat Rev Immunol. 2006;6:218–230.
   PubMed Web of Science ®Google Scholar
• Gaudenzio N, Sibilano R, Marichal T, et al. Different activation signals induce distinct mast cell degranulation strategies. J Clin Invest. 2016;126:3981–3998.
   Web of Science ®Google Scholar
• Sibilano R, Frossi B, Pucillo CE. Mast cell activation: a complex interplay of positive and negative signaling pathways. Eur J Immunol. 2014;44:2558–2566.
   PubMed Web of Science ®Google Scholar
• Crivellato E, Nico B, Gallo VP, et al. Cell secretion mediated by granule-associated vesicle transport: a glimpse at evolution. Anat Rec (Hoboken). 2010;293:1115–1124.
   PubMedGoogle Scholar
• Smrz D, Kim MS, Zhang S, et al. mTORC1 and mTORC2 differentially regulate homeostasis of neoplastic and non-neoplastic human mast cells. Blood. 2011;118:6803–6813.
   PubMed Web of Science ®Google Scholar
• Patel AB, Theoharides TC. Methoxyluteolin inhibits neuropeptide-stimulated proinflammatory mediator release via mTOR activation from human mast cells. J Pharmacol Exp Ther. 2017;361:462–471.
   PubMed Web of Science ®Google Scholar
• Nakae S, Suto H, Kakurai M, et al. Mast cells enhance T cell activation: importance of mast cell-derived TNF. Proc Natl Acad Sci U S A. 2005;102:6467–6472.
   PubMed Web of Science ®Google Scholar
• Kempuraj D, Tagen M, Iliopoulou BP, et al. Luteolin inhibits myelin basic protein-induced human mast cell activation and mast cell dependent stimulation of Jurkat T cells. Br J Pharmacol. 2008;155:1076–1084.
   PubMed Web of Science ®Google Scholar
• Nakamura Y, Nakano N, Ishimaru K, et al. Inhibition of IgE-mediated allergic reactions by pharmacologically targeting the circadian clock. J Allergy Clin Immunol. 2016;137:1226–1235.
   PubMed Web of Science ®Google Scholar
• Nakao A, Nakamura Y, Shibata S. The circadian clock functions as a potent regulator of allergic reaction. Allergy. 2015;70:467–473.
   PubMed Web of Science ®Google Scholar
• Hatziagelaki E, Adamaki M, Dimitriadis G, et al. Myalgic encephalomyelitis/chronic fatigue syndrome-metabolic diseases or disturbed homeostasis? Jpet 2018;In press.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Tsilioni I, Arbetman L, et al. Fibromyalgia, a syndrome in search of pathogenesis and therapy. J Pharmacol Exp Ther. 2015;355:255–263.
   PubMed Web of Science ®Google Scholar
• Alevizos M, Karagkouni A, Panagiotidou S, et al. Stress triggers coronary mast cells leading to cardiac events. Ann Allergy Asthma Immunol. 2013;112:309–316.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Sismanopoulos N, Delivanis DA, et al. Mast cells squeeze the heart and stretch the gird: their role in atherosclerosis and obesity. Trends Pharmacol Sci. 2011;32:534–542.
   PubMed Web of Science ®Google Scholar
• Metcalfe DD, Schwartz LB. Assessing anaphylactic risk? Consider mast cell clonality. J Allergy Clin Immunol. 2009;123:687–688.
   PubMed Web of Science ®Google Scholar
• Bonadonna P, Perbellini O, Passalacqua G, et al. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol. 2009;123:680–686.
   PubMed Web of Science ®Google Scholar
• Niedoszytko M, de MJ, van Doormaal JJ, et al. Mastocytosis and insect venom allergy: diagnosis, safety and efficacy of venom immunotherapy. Allergy. 2009;64:1237–1245.
   PubMed Web of Science ®Google Scholar
• Bonadonna P, Zanotti R, Muller U. Mastocytosis and insect venom allergy. Curr Opin Allergy Clin Immunol. 2010;10:347–353.
   PubMed Web of Science ®Google Scholar
• Wimazal F, Geissler P, Shnawa P, et al. Severe life-threatening or disabling anaphylaxis in patients with systemic mastocytosis: a single-center experience. Int Arch Allergy Immunol. 2012;157:399–405.
   Web of Science ®Google Scholar
• Lieberman P, Nicklas RA, Oppenheimer J, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol. 2010;126:477–480.
   PubMed Web of Science ®Google Scholar
• Kritas SK, Saggini A, Varvara G, et al. Mast cell involvement in rheumatoid arthritis. J Biol Regul Homeost Agents. 2013;27:655–660.
   PubMed Web of Science ®Google Scholar
• Schwartz LB. Mast cells and basophils. Clin Allergy Immunol. 2002;16:3–42.
   PubMedGoogle Scholar
• Hauswirth AW, Natter S, Ghannadan M, et al. Recombinant allergens promote expression of CD203c on basophils in sensitized individuals. J Allergy Clin Immunol. 2002;110:102–109.
   PubMed Web of Science ®Google Scholar
• Valent P, Hauswirth AW, Natter S, et al. Assays for measuring in vitro basophil activation induced by recombinant allergens. Methods. 2004;32:265–270.
   PubMed Web of Science ®Google Scholar
• Hauswirth AW, Escribano L, Prados A, et al. CD203c is overexpressed on neoplastic mast cells in systemic mastocytosis and is upregulated upon IgE receptor cross-linking. Int J Immunopathol Pharmacol. 2008;21:797–806.
   PubMed Web of Science ®Google Scholar
• Wilcock A, Bahri R, Bulfone-Paus S, et al. Mast cell disorders: from infancy to maturity. Allergy. 2019;74:53–63.
   PubMed Web of Science ®Google Scholar
• Metcalfe DD, Mekori YA. Pathogenesis and pathology of mastocytosis. Annu Rev Pathol. 2017;12:487–514.
   PubMed Web of Science ®Google Scholar
• Valent P, Akin C, Arock M, et al. 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.
   PubMed Web of Science ®Google Scholar
• Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol. 2010;126:1099–1104.
   PubMed Web of Science ®Google Scholar
• Molderings GJ. The genetic basis of mast cell activation disease - looking through a glass darkly. Crit Rev Oncol Hematol. 2015;93:75–89.
   PubMed Web of Science ®Google Scholar
• Pardanani A. Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management. Am J Hematol. 2019;94:363–377.
   PubMed Web of Science ®Google Scholar
• Horny HP, Sotlar K, Valent P. Evaluation of mast cell activation syndromes: impact of pathology and immunohistology. Int Arch Allergy Immunol. 2012;159:1–5.
   PubMed Web of Science ®Google Scholar
• Butterfield JH, Li CY. Bone marrow biopsies for the diagnosis of systemic mastocytosis: is one biopsy sufficient?. Am J Clin Pathol. 2004;121:264–267.
   PubMed Web of Science ®Google Scholar
• Valent P, Akin C, Escribano L, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. 2007;37:435–453.
   PubMed Web of Science ®Google Scholar
• Lindner PS, Pardanani B, Angadi C, et al. Acute nonlymphocytic leukemia in systemic mastocytosis with biclonal gammopathy. J Allergy Clin Immunol. 1992;90:410–412.
   PubMed Web of Science ®Google Scholar
• Sonneck K, Florian S, Mullauer L, et al. Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: monoclonal mast cell activation syndrome. Int Arch Allergy Immunol. 2006;142:158–164.
   PubMed Web of Science ®Google Scholar
• Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25:603–625.
   PubMed Web of Science ®Google Scholar
• Alvarez-Twose I, Zanotti R, Gonzalez-de-Olano D, et al. Nonaggressive systemic mastocytosis (SM) without skin lesions associated with insect-induced anaphylaxis shows unique features versus other indolent SM. J Allergy Clin Immunol. 2014;133:520–528.
   PubMed Web of Science ®Google Scholar
• Wang SA, Hutchinson L, Tang G, et al. Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease: clinical significance and comparison of chomosomal abnormalities in SM and AHNMD components. Am J Hematol. 2013;88:219–224.
   PubMed Web of Science ®Google Scholar
• Furitsu T, Tsujimura T, Tono T, et al. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest. 1993;92:1736–1744.
   PubMed Web of Science ®Google Scholar
• Gagari E, Tsai M, Lantz CS, et al. Differential release of mast cell interleukin-6 via c-kit. Blood. 1997;89:2654–2663.
   PubMed Web of Science ®Google Scholar
• Akin C, Scott LM, Kocabas CN, et al. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood. 2007;110:2331–2333.
   PubMed Web of Science ®Google Scholar
• Hamilton MJ, Hornick JL, Akin C, et al. Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol. 2011;128:147–152.
   PubMed Web of Science ®Google Scholar
• Valent P, Horny HP, Triggiani M, et al. Clinical and laboratory parameters of mast cell activation as basis for the formulation of diagnostic criteria. Int Arch Allergy Immunol. 2011;156:119–127.
   PubMed Web of Science ®Google Scholar
• Pardanani A, Brockman SR, Paternoster SF, et al. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood. 2004;104:3038–3045.
   PubMed Web of Science ®Google Scholar
• Matito A, Azana JM, Torrelo A, et al. Cutaneous mastocytosis in adults and children: new classification and prognostic factors. Immunol Allergy Clin North Am. 2018;38:351–363.
   PubMed Web of Science ®Google Scholar
• Castells M, Metcalfe DD, Escribano L. Diagnosis and treatment of cutaneous mastocytosis in children: practical recommendations. Am J Clin Dermatol. 2011;12:259–270.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Alvarez-Twose I, Vano-Galvan S, Sanchez-Munoz L, et al. Increased serum baseline tryptase levels and extensive skin involvement are predictors for the severity of mast cell activation episodes in children with mastocytosis. Allergy. 2012;67:813–821.
   PubMed Web of Science ®Google Scholar
• Barnes M, Van L, DeLong L, et al. Severity of cutaneous findings predict the presence of systemic symptoms in pediatric maculopapular cutaneous mastocytosis. Pediatr Dermatol. 2014;31:271–275.
   PubMed Web of Science ®Google Scholar
• Hosking AM, Makdisi J, Ortenzio F, et al. Diffuse cutaneous mastocytosis: case report and literature review. Pediatr Dermatol. 2018;35:e348–e352.
   PubMed Web of Science ®Google Scholar
• Carter MC, Bai Y, Ruiz-Esteves KN, et al. Detection of KIT D816V in peripheral blood of children with manifestations of cutaneous mastocytosis suggests systemic disease. Br J Haematol. 2018;183:775–782.
   PubMed Web of Science ®Google Scholar
• Horigome K, Bullock ED, Johnson EM Jr. Effects of nerve growth factor on rat peritoneal mast cells. J Biol Chem. 1994;169:2695–2702.
   Google Scholar
• Conti P, Pang X, Boucher W, et al. Impact of Rantes and MCP-1 chemokines on in vivo basophilic mast cell recruitment in rat skin injection model and their role in modifying the protein and mRNA levels for histidine decarboxylase. Blood. 1997;89:4120–4127.
   PubMed Web of Science ®Google Scholar
• Ito N, Sugawara K, Bodo E, et al. Corticotropin-releasing hormone stimulates the in situ generation of mast cells from precursors in the human hair follicle mesenchyme. J Invest Dermatol. 2010;130:995–1004.
   PubMed Web of Science ®Google Scholar
• Kalogeromitros D, Gregoriou S, Makris M, et al. Secondary anetoderma associated with mastocytosis. Int Arch Allergy Immunol. 2007;142:86–88.
   PubMed Web of Science ®Google Scholar
• Bonadonna P, Scaffidi L. Hymenoptera anaphylaxis as a clonal mast cell disorder. Immunol Allergy Clin North Am. 2018;38:455–468.
   PubMed Web of Science ®Google Scholar
• Worobec AS, Semere T, Nagata H, et al. Clinical correlates of the presence of the Asp816Val c-kit mutation in the peripheral blood mononuclear cells of patients with mastocytosis. Cancer. 1998;83:2120–2129.
   PubMed Web of Science ®Google Scholar
• Mousli M, Bueb J-L, Bronner C, et al. G protein activation: a receptor-independent mode of action for cationic amphiphilic neuropeptides and venom peptides. T I P S. 1990;11:358–362.
   Web of Science ®Google Scholar
• Woolhiser MR, Brockow K, Metcalfe DD. Activation of human mast cells by aggregated IgG through FcγRI: additive effects of C3a. Clin Immunol. 2004;110:172–180.
   PubMed Web of Science ®Google Scholar
• Abraham SN, St John AL. Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol. 2010;10:440–452.
   PubMed Web of Science ®Google Scholar
• Shih AR, Deshpande V, Ferry JA, et al. Clinicopathological characteristics of systemic mastocytosis in the intestine. Histopathology. 2016;69:1021–1027.
   PubMed Web of Science ®Google Scholar
• Doyle LA, Sepehr GJ, Hamilton MJ, et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol. 2014;38:832–843.
   PubMed Web of Science ®Google Scholar
• Akin C. Mast Cell Activation Disorders. J Allergy Clin Immunol Pract. 2014;2:252–257.
   PubMed Web of Science ®Google Scholar
• Petra AI, Panagiotidou S, Stewart JM, et al. Spectrum of mast cell activation disorders. Expert Rev Clin Immunol. 2014;10:729–739.
   PubMed Web of Science ®Google Scholar
• Afrin LB, Self S, Menk J, et al. Characterization of Mast Cell Activation Syndrome. Am J Med Sci. 2017;353:207–215.
   PubMed Web of Science ®Google Scholar
• Valent P, Akin C, Bonadonna P, et al. Mast cell activation syndrome: importance of consensus criteria and call for research. J Allergy Clin Immunol. 2018;142;1008–1010.
   PubMed Web of Science ®Google Scholar
• Valent P, Akin C, Bonadonna P, et al. Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome. J Allergy Clin Immunol Pract. 2019 Feb 5 [Epub ahead of print]
   Web of Science ®Google Scholar
• Theoharides TC, Stewart JM, Hatziagelaki E, et al. Brain “fog,” inflammation and obesity: key aspects of 2 neuropsychiatric disorders improved by luteolin. Front Neurosci. 2015;9:225.
   PubMed Web of Science ®Google Scholar
• Ghosh D, Bernstein JA. Systemic and localized seminal plasma hypersensitivity patients exhibit divergent immunologic characteristics. J Allergy Clin Immunol. 2014;134: 969–972.
   PubMed Web of Science ®Google Scholar
• Russell N, Jennings S, Jennings B, et al. The mastocytosis society survey on mast cell disorders: part 2-patient clinical experiences and beyond. J Allergy Clin Immunol Pract. 2018 Aug 8 [Epub ahead of print]
   Web of Science ®Google Scholar
• Jennings S, Russell N, Jennings B, et al. The mastocytosis society survey on mast cell disorders: patient experiences and perceptions. J Allergy Clin Immunol Pract. 2014;2:70–76.
   PubMed Web of Science ®Google Scholar
• Moura DS, Georgin-Lavialle S, Gaillard R, et al. Neuropsychological features of adult mastocytosis. Immunol Allergy Clin North Am. 2014;34:407–422.
   PubMed Web of Science ®Google Scholar
• Moura DS, Sultan S, Georgin-Lavialle S, et al. Evidence for cognitive impairment in mastocytosis: prevalence, features and correlations to depression. PLoS ONE. 2012;7:e39468.
   PubMed Web of Science ®Google Scholar
• Afrin LB, Pohlau D, Raithel M, et al. Mast cell activation disease: an underappreciated cause of neurologic and psychiatric symptoms and diseases. Brain Behav Immun. 2015;50:314–321.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Kempuraj D, Marchand J, et al. Urticaria pigmentosa associated with acute stress and lesional skin mast cell expression of CRF-R1. Clin Exp Dermatol. 2008;34:e163–e166.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Petra AI, Stewart JM, et al. High serum corticotropin-releasing hormone (CRH) and bone marrow mast cell CRH receptor expression in a mastocytosis patient. J Allergy Clin Immunol. 2014;134:1197–1199.
   PubMed Web of Science ®Google Scholar
• Theoharides TC. Mold and Immunity. Clin Ther. 2018;40:882–884.
   PubMed Web of Science ®Google Scholar
• Ratnaseelan AM, Tsilioni I, Theoharides TC. Effects of mycotoxins on neuropsychiatric symptoms and immune processes. Clin Ther. 2018;40:903–917.
   PubMed Web of Science ®Google Scholar
• Romo-Lozano Y, Hernandez-Hernandez F, Salinas E. Sporothrix schenckii yeasts induce ERK pathway activation and secretion of IL-6 and TNF-alpha in rat mast cells, but no degranulation. Med Mycol. 2014;52:862–868.
   PubMed Web of Science ®Google Scholar
• Talkington J, Nickell SP. Borrelia burgdorferi spirochetes induce mast cell activation and cytokine release. Infect Immun. 1999;67:1107–1115.
   PubMed Web of Science ®Google Scholar
• Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007;85:1185–1196.
   PubMed Web of Science ®Google Scholar
• Bulfone-Paus S, Nilsson G, Draber P, et al. Negative signals in mast cell activation. Trends Immunol. 2017;38:657–667.
   PubMed Web of Science ®Google Scholar
• Hanjra P, Lee CR, Maric I, et al. Chromogranin A is not a biomarker of mastocytosis. J Allergy Clin Immunol Pract. 2018;6:687–689.
   PubMed Web of Science ®Google Scholar
• Theoharides TC. Atopic conditions in search of pathogenesis and therapy. Clin Ther. 2013;35:544–547.
   PubMed Web of Science ®Google Scholar
• Theoharidess TC. Irritable bowel syndrome and ulcerative colitis: mast cell numbers are increased, but activation is more important. Dig Dis Sci. 2014;59(5):897–898.
   PubMedGoogle Scholar
• Butterfield JH, Ravi A, Pongdee T. Mast cell mediators of significance in clinical practice in mastocytosis. Immunol Allergy Clin North Am. 2018;38:397–410.
   PubMed Web of Science ®Google Scholar
• Samorapoompichit P, Kiener HP, Schernthaner GH, et al. Detection of tryptase in cytoplasmic granules of basophils in patients with chronic myeloid leukemia and other myeloid neoplasms. Blood. 2001;98:2580–2583.
   PubMed Web of Science ®Google Scholar
• Jogie-Brahim S, Min HK, Fukuoka Y, et al. Expression of alpha-tryptase and beta-tryptase by human basophils. J Allergy Clin Immunol. 2004;113:1086–1092.
   PubMed Web of Science ®Google Scholar
• Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol. 2014;3:1–17.
   Google Scholar
• Shanmugam G, Schwartz LB, Khan DA. Prolonged elevation of serum tryptase in idiopathic anaphylaxis. J Allergy Clin Immunol. 2006;117:950–951.
   PubMed Web of Science ®Google Scholar
• Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol Allergy Clin North Am. 2006;26:451–463.
   PubMed Web of Science ®Google Scholar
• Lin RY, Schwartz LB, Curry A, et al. Histamine and tryptase levels in patients with acute allergic reactions: an emergency department-based study. J Allergy Clin Immunol. 2000;106:65–71.
   PubMed Web of Science ®Google Scholar
• Oosting E, Neugebauer E, Keyzer JJ, et al. Determination of histamine in human plasma: the European external quality control study 1988. Clin Exp Allergy. 1990;20:349–357.
   PubMed Web of Science ®Google Scholar
• Awad JA, Morrow JD, Roberts LJ. Detection of the major urinary metabolite of prostaglandin D2 in the circulation: demonstration of elevated levels in patients with disorders of systemic mast cell activation. J Allergy Clin Immunol. 1994;93:817–824.
   PubMed Web of Science ®Google Scholar
• Ravi A, Butterfield J, Weiler CR. Mast cell activation syndrome: improved identification by combined determinations of serum tryptase and 24-hour urine 11beta-prostaglandin2alpha. J Allergy Clin Immunol Pract. 2014;2:775–778.
   PubMed Web of Science ®Google Scholar
• Vysniauskaite M, Hertfelder HJ, Oldenburg J, et al. Determination of plasma heparin level improves identification of systemic mast cell activation disease. PLoS ONE. 2015;10:e0124912.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Boucher W, Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol. 2002;128:344–350.
   PubMed Web of Science ®Google Scholar
• Brockow K, Akin C, Huber M, et al. IL-6 levels predict disease variant and extent of organ involvement in patients with mastocytosis. Clin Immunol. 2005;115:216–223.
   PubMed Web of Science ®Google Scholar
• Mayado A, Teodosio C, Garcia-Montero AC, et al. Increased IL6 plasma levels in indolent systemic mastocytosis patients are associated with high risk of disease progression. Leukemia. 2015;30:124–130.
   PubMed Web of Science ®Google Scholar
• Greiner G, Witzeneder N, Berger A, et al. CCL2 is a KIT D816V-dependent modulator of the bone marrow microenvironment in systemic mastocytosis. Blood. 2017;129:371–382.
   PubMed Web of Science ®Google Scholar
• Maintz L, Wardelmann E, Walgenbach K, et al. Neuropeptide blood levels correlate with mast cell load in patients with mastocytosis. Allergy. 2011;66:862–869.
   PubMed Web of Science ®Google Scholar
• Levi-Schaffer F, Scheffel J. Dangerous liaisons in anaphylaxis. Science. 2018;362:640–641.
   PubMed Web of Science ®Google Scholar
• Skokos D, Botros HG, Demeure C, et al. Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. J Immunol. 2003;170:3037–3045.
   PubMed Web of Science ®Google Scholar
• Bryniarski K, Ptak W, Jayakumar A, et al. Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity. J Allergy Clin Immunol. 2013;132:170–181.
   PubMed Web of Science ®Google Scholar
• Halova I, Ronnberg E, Draberova L, et al. Changing the threshold-Signals and mechanisms of mast cell priming. Immunol Rev. 2018;282:73–86.
   PubMed Web of Science ®Google Scholar
• Alysandratos KD, Asadi S, Angelidou A, et al. Neurotensin and CRH interactions augment human mast cell activation. PloS One. 2012;7:e48934.
   PubMed Web of Science ®Google Scholar
• Asadi S, Alysandratos KD, Angelidou A, et al. Substance P (SP) induces expression of functional corticotropin-releasing hormone receptor-1 (CRHR-1) in human mast cells. J Invest Dermatol. 2012;132:324–329.
   PubMed Web of Science ®Google Scholar
• Drube S, Heink S, Walter S, et al. The receptor tyrosine kinase c-Kit controls IL-33 receptor signaling in mast cells. Blood. 2010;115:3899–3906.
   PubMed Web of Science ®Google Scholar
• Kounis NG, Hahalis G, Theoharides TC. Coronary stents, hypersensitivity reactions and the Kounis syndrome. J Invasive Cardiol. 2007;20:314–323.
   Google Scholar
• Paratz ED, Khav N, Burns AT. Systemic mastocytosis, kounis syndrome and coronary intervention: case report and systematic review. Heart Lung Circ. 2017;26:772–778.
   PubMed Web of Science ®Google Scholar
• Rossi S, Pitidis A. Multiple chemical sensitivity: review of the state of the art in epidemiology, diagnosis, and future perspectives. J Occup Environ Med. 2018;60:138–146.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Tsilioni I, Patel AB, et al. Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders. Transl Psychiatry. 2016;6:e844.
   PubMed Web of Science ®Google Scholar
• Theoharides TC. Autism spectrum disorders and mastocytosis. Int J Immunopathol Pharmacol. 2009;22:859–865.
   PubMed Web of Science ®Google Scholar
• Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res. 2009;65:591–598.
   PubMed Web of Science ®Google Scholar
• McPartland J, Volkmar FR. Autism and related disorders. Handb Clin Neurol. 2012;106:407–418.
   PubMedGoogle Scholar
• Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2014;383:896–910.
   PubMed Web of Science ®Google Scholar
• Mostafa GA, Hamza RT, El-Shahawi HH. Allergic manifestations in autistic children: relation to disease severity. J Pediatr Neurol. 2008;6:115–123.
   Google Scholar
• Otani IM, Carroll RW, Yager P, et al. Diffuse cutaneous mastocytosis with novel somatic KIT mutation K509I and association with tuberous sclerosis. Clin Case Rep. 2018;6:1834–1840.
   PubMed Web of Science ®Google Scholar
• Kotey S, Ertel K, Whitcomb B. Co-occurrence of autism and asthma in a nationally-representative sample of children in the United States. J Autism Dev Disord. 2014;44:3083–3088.
   PubMed Web of Science ®Google Scholar
• Lyall K, de WJ V, Ashwood P, et al. Allergies in children with autism spectrum disorders: results from the CHARGE study. Autism Res. 2015;8:567–574.
   PubMed Web of Science ®Google Scholar
• Zerbo O, Leong A, Barcellos L, et al. Immune mediated conditions in autism spectrum disorders. Brain Behav Immun. 2015;46:232–236.
   PubMed Web of Science ®Google Scholar
• Chen SW, Zhong XS, Jiang LN, et al. Maternal autoimmune diseases and the risk of autism spectrum disorders in offspring: a systematic review and meta-analysis. Behav Brain Res. 2015;296:61–69.
   PubMed Web of Science ®Google Scholar
• Billeci L, Tonacci A, Tartarisco G, et al. Association between atopic dermatitis and autism spectrum disorders: a systematic review. Am J Clin Dermatol. 2015;16:371–388.
   PubMed Web of Science ®Google Scholar
• Wills S, Cabanlit M, Bennett J, et al. Detection of autoantibodies to neural cells of the cerebellum in the plasma of subjects with autism spectrum disorders. Brain Behav Immun. 2008;23:64–74.
   PubMed Web of Science ®Google Scholar
• Rossi CC, de WJ V, Rogers SJ, et al. Detection of plasma autoantibodies to brain tissue in young children with and without autism spectrum disorders. Brain Behav Immun. 2011;25:1123–1135.
   PubMed Web of Science ®Google Scholar
• Mostafa GA, Al-Ayadhi LY. The possible relationship between allergic manifestations and elevated serum levels of brain specific auto-antibodies in autistic children. J Neuroimmunol. 2013;261:77–81.
   PubMed Web of Science ®Google Scholar
• Netea MG, Balkwill F, Chonchol M, et al. A guiding map for inflammation. Nat Immunol. 2017;18:826–831.
   PubMed Web of Science ®Google Scholar
• Rider P, Voronov E, Dinarello CA, et al. Alarmins: feel the stress. J Immunol. 2017;198:1395–1402.
   PubMed Web of Science ®Google Scholar
• Ransohoff RM, Brown MA. Innate immunity in the central nervous system. J Clin Invest. 2012;122:1164–1171.
   PubMed Web of Science ®Google Scholar
• Skaper SD, Giusti P, Facci L. Microglia and mast cells: two tracks on the road to neuroinflammation. FASEB J. 2012;26:3103–3117.
   PubMed Web of Science ®Google Scholar
• Forsythe P. Mast cells in neuroimmune interactions. Trends Neurosci. 2019;42:43–55.
   PubMed Web of Science ®Google Scholar
• Zhang X, Wang Y, Dong H, et al. Induction of microglial activation by mediators released from mast cells. Cell Physiol Biochem. 2016;38:1520–1531.
   PubMed Web of Science ®Google Scholar
• Estes ML, McAllister AK. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci. 2015;16:469–486.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Stewart JM, Panagiotidou S, et al. Mast cells, brain inflammation and autism. Eur J Pharmacol. 2015;778:96–102.
   PubMed Web of Science ®Google Scholar
• Edvinsson L, Cervos-Navarro J, Larsson LI, et al. Regional distribution of mast cells containing histamine, dopamine or 5-hydroxytryptamine in the mammalian brain. Neurology. 1977;27:878–884.
   PubMed Web of Science ®Google Scholar
• Pang X, Letourneau R, Rozniecki JJ, et al. Definitive characterization of rat hypothalamic mast cells. Neuroscience. 1996;73(3):889–902.
   PubMed Web of Science ®Google Scholar
• Theoharides TC. Mast cells: the immune gate to the brain. Life Sci. 1990;46:607–617.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Konstantinidou A. Corticotropin-releasing hormone and the blood-brain-barrier. Front Biosci. 2007;12:1615–1628.
   PubMed Web of Science ®Google Scholar
• Esposito P, Chandler N, Kandere-Grzybowska K, et al. Corticotropin-releasing hormone (CRH) and brain mast cells regulate blood-brain-barrier permeability induced by acute stress. J Pharmacol Exp Ther. 2002;303:1061–1066.
   PubMed Web of Science ®Google Scholar
• Ribatti D. The crucial role of mast cells in blood-brain barrier alterations. Exp Cell Res. 2015;338:119–125.
   PubMed Web of Science ®Google Scholar
• Polyzoidis S, Koletsa T, Panagiotidou S, et al. Mast cells in meningiomas and brain inflammation. J Neuroinflammation. 2015;12:170.
   PubMed Web of Science ®Google Scholar
• Molderings GJ, Haenisch B, Bogdanow M, et al. Familial occurrence of systemic mast cell activation disease. PloS One. 2013;8:e76241.
   PubMed Web of Science ®Google Scholar
• Scherber RM, Borate U. How we diagnose and treat systemic mastocytosis in adults. Br J Haematol. 2018;180:11–23.
   PubMed Web of Science ®Google Scholar
• Siebenhaar F, Redegeld FA, Bischoff SC, et al. Mast Cells as Drivers of Disease and Therapeutic Targets. Trends Immunol. 2018;39(2):151–162.
   PubMed Web of Science ®Google Scholar
• Molderings GJ, Haenisch B, Brettner S, et al. Pharmacological treatment options for mast cell activation disease. Naunyn Schmiedebergs Arch Pharmacol. 2016;389:671–694.
   PubMed Web of Science ®Google Scholar
• Alvarez-Twose I, Gonzalez-de-Olano D, Sanchez-Munoz L, et al. Validation of the REMA score for predicting mast cell clonality and systemic mastocytosis in patients with systemic mast cell activation symptoms. Int Arch Allergy Immunol. 2012;157:275–280.
   PubMed Web of Science ®Google Scholar
• Kettelhut BV, Berkebile C, Bradley D, et al. A double-blind, placebo-controlled, crossover trial of ketotifen versus hydroxyzine in the treatment of pediatric mastocytosis. J Allergy Clin Immunol. 1989;83:866–870.
   PubMed Web of Science ®Google Scholar
• Schoch C. In vitro inhibition of human conjunctival mast-cell degranulation by ketotifen. J Ocul Pharmacol Ther. 2003;19:75–81.
   PubMed Web of Science ®Google Scholar
• Vasiadi M, Kalogeromitros K, Kempuraj D, et al. Rupatadine inhibits pro-inflammatory mediator secretion from human mast cells triggered by different stimuli. Int Arch Allergy Immunol. 2010;151:38–45.
   PubMed Web of Science ®Google Scholar
• Alevizos M, Karagkouni A, Vasiadi M, et al. Rupatadine inhibits inflammatory mediator release from human LAD2 cultured mast cells stimulated by PAF. Ann Allergy Asthma Immunol. 2013;111:524–527.
   Web of Science ®Google Scholar
• Wolff SC, Brubaker KNTFEHLJRBJ. Anticholinergic effects of antihistamine drugs used in the clinic. J Allergy Clin Immunol. 2007;119.
   Web of Science ®Google Scholar
• Shimizu T, Tokuda Y. Acute urinary retention. Intern Med. 2011;50:2255.
   PubMed Web of Science ®Google Scholar
• Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015;175:401–407.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Stewart JM. Antihistamines and mental status. J Clin Psychopharmacol. 2016;36:195–197.
   PubMed Web of Science ®Google Scholar
• Zhang T, Finn DF, Barlow JW, et al. Mast cell stabilisers. Eur J Pharmacol. 2016;778:158–168.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Sieghart W, Greengard P, et al. Antiallergic drug cromolyn may inhibit histamine secretion by regulating phosphorylation of a mast cell protein. Science. 1980;207:80–82.
   PubMed Web of Science ®Google Scholar
• Oka T, Kalesnikoff J, Starkl P, et al. Evidence questioning cromolyn’s effectiveness and selectivity as a ‘mast cell stabilizer’ in mice. Lab Invest. 2012;92:1472–1482.
   PubMed Web of Science ®Google Scholar
• Vieira Dos SR, Magerl M, Martus P, et al. Topical sodium cromoglicate relieves allergen- and histamine-induced dermal pruritus. Br J Dermatol. 2010;162:674–676.
   PubMed Web of Science ®Google Scholar
• Butterfield JH. Increased leukotriene E4 excretion in systemic mastocytosis. Prostaglandins Other Lipid Mediat. 2010 Jun;92(1-4):73–76.
   PubMed Web of Science ®Google Scholar
• Conti P, Varvara G, Murmura G, et al. Comparison of beneficial actions of non-steroidal anti-inflammatory drugs to flavonoids. J Biol Regul Homeost Agents. 2013;27:1–7.
   PubMed Web of Science ®Google Scholar
• Varvara G, Tettamanti L, Gallenga CE, et al. Stimulated mast cells release inflammatory cytokines: potential suppression and therapeutical aspects. J Biol Regul Homeost Agents. 2018;32:1355–1360.
   PubMed Web of Science ®Google Scholar
• Butterfield JH, Kao PC, Klee GC, et al. Aspirin idiosyncrasy in systemic mast cell disease: a new look at mediator release during aspirin desensitization. Mayo Clin Proc. 1995;70:481–487.
   PubMed Web of Science ®Google Scholar
• Molderings GJ, Raithel M, Kratz F, et al. Omalizumab treatment of systemic mast cell activation disease: experiences from four cases. Intern Med. 2011;50:611–615.
   PubMed Web of Science ®Google Scholar
• Jayapal M, Tay HK, Reghunathan R, et al. Genome-wide gene expression profiling of human mast cells stimulated by IgE or FcepsilonRI-aggregation reveals a complex network of genes involved in inflammatory responses. BMC Genomics. 2006;7:210.
   PubMed Web of Science ®Google Scholar
• Kalogeromitros D, Makris M, Koti I, et al. A simple 3-day “rush” venom immunotherapy protocol: documentation of safety. Allergol Immunopathol (Madr). 2010;38:69–73.
   PubMed Web of Science ®Google Scholar
• Gotlib J, Kluin-Nelemans HC, George TI, et al. Safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374:2530–2541.
   PubMed Web of Science ®Google Scholar
• Rapid responses to avapritinib (BLU-285) in mastocytosis. Cancer Discov. 2018;8:133.
   PubMed Web of Science ®Google Scholar
• Guo W, Kong E, Meydani M. Dietary polyphenols, inflammation, and cancer. Nutr Cancer. 2009;61:807–810.
   PubMed Web of Science ®Google Scholar
• Middleton EJ, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease and cancer. Pharmacol Rev. 2000;52:673–751.
   PubMed Web of Science ®Google Scholar
• Xiao ZP, Peng ZY, Peng MJ, et al. Flavonoids health benefits and their molecular mechanism. Mini Rev Med Chem. 2011;11:169–177.
   PubMed Web of Science ®Google Scholar
• Gupta K, Kumar S, Gupta RK, et al. Reversion of Asthmatic Complications and Mast Cell Signalling Pathways in BALB/c Mice Model Using Quercetin Nanocrystals. J Biomed Nanotechnol. 2016 Apr;12(4):717–731.
   PubMed Web of Science ®Google Scholar
• Kimata M, Shichijo M, Miura T, et al. Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells. Clin Exp Allergy. 2000;30:501–508.
   PubMed Web of Science ®Google Scholar
• Asadi S, Zhang B, Weng Z, et al. Luteolin and thiosalicylate inhibit HgCl(2) and thimerosal-induced VEGF release from human mast cells. Int J Immunopathol Pharmacol. 2010;23:1015–1020.
   PubMed Web of Science ®Google Scholar
• Weng Z, Patel AB, Panagiotidou S, et al. The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells. J Allergy Clin Immunol. 2015;135:1044–1052.
   PubMed Web of Science ®Google Scholar
• Lee JY, Kim JM, Kim CJ. Flavones derived from nature attenuate the immediate and late-phase asthmatic responses to aerosolized-ovalbumin exposure in conscious guinea pigs. Inflamm Res. 2014;63:53–60.
   PubMed Web of Science ®Google Scholar
• Jin M, Son KH, Chang HW. Luteolin-7-O-glucoside suppresses leukotriene C(4) production and degranulation by inhibiting the phosphorylation of mitogen activated protein kinases and phospholipase Cgamma1 in activated mouse bone marrow-derived mast cells. Biol Pharm Bull. 2011;34:1032–1036.
   PubMed Web of Science ®Google Scholar
• Patel AB, Tsilioni I, Weng Z, et al. TNF stimulates IL-6, CXCL8 and VEGF secretion from human keratinocytes via activation of mTOR, inhibited by tetramethoxyluteolin. Exp Dermatol. 2018;27:135–143.
   PubMed Web of Science ®Google Scholar
• Sharma V, Mishra M, Ghosh S, et al. Modulation of interleukin-1beta mediated inflammatory response in human astrocytes by flavonoids: implications in neuroprotection. Brain Res Bull. 2007;73:55–63.
   PubMed Web of Science ®Google Scholar
• Jang S, Kelley KW, Johnson RW. Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci USA. 2008;105:7534–7539.
   PubMed Web of Science ®Google Scholar
• Patel AB, Tsilioni I, Leeman SE, et al. Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism. Proc Natl Acad Sci U S A. 2016;113:E7049–E7058.
   PubMed Web of Science ®Google Scholar
• Dirscherl K, Karlstetter M, Ebert S, et al. Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype. J Neuroinflammation. 2010;7:3.
   PubMed Web of Science ®Google Scholar
• Jang S, Dilger RN, Johnson RW. Luteolin inhibits microglia and alters hippocampal-dependent spatial working memory in aged mice. J Nutr. 2010;140:1892–1898.
   PubMed Web of Science ®Google Scholar
• Kao TK, Ou YC, Lin SY, et al. Luteolin inhibits cytokine expression in endotoxin/cytokine-stimulated microglia. J Nutr Biochem. 2011;22:612–624.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Asadi S, Panagiotidou S. A case series of a luteolin formulation (Neuroprotek®) in children with autism spectrum disorders. Int J Immunopathol Pharmacol. 2012;25:317–323.
   PubMed Web of Science ®Google Scholar
• Seelinger G, Merfort I, Schempp CM. Anti-oxidant, anti-inflammatory and anti-allergic activities of luteolin. Planta Med. 2008;74:1667–1677.
   PubMed Web of Science ®Google Scholar
• Nabavi SF, Braidy N, Gortzi O, et al. Luteolin as an anti-inflammatory and neuroprotective agent: a brief review. Brain Res Bull. 2015;119:1–11.
   PubMed Web of Science ®Google Scholar
• Chen HQ, Jin ZY, Wang XJ, et al. Luteolin protects dopaminergic neurons from inflammation-induced injury through inhibition of microglial activation. Neurosci Lett. 2008;448:175–179.
   PubMed Web of Science ®Google Scholar
• Franco JL, Posser T, Missau F, et al. Structure-activity relationship of flavonoids derived from medicinal plants in preventing methylmercury-induced mitochondrial dysfunction. Environ Toxicol Pharmacol. 2010;30:272–278.
   PubMed Web of Science ®Google Scholar
• Xu SL, Bi CW, Choi RC, et al. Flavonoids induce the synthesis and secretion of neurotrophic factors in cultured rat astrocytes: a signaling response mediated by estrogen receptor. Evid Based Complement Alternat Med. 2013;2013:127075.
   PubMed Web of Science ®Google Scholar
• Jang SW, Liu X, Yepes M, et al. A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci USA. 2010;107:2687–2692.
   PubMed Web of Science ®Google Scholar
• Johnson RA, Lam M, Punzo AM, et al. 7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome. J Appl Physiol. 2012;112:704–710.
   PubMed Web of Science ®Google Scholar
• Fatokun AA, Liu JO, Dawson VL, et al. Identification through high-throughput screening of 4ʹ-methoxyflavone and 3ʹ,4ʹ-dimethoxyflavone as novel neuroprotective inhibitors of parthanatos. Br J Pharmacol. 2013;169:1263–1278.
   PubMed Web of Science ®Google Scholar
• Kang OH, Choi JG, Lee JH, et al. Luteolin isolated from the flowers of Lonicera japonica suppresses inflammatory mediator release by blocking NF-kappaB and MAPKs activation pathways in HMC-1 cells. Molecules. 2010;15:385–398.
   PubMed Web of Science ®Google Scholar
• Yang Y, Oh JM, Heo P, et al. Polyphenols differentially inhibit degranulation of distinct subsets of vesicles in mast cells by specific interaction with granule-type-dependent SNARE complexes. Biochem J. 2013;450:537–546.
   PubMed Web of Science ®Google Scholar
• Theoharides TC. Luteolin as a therapeutic option for multiple sclerosis. J Neuroinflammation. 2009;6:29.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Tsilioni I. Tetramethoxyluteolin for the treatment of neurodegenerative diseases. Curr Top Med Chem. 2018;18:1872–1882.
   PubMed Web of Science ®Google Scholar
• Ashaari Z, Hadjzadeh MA, Hassanzadeh G, et al. The flavone luteolin improves central nervous system disorders by different mechanisms: a review. J Mol Neurosci. 2018;65:491–506.
   PubMed Web of Science ®Google Scholar
• Prasain JK, Barnes S. Metabolism and bioavailability of flavonoids in chemoprevention: current analytical strategies and future prospectus. Mol Pharm. 2007;4:846–864.
   PubMed Web of Science ®Google Scholar
• Walle T. Absorption and metabolism of flavonoids. Free Radic Biol Med. 2004;36:829–837.
   PubMed Web of Science ®Google Scholar
• Graefe EU, Derendorf H, Veit M. Pharmacokinetics and bioavailability of the flavonol quercetin in humans. Int J Clin Pharmacol Ther. 1999;37:219–233.
   PubMed Web of Science ®Google Scholar
• Chen Z, Zheng S, Li L, et al. Metabolism of flavonoids in human: a comprehensive review. Curr Drug Metab. 2014;15:48–61.
   PubMed Web of Science ®Google Scholar
• Walle T. Methylation of dietary flavones greatly improves their hepatic metabolic stability and intestinal absorption. Mol Pharm. 2007;4:826–832.
   PubMed Web of Science ®Google Scholar
• Corcoran MP, McKay DL, Blumberg JB. Flavonoid basics: chemistry, sources, mechanisms of action, and safety. J Nutr Gerontol Geriatr. 2012;31:176–189.
   PubMedGoogle Scholar
• Harwood M, Nielewska-Nikiel B, Borzelleca JF, et al. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol. 2007;45:2179–2205.
   PubMed Web of Science ®Google Scholar
• Kawanishi S, Oikawa S, Murata M. Evaluation for safety of antioxidant chemopreventive agents. Antioxid Redox Signal. 2005;7:1728–1739.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Conti P, Economu M. Brain inflammation, neuropsychiatric disorders, and immunoendocrine effects of luteolin. J Clin Psychopharmacol. 2014;34:187–189.
   PubMed Web of Science ®Google Scholar
• Domitrovic R, Jakovac H, Milin C, et al. Dose- and time-dependent effects of luteolin on carbon tetrachloride-induced hepatotoxicity in mice. Exp Toxicol Pathol. 2009;61:581–589.
   PubMedGoogle Scholar
• Weng Z, Zhang B, Asadi S, et al. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans. PloS One. 2012;7:e33805–k.
   PubMed Web of Science ®Google Scholar
• Tsilioni I, Taliou A, Francis K, et al. Children with autism spectrum disorders, who improved with a luteolin containing dietary formulation, show reduced serum levels of TNF and IL-6. Transl Psychiatry. 2015;5:e647.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Stewart JM. Post-lyme syndrome-associated polyneuropathy treated with immune immunoglobulin and a luteolin-containing formulation. J Clin Psychopharmacol. 2016;36:290–291.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Stewart JM, Tsilioni I. Tolerability and benefit of a tetramethoxyluteolin-containing skin lotion. Int J Immunopathol Pharmacol. 2017;30:146–151.
   PubMed Web of Science ®Google Scholar
• Theoharides TC. Vitamin D and Atopy. Clin Ther. 2017;39:880–883.
   PubMed Web of Science ®Google Scholar
• Clemons A, Vasiadi M, Kempuraj D, et al. Amitriptyline and prochlorperazine inhibit proinflammatory mediator release from human mast cells: possible relevance to chronic fatigue syndrom. J Clin Psychopharmacol. 2011;31:385–387.
   PubMed Web of Science ®Google Scholar
• Krystel-Whittemore M, Dileepan KN, Wood JG. Mast cell: a multi-functional master cell. Front Immunol. 2015;6:620.
   PubMed Web of Science ®Google Scholar
• Olivera A, Beaven MA, Metcalfe DD. Mast cells signal their importance in health and disease. J Allergy Clin Immunol. 2018;142:381–393.
   PubMed Web of Science ®Google Scholar
• Theoharides TC, Leeman SE. Effect of IL-33 on de novo synthesized mediators from human mast cells. J Allergy Clin Immunol. 2019;143:451.
   PubMed Web of Science ®Google Scholar
• Caslin HL, Kiwanuka KN, Haque TT, et al. Controlling mast cell activation and homeostasis: work influenced by bill paul that continues today. Front Immunol. 2018;9:868.
   PubMed Web of Science ®Google Scholar
• Seok J, Warren HS, Cuenca AG, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Pnas. 2013;110:3507–3512.
   PubMed Web of Science ®Google Scholar
• Frossi B, Mion F, Sibilano R, et al. Is it time for a new classification of mast cells? What do we know about mast cell heterogeneity? Immunol Rev. 2018;282:35–46.
   PubMed Web of Science ®Google Scholar
• Tellechea A, Leal EC, Kafanas A, et al. Mast cells regulate wound healing in diabetes. Diabetes. 2016;65:2006–2019.
   PubMed Web of Science ®Google Scholar
• Ribatti D. Mast cells as therapeutic target in cancer. Eur J Pharmacol. 2016;778:152–157.
   PubMedGoogle Scholar
• Silver R, Ramos CL, Silverman AJ. Sexual behavior triggers the appearance of non-neuronal cells containing gonadotropin-releasing hormone-like immunoreactivity. J Neuroendocrinol. 1991;4:1–3.
   Web of Science ®Google Scholar
• Lenz KM, Pickett LA, Wright CL, et al. Mast cells in the developing brain determine adult sexual behavior. J Neurosci. 2018;38:8044–8059.
   PubMed Web of Science ®Google Scholar
• Kim DK, Cho YE, Komarow HD, et al. Mastocytosis-derived extracellular vesicles exhibit a mast cell signature, transfer KIT to stellate cells, and promote their activation. Proc Natl Acad Sci U S A. 2018.
   Web of Science ®Google Scholar
• Haenisch B, Bonisch H, Cichon S, et al. Effects of exogenous agmatine in human leukemia HMC-1 and HL-60 cells on proliferation, polyamine metabolism and cell cycle. Leuk Res. 2011;35:1248–1253.
   PubMed Web of Science ®Google Scholar
• Vliagoftis H, Boucher WS, Mak LL, et al. Inhibition of mast cell secretion by oxidation products of natural polyamines. Biochem Pharmacol. 1992;43:2237–2245.
   PubMed Web of Science ®Google Scholar
• Garcia-Faroldi G, Rodriguez CE, Urdiales JL, et al. Polyamines are present in mast cell secretory granules and are important for granule homeostasis. PLoS ONE. 2010;5:e15071.
   PubMed Web of Science ®Google Scholar
• Gross AR, Theoharides TC. Chondroitin sulfate inhibits secretion of TNF and CXCL8 from human mast cells stimulated by IL-33. Biofactors. 2019;45:49–61.
   PubMed Web of Science ®Google Scholar
• Abramson J, Licht A, Pecht I. Selective inhibition of the Fc epsilon RI-induced de novo synthesis of mediators by an inhibitory receptor. Embo J. 2006;25:323–334.
   PubMed Web of Science ®Google Scholar
• Bulfone-Paus S, Nilsson G, Draber P, et al. Positive and negative signals in mast cell activation. Trends Immunol. 2017;38:657–667.
   PubMed Web of Science ®Google Scholar
• Levi-Schaffer F, Mandelboim O. Inhibitory and coactivating receptors recognizing the same ligand: immune homeostasis exploited by pathogens and tumors. Trends Immunol. 2018;39:122–122.
   Google Scholar
• Karra L, Singh Gangwar R, Shamri R, et al. Leukocyte SD300a contributes to the resolution of murine allergic inflammation. J Immunol. 2018;201:2998–3005.
   PubMed Web of Science ®Google Scholar
• Dinarello CA, Bufler P. Interleukin-37. Semin Immunol. 2013;25:466–468.
   PubMed Web of Science ®Google Scholar
• Dinarello CA, Nold-Petry C, Nold M, et al. Suppression of innate inflammation and immunity by interleukin-37. Eur J Immunol. 2016;46:1067–1081.
   PubMed Web of Science ®Google Scholar
• Tettamanti L, Kritas SK, Gallenga CE, et al. IL-33 mediates allergy through mast cell activation: potential inhibitory effect of certain cytokines. J Biol Regul Homeost Agents. 2018;32:1061–1065.
   PubMed Web of Science ®Google Scholar
• Mastrangelo F, Frydas I, Ronconi G, et al. Low-grade chronic inflammation mediated by mast cells in fibromyalgia: role of IL-37. J Biol Regul Homeost Agents. 2018;32:195–198.
   PubMed Web of Science ®Google Scholar