Mast cells and eosinophils in allergic and eosinophilia diseases

Abstract

Activation of eosinophils and mast cells in dysregulated type 2 immunity may play key roles in allergic diseases. Eosinophils are linked to the pathobiology of multiple human diseases, including eosinophilic gastrointestinal disorders (EGIDs), functional gastrointestinal disorders (FGIDs), Kimura’s disease, hypereosinophilic syndrome (HES), rheumatoid lesions, allergy, asthma, and some forms of heart disease etc. Eosinophils are part of the innate immune response involved in combating multicellular parasites and some infections. Mast cells play a key role in allergies, allergic conjunctivitis, allergic dermatitis (eczema), allergic rhinitis (hay fever), anaphylaxis, asthma, and mast cell activation syndrome (MCAS). Mast cells can also play a key role in eosinophilic diseases. Eosinophils respond to interleukin 5 (IL-5) and chemotactic chemokine eosinophil chemotactic factor (eotaxin) released from activated mast cells. Mast cells can be activated by fragment crystallizable (Fc) receptor bound immunoglobulin E (IgE) and G (IgG) antibodies bound to allergens and viruses. Cross talk between eosinophils and mast cells can result in chronic inflammations or eosinophilias. Vasoconstriction of capillaries by histamine contracted pericytes is also predicted to contribute to a subset of these diseases. This article proposes that for these diseases, activation of mast cells is a key step in disease pathogenesis. Targeting activated mast cells in these diseases are potential adjunctive therapies to evaluate in clinical studies. A review of relevant eosinophilia literature is presented that supports the role of mast cells in the pathogenesis of multiple allergic and eosinophilia diseases.

Keywords

Mast cells / eosinophils / allergy / asthma / hypereosinophilic syndrome / chronic heart failure

References

[1] O’Donnell MC, Ackerman SJ, Gleich GJ, Thomas LL. Activation of basophil and mast cell histamine release by eosinophil granule major basic protein. J Exp Med. 1983; 157: 1981-91.

[2] Bochner BS. Systemic activation of basophils and eosinophils: markers and consequences. J Allergy Clin Immunol. 2000; 106: S292-302.

[3] Hamid Q. Eosinophils in allergic inflammation. J Allergy Clin Immunol. 2004; 113: 182-4.

[4] Trigg CJ, Davies RJ. Allergic rhinitis. Arch Dis Child. 1991; 66: 565-7.

[5] Naclerio RM, Baroody FM, Kagey-Sobotka A, Lichtenstein LM. Basophils and eosinophils in allergic rhinitis. J Allergy Clin Immunol. 1994; 94: 1303-9.

[6] Reed CC, Genta RM, Youngblood BA, Wechsler JB, Dellon ES. Mast Cell and Eosinophil Counts in Gastric and Duodenal Biopsy Specimens From Patients With and Without Eosinophilic Gastroenteritis. Clin Gastroenterol Hepatol. 2021; 19: 2102-11.

[7] Šojat D, Volarić M, Keškić T, Volarić N, Cerovečki V, Trtica Majnarić L. Putting Functional Gastrointestinal Disorders within the Spectrum of Inflammatory Disorders Can Improve Classification and Diagnostics of These Disorders. Biomedicines. 2024; 12: 702.

[8] Dhingra H, Nagpal R, Baliyan A, Alva SR. Kimura disease: case report and brief review of literature. Med Pharm Rep. 2019; 92: 195-9.

[9] Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore). 1975; 54: 1-27.

[10] Qin Y, Jin HZ, Li YJ, Chen Z. Emerging Role of Eosinophils in Resolution of Arthritis. Front Immunol. 2021; 12: 764825.

[11] Ellis AG. The pathological anatomy of bronchial asthma. Am J Med Sci. 1908; 136: 407.

[12] Matucci A, Vultaggio A, Maggi E, Kasujee I. Is IgE or eosinophils the key player in allergic asthma pathogenesis? Are we asking the right question? Respir Res. 2018; 19: 113.

[13] Walford HH, Doherty TA. Diagnosis and management of eosinophilic asthma: a US perspective. J Asthma Allergy. 2014; 7: 53-65.

[14] Mauro MJ. HES and SMCD-eos: birds of a FIP1L1-PDGFRA feather . Blood. 2003; 102: 3082.

[15] Liu J, Yang C, Liu T, Deng Z, Fang W, Zhang X, et al. Eosinophils improve cardiac function after myocardial infarction. Nat Commun. 2020; 11: 6396.

[16] Zhong Z, Yang Z, Peng Y, Wang L, Yuan X. Diagnosis and treatment of eosinophilic myocarditis. J Transl Autoimmun. 2021; 4: 100118.

[17] Kirsch R, Bokhary R, Marcon MA, Cutz E. Activated Mucosal Mast Cells Differentiate Eosinophilic (Allergic) Esophagitis From Gastroesophageal Reflux Disease. J Pediatr Gastroenterol Nutr. 2007; 44: 20-6.

[18] Banafea GH, Bakhashab S, Alshaibi HF, Pushparaj PN, Rasool M. The role of human mast cells in allergy and asthma. Bioengineered. 2022; 13: 7049-64.

[19] Amin K. The role of mast cells in allergic inflammation. Respir Med. 2012; 106: 9-14.

[20] Elieh Ali Komi D, Rambasek T, Bielory L. Clinical implications of mast cell involvement in allergic conjunctivitis. Allergy. 2018; 73: 528-39.

[21] Kawakami T, Ando T, Kimura M, Wilson BS, Kawakami Y. Mast cells in atopic dermatitis. Curr Opin Immunol. 2009; 21: 666-78.

[22] Zoabi Y, Levi-Schaffer F, Eliashar R. Allergic Rhinitis: Pathophysiology and Treatment Focusing on Mast Cells. Biomedicines. 2022; 10: 2486.

[23] Pałgan K. Mast Cells and Basophils in IgE-Independent Anaphylaxis. Int J Mol Sci. 2023; 24: 12802.

[24] Wilder-Smith CH, Drewes AM, Materna A, Olesen SS. Symptoms of mast cell activation syndrome in functional gastrointestinal disorders. Scand J Gastroenterol. 2019; 54: 1322-5.

[25] Kounis NG. Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med. 2016; 54: 1545-59.

[26] Forlani D, Scarano G, D’Alleva A, Di Marco M, Paloscia L, Gatta A, et al. Kounis Syndrome as First Manifestation of Allergic Sensitization. Case Rep Med. 2019; 2019: 6317956.

[27] Özdemir Ö, Kasımoğlu G, Bak A, Sütlüoğlu H, Savaşan S. Mast cell activation syndrome: An up-to-date review of literature. World J Clin Pediatr. 2024; 13: 92813.

[28] Rossignol J, Polivka L, Maouche-Chrétien L, Frenzel L, Dubreuil P, Hermine O. Recent advances in the understanding and therapeutic management of mastocytosis. F1000Res. 2019; 8: F1000 Faculty Rev-1961.

[29] Puxeddu I, Ribatti D, Crivellato E, Levi-Schaffer F. Mast cells and eosinophils: a novel link between inflammation and angiogenesis in allergic diseases. J Allergy Clin Immunol. 2005; 116: 531-6.

[30] Buchheit KM, Shaw D, Chupp G, Lehtimaki L, Heffler E, Finney-Hayward T, et al. Interleukin-5 as a pleiotropic cytokine orchestrating airway type 2 inflammation: Effects on and beyond eosinophils. Allergy. 2024; 79: 2662-79.

[31] Kovalszki A, Weller PF. Eosinophilia in Mast Cell Disease. Immunol Allergy Clin North Am. 2014; 34: 357-64.

[32] Fremont-Smith M, Gherlone N, Smith N, Tisdall P, Ricke DO. Models for COVID-19 Early Cardiac Pathology Following SARS-CoV-2 Infection. Int J Infect Dis. 2021; 113: 331-5.

[33] Mast Cell [Internet]. NIAD NIH BIOART; [cited 2025 May 10]. Available from: https://bioart.niaid.nih.gov/bioart/335

[34] Eosinophil [Internet]. NIAD NIH BIOART; [cited 2025 May 10]. Available from: https://bioart.niaid.nih.gov/bioart/141

[35] Red Blood Cell [Internet]. NIAID NIH BIOART; [cited 2025 May 10]. Available from: https://bioart.niaid.nih.gov/bioart/442

[36] Pericyte cell [Internet]. scidrawio; [cited 2025 May 10]. Available from: https://scidraw.io/?q=pericyte

[37] Liu F, Goodarzi H, Chen HY. IgE, Mast Cells, and Eosinophils in Atopic Dermatitis. Clin Rev Allergy Immunol. 2011; 41: 298-310.

[38] Simon D, Braathen LR, Simon HU. Eosinophils and atopic dermatitis. Allergy. 2004; 59: 561-70.

[39] Tosca N, Stratigos JD. Possible pathogenetic mechanisms in allergic cutaneous vasculitis. Int J Dermatol. 1988; 27: 291-6.

[40] Grunwald MH, Halevy S, Livni E. Allergic vasculitis induced by hydrochlorothiazide: confirmation by mast cell degranulation test. Isr J Med Sci. 1989; 25: 572-4.

[41] Soter NA, Mihm MC Jr, Dvorak HF, Austen KF. Cutaneous necrotizing venulitis: a sequential analysis of the morphological alterations occurring after mast cell degranulation in a patient with a unique syndrome. Clin Exp Immunol. 1978; 32: 46-58.

[42] Kingsley PJ. Letter: Oral sodium cromoglycate in gastrointestinal allergy. Lancet. 1974; 2: 1011.

[43] Frigas E, Gleich GJ. The eosinophil and the pathophysiology of asthma. J Allergy Clin Immunol. 1986; 77: 527-37.

[44] Nakagome K, Nagata M. Involvement and Possible Role of Eosinophils in Asthma Exacerbation. Front Immunol. 2018; 9: 2220.

[45] Siddiqui S, Bachert C, Bjermer L, Buchheit KM, Castro M, Qin Y, et al. Eosinophils and tissue remodeling: Relevance to airway disease. J Allergy Clin Immunol. 2023; 152: 841-57.

[46] Lezmi G, Galmiche-Rolland L, Rioux S, Jaubert F, Tillie-Leblond I, Scheinmann P, et al. Mast cells are associated with exacerbations and eosinophilia in children with severe asthma. Eur Respir J. 2016; 48: 1320-8.

[47] Knoflach M, Kiechl S, Mayr A, Willeit J, Poewe W, Wick G. Allergic Rhinitis, Asthma, and Atherosclerosis in the Bruneck and ARMY Studies. Arch Intern Med. 2005; 165: 2521-6.

[48] Bousquet J, Cabrera P, Berkman N, Buhl R, Holgate S, Wenzel S, et al. The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma. Allergy. 2005; 60: 302-8.

[49] Wang G, Baines KJ, Fu JJ, Wood LG, Simpson JL, McDonald VM, et al. Sputum mast cell subtypes relate to eosinophilia and corticosteroid response in asthma. Eur Respir J. 2016; 47: 1123-33.

[50] Hussain M, Liu G. Eosinophilic Asthma: Pathophysiology and Therapeutic Horizons. Cells. 2024; 13: 384.

[51] Jackson DJ, Wechsler ME, Brusselle G, Buhl R. Targeting the IL-5 pathway in eosinophilic asthma: A comparison of anti-IL-5 versus anti-IL-5 receptor agents. Allergy. 2024; 79: 2943-52.

[52] Impellizzeri G, Marasco G, Eusebi LH, Salfi N, Bazzoli F, Zagari RM. Eosinophilic colitis: A clinical review. Dig Liver Dis. 2019; 51: 769-73.

[53] Alfadda AA, Storr MA, Shaffer EA. Eosinophilic colitis: epidemiology, clinical features, and current management. Therap Adv Gastroenterol. 2011; 4: 301-9.

[54] Dellon ES, Gonsalves N, Hirano I, Furuta GT, Liacouras CA, Katzka DA, et al. ACG clinical guideline: Evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE). Am J Gastroenterol. 2013; 108: 679-92.

[55] Reed CC, Dellon ES. Eosinophilic Esophagitis. Med Clin North Am. 2019; 103: 29-42.

[56] Alkhowaiter S. Eosinophilic esophagitis. Saudi Med J. 2023; 44: 640-6.

[57] Bolton SM, Kagalwalla AF, Arva NC, Wang MY, Amsden K, Melin-Aldana H, et al. Mast Cell Infiltration Is Associated With Persistent Symptoms and Endoscopic Abnormalities Despite Resolution of Eosinophilia in Pediatric Eosinophilic Esophagitis. Am J Gastroenterol. 2020; 115: 224-33.

[58] Abonia JP, Blanchard C, Butz BB, Rainey HF, Collins MH, Stringer K, et al. Involvement of mast cells in eosinophilic esophagitis. J Allergy Clin Immunol. 2010; 126: 140-9.

[59] Strasser DS, Seger S, Bussmann C, Pierlot GM, Groenen PMA, Stalder AK, et al. Eosinophilic oesophagitis: relevance of mast cell infiltration. Histopathology. 2018; 73: 454-63.

[60] Tappata M, Eluri S, Perjar I, Hollyfield J, Betancourt R, Randall C, et al. Association of mast cells with clinical, endoscopic, and histologic findings in adults with eosinophilic esophagitis. Allergy. 2018; 73: 2088-92.

[61] Niranjan R, Mavi P, Rayapudi M, Dynda S, Mishra A. Pathogenic role of mast cells in experimental eosinophilic esophagitis. Am J Physiol Gastrointest Liver Physiol. 2013; 304: G1087-94.

[62] Blanchard C, Stucke EM, Rodriguez-Jimenez B, Burwinkel K, Collins MH, Ahrens A, et al. A striking local esophageal cytokine expression profile in eosinophilic esophagitis. J Allergy Clin Immunol. 2011; 127: 208-17, 217.e1.

[63] Liacouras CA, Spergel JM, Ruchelli E, Verma R, Mascarenhas M, Semeao E, et al. Eosinophilic Esophagitis: A 10-Year Experience in 381 Children. Clin Gastroenterol Hepatol. 2005; 3: 1198-206.

[64] Otani IM, Anilkumar AA, Newbury RO, Bhagat M, Beppu LY, Dohil R, et al. Anti-IL-5 therapy reduces mast cell and IL-9 cell numbers in pediatric patients with eosinophilic esophagitis. J Allergy Clin Immunol. 2013; 131: 1576-82.

[65] Wang YH, Hogan SP, Fulkerson PC, Abonia JP, Rothenberg ME. Expanding the paradigm of eosinophilic esophagitis: mast cells and IL-9. J Allergy Clin Immunol. 2013; 131: 1583-5.

[66] Caldwell JH, Tennenbaum JI, Bronstein HA. Serum IgE in Eosinophilic Gastroenteritis - Response to Intestinal Challenge in Two Cases. N Engl J Med. 1975; 292: 1388-90.

[67] Cello JP. Eosinophilic gastroenteritis-A complex disease entity. Am J Med. 1979; 67: 1097-4.

[68] Lorentz A, Schwengberg S, Mierke C, Manns MP, Bischoff SC. Human intestinal mast cells produce IL-5 in vitro upon IgE receptor cross-linking and in vivo in the course of intestinal inflammatory disease . Eur J Immunol. 1999; 29: 1496-503.

[69] Moots RJ, Prouse P, Gumpel JM. Near fatal eosinophilic gastroenteritis responding to oral sodium chromoglycate. Gut. 1988; 29: 1282-5.

[70] Van Dellen RG, Lewis JC. Oral administration of cromolyn in a patient with protein-losing enteropathy, food allergy, and eosinophilic gastroenteritis. Mayo Clin Proc. 1994; 69: 441-4.

[71] Melamed I, Feanny SJ, Sherman PM, Roifman CM. Benefit of ketotifen in patients with eosinophilic gastroenteritis. Am J Med. 1991; 90: 310-4.

[72] Bolukbas FF, Bolukbas C, Uzunkoy A, Baba F, Horoz M, Ozturk E. A Dramatic Response to Ketotifen in a Case of Eosinophilic Gastroenteritis Mimicking Abdominal Emergency. Dig Dis Sci. 2004; 49: 1782-5.

[73] Schwartz DA, Pardi DS, Murray JA. Use of Montelukast as Steroid-Sparing Agent for Recurrent Eosinophilic Gastroenteritis. Dig Dis Sci. 2001; 46: 1787-90.

[74] Quack I, Sellin L, Buchner NJ, Theegarten D, Rump LC, Henning BF. Eosinophilic gastroenteritis in a young girl-long term remission under Montelukast. BMC Gastroenterol. 2005; 5: 24.

[75] Li K, Ruan G, Liu S, Xu T, Guan K, Li J, et al. Eosinophilic gastroenteritis: Pathogenesis, diagnosis, and treatment. Chin Med J (Engl). 2023; 136: 899-909.

[76] Oyaizu N, Uemura Y, Izumi H, Morii S, Nishi M, Hioki K. Eosinophilic gastroenteritis. Immunohistochemical evidence for IgE mast cell-mediated allergy. Acta Pathol Jpn. 1985; 35: 759-66.

[77] Whitington PF, Whitington GL. Eosinophilic gastroenteropathy in childhood. J Pediatr Gastroenterol Nutr. 1988; 7: 379-85.

[78] Talley NJ, Shorter RG, Phillips SF, Zinsmeister AR. Eosinophilic gastroenteritis: a clinicopathological study of patients with disease of the mucosa, muscle layer, and subserosal tissues. Gut. 1990; 31: 54-8.

[79] White J, Dubey S. Eosinophilic granulomatosis with polyangiitis: A review. Autoimmun Rev. 2023; 22: 103219.

[80] Vaglio A, Buzio C, Zwerina J. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): state of the art. Allergy. 2013; 68: 261-73.

[81] Winchester DE, Jacob A, Murphy T. Omalizumab for asthma. N Engl J Med. 2006; 355: 1281-2.

[82] Manohar M, Verma AK, Venkateshaiah SU, Mishra A. Role of eosinophils in the initiation and progression of pancreatitis pathogenesis. Am J Physiol Gastrointest Liver Physiol. 2018; 314: G211-22.

[83] Walker MM, Warwick A, Ung C, Talley NJ. The Role of Eosinophils and Mast Cells in Intestinal Functional Disease. Curr Gastroenterol Rep. 2011; 13: 323-30.

[84] Xie H, He S. Roles of histamine and its receptors in allergic and inflammatory bowel diseases. World J Gastroenterol. 2005; 11: 2851-7.

[85] Aguilera-Lizarraga J, Florens MV, Viola MF, Jain P, Decraecker L, Appeltans I, et al. Local immune response to food antigens drives meal-induced abdominal pain. Nature. 2021; 590: 151-6.

[86] Stasikowska-Kanicka O, Danilewicz M, Głowacka A, Wągrowska-Danilewicz M. Mast cells and eosinophils are involved in activation of ulcerative colitis. Adv Med Sci. 2012; 57: 230-6.

[87] Nanagas VC, Kovalszki A. Gastrointestinal Manifestations of Hypereosinophilic Syndromes and Mast Cell Disorders: a Comprehensive Review. Clin Rev Allergy Immunol. 2019; 57: 194-212.

[88] Klion AD. Approach to the patient with suspected hypereosinophilic syndrome. Hematology Am Soc Hematol Educ Program. 2022; 2022: 47-54.

[89] Fairweather D, Frisancho-Kiss S. Mast Cells and Inflammatory Heart Disease: Potential Drug Targets. Cardiovasc Hematol Disord Drug Targets. 2008; 8: 80-90.

[90] Kalsner S, Richards R. Coronary Arteries of Cardiac Patients Are Hyperreactive and Contain Stores of Amines: A Mechanism for Coronary Spasm. Science. 1984; 223: 1435-7.

[91] Ali D, Snead D, Dhakshinamurthy VA, Banerjee P. Rise and fall of the eosinophils in heart failure: a rare but important phenomenon seen with cardiomyopathy. BMJ Case Rep. 2018; 2018: bcr2017221081.

[92] Thongsri T, Chularojanamontri L, Pichler WJ. Cardiac involvement in DRESS syndrome. Asian Pac J Allergy Immunol. 2017; 35: 3-10.

[93] Estensen RD. Eosinophilic myocarditis: a role for mast cells? Arch Pathol Lab Med. 1984; 108: 358-9.

[94] Hara M, Ono K, Hwang MW, Iwasaki A, Okada M, Nakatani K, et al. Evidence for a Role of Mast Cells in the Evolution to Congestive Heart Failure. J Exp Med. 2002; 195: 375-81.

[95] Palaniyandi SS, Watanabe K, Ma M, Tachikawa H, Kodama M, Aizawa Y. Inhibition of mast cells by interleukin-10 gene transfer contributes to protection against acute myocarditis in rats. Eur J Immunol. 2004; 34: 3508-15.

[96] Fairweather D, Stafford KA, Sung YK. Update on coxsackievirus B3 myocarditis. Curr Opin Rheumatol. 2012; 24: 401-7.

[97] Ginsburg R, Bristow MR, Kantrowitz N, Baim DS, Harrison DC. Histamine provocation of clinical coronary artery spasm: implications concerning pathogenesis of variant angina pectoris. Am Heart J. 1981; 102: 819-22.

[98] Kim J, Ogai A, Nakatani S, Hashimura K, Kanzaki H, Komamura K, et al. Impact of Blockade of Histamine H₂Receptors on Chronic Heart Failure Revealed by Retrospective and Prospective Randomized Studies . J Am Coll Cardiol. 2006; 48: 1378-84.

[99] Lee CC, Yu KH, Chan TM. Kimura’s disease: A clinicopathological study of 23 cases. Front Med (Lausanne). 2022; 9: 1069102.

[100] Yang B, Liao H, Wang M, Long Q, Zhong H, Luo L, et al. Kimura’s disease successively affecting multiple body parts: a case-based literature review. BMC Ophthalmol. 2022; 22: 154.

[101] Kelley C, D’Amore P, Hechtman HB, Shepro D. Vasoactive hormones and cAMP affect pericyte contraction and stress fibres in vitro . J Muscle Res Cell Motil. 1988; 9: 184-94.

[102] Hamilton NB, Attwell D, Hall CN. Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. Front Neuroenergetics. 2010; 2: 5.

[103] Ricke DO, Gherlone N, Fremont-Smith P, Tisdall P, Fremont-Smith M, et al. Kawasaki Disease, Multisystem Inflammatory Syndrome in Children: Antibody-Induced Mast Cell Activation Hypothesis. J Pediatr Pediatr Med. 2020; 4: 1-7.

[104] Ricke D. COVID-19 Project. Harvard Dataverse; 2025.

[105] Burchett JR, Dailey JM, Kee SA, Pryor DT, Kotha A, Kankaria RA, et al. Targeting Mast Cells in Allergic Disease: Current Therapies and Drug Repurposing. Cells. 2022; 11: 3031.

[106] Malone RW. More Than Just Heartburn: Does Famotidine Effectively Treat Patients with COVID-19? Dig Dis Sci. 2021; 66: 3672-3.