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investigate the eosinophil in equine health and disease at a molecular level. Considering the material presented in this series and the larger body of eosinophil research, efforts to address the following questions will be of significant value.


• Do equine eosinophils express different phenotypes based upon tissue of residence, activation status and the horse’s health status? Eosinophil phenotypes are recognised in laboratory animals (Mesnil et al. 2016; Percopo et al. 2017) and human subjects (Ying et al. 1999; Roth et al. 2011; Khoury et al. 2018). Few attempts have been made to identify eosinophil phenotypes in horses (Greenaway et al. 2003; Riihimaki et al. 2008). The use of advanced techniques (Roth et al. 2011; Wilkerson et al. 2016) to identify surface and secreted proteins in health and disease states in the horse would firstly improve the clinical utility of eosinophil counts, and secondly facilitate research as described below.


• What is the effect of age on equine eosinophil biology? Age-related variation in eosinophil function is recognised in human subjects (Mathur et al. 2008; Lingblom et al. 2017). Age-associated variation in eosinophils is evident in normal horses, response to pathogens and EADs, but molecular mechanisms are unknown. Exogenous ACTH decreases PBEs (Alexander and Ash 1955; James et al. 1970; Eiler et al. 1979; Stewart et al. 2011), an effect also observed in human subjects (Hain 1951), but effects of endogenous ACTH on eosinophils in horses with pituitary pars intermedia dysfunction remain uninvestigated.


• Do eosinophils perform novel functions in the horse? Eosinophils contribute to diverse homeostatic functions in other species such as metabolic control of adipose tissue, transplant rejection, regulation of haematopoiesis, tissue regeneration and angiogenesis (Lee et al. 2010; Kita 2011; Takeda et al. 2015; Strandmark et al. 2016; De Palma et al. 2017; Weller and Spencer 2017; Knights et al. 2018; Bentley et al. 2019). A role in tissue repair is suggested in the horse (O’Callaghan et al. 1987; Monahan et al. 1994), but this and other roles remain uninvestigated.


• Do parasites, anthelmintics or other drugs affect eosinophil function and EAD occurrence? In some species, helminths ameliorate eosinophilia in experimental diseases (Stiemsma et al. 2015), whereas in the horse eosinophilia often is attributed categorically to parasites despite parasite studies showing poor correlation between PBEs and parasite loads. Parasite life cycles are intimately related to the eosinophilic response in horses (Monahan et al. 1994), and tissue infiltrates are affected by anthelmintics (Slocombe and McCraw 1975; Herd and Donham 1981; Nielsen et al. 2015; Steuer et al. 2018). The whole-organism effects of parasite elimination or life cycle disruption in horses are unknown, but it is interesting that EADs appear around the time that accessible, effective anthelmintics changed the dynamics of equine gastrointestinal parasitism (Kaplan 2002). In human subjects, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a delayed response to drugs including NSAIDs and sulfonamides (Choudhary et al. 2013). Drugs have not been investigated as a contributing factor to EADs.


• Are there better interim pharmacologics for pathologic eosinophilia? Corticosteroids decrease PBEs in the horse (Targowski 1975; Simon et al. 1990), and are the mainstay of treatment for EADs. Immunopharmacologics such as


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antibodies against IL-5 and a variety of eosinophil surface molecules, including the IL-5 receptor, are used in human subjects. These have shown variable success depending on the specific condition being treated, and clinical trials are ongoing (Legrand and Klion 2015). These medications have not been tested in horses.


• What triggers degranulation in vivo? Extensive mechanistic data exist on equine eosinophil degranulation in vitro (Lindau et al. 1994; Scepek et al. 1994; Hartmann et al. 1995; Hafez et al. 2003; Valero et al. 2008), but in vivo knowledge is lacking.


• What is the role of mast cells and platelets? Mast cell associations are highly variable as described above (Crane et al. 1989; Sweeney et al. 1992; Williamson et al. 1997; Collobert-Laugier et al. 2002; Pittaway et al. 2014; Hostetter et al. 2017). Investigation of this other rare cell (Mair et al. 1988; Jorgensen et al. 2018) would be beneficial. Platelets are coming under increased scrutiny in human subjects and laboratory models for a broader role in immunomodulation of allergic reactions, particularly for their effect on eosinophil recruitment and function (Shah et al. 2017).


Author’s declaration of interests No conflicts of interest have been declared.


Ethical animal research Not applicable to this review of literature.


Source of funding None.


References


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Allen, B.V. and Frank, C.J. (1982) Haematological changes in 2 ponies before and during an infection with equine influenza. Equine Vet. J. 14, 171-172.


Archer, D.C., Edwards, G.B., Kelly, D.F., French, N.P. and Proudman, C.J. (2006) Obstruction of equine small intestine associated with focal idiopathic eosinophilic enteritis: an emerging disease? Vet. J. 171, 504-512.


Archer, D.C., Costain, D.A. and Sherlock, C. (2014) Idiopathic focal eosinophilic enteritis (IFEE), an emerging cause of abdominal pain in horses: the effect of age, time and geographical location on risk. PLoS ONE 9, e112072.


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Bedenice, D., Mazan, M.R. and Hoffman, A.M. (2008) Association between cough and cytology of bronchoalveolar lavage fluid and pulmonary function in horses diagnosed with inflammatory airway disease. J. Vet. Intern. Med. 22, 1022-1028.


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