Morphology of eosinophils

Eosinophils are polymorphonuclear white blood cells that play a role in innate, acquired, and adaptive immunity, as well as in tissue remodeling. Eosinophils are characterized by the fact that their cytoplasm can be stained intensively with anionic dyes, such as eosin (Khan, Reference Khan2005; Young and Meadows, Reference Young, Meadows, Weiss and Wardrop2010). Eosinophils contain small primary granules that contain acrylsulfatase, peroxidase, and acid phosphatase and large crystalloid granules that contain major basic proteins (MBPs), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN) (Tizard, Reference Tizard and Tizerd2009) (Table 1, Fig. 1). MBPs, which are located in the core of large granules, have activities that affect smooth muscle contraction and peripheral nerve plasticity (Rothenberg and Hogan, Reference Rothenberg and Hogan2006). ECP, EPO, and EDN are found in the cellular matrix of the large granules. ECP is a ribonuclease A (RNase A) that has both cytotoxic and noncytotoxic activities. ECP has anti-viral activity and can also suppress the proliferation of T cells and immunoglobulin synthesis by B cells (Rothenberg and Hogan, Reference Rothenberg and Hogan2006). EPO is more potent than myeloperoxidase (MPO), which is secreted by neutrophils to kill infectious organisms. EPO, in contrast to MPO, forms a highly reactive oxygen species (hypobromous acid (HOBr)) in the presence of superoxide (Weiss et al., Reference Weiss, Test, Eckmann, Roos and Regiani1986). EDN, which is an RNase A and a cytotoxic agent, is associated with host defense against viruses and can be secreted by other inflammatory cells, such as mononuclear cells and neutrophils (Rothenberg and Hogan, Reference Rothenberg and Hogan2006; Young and Meadows, Reference Young, Meadows, Weiss and Wardrop2010).

Fig. 1.

The intracellular structure of an eosinophil contains small primary granules and large crystalloid granules.

Table 1.

The location and activity of the major proteins in large crystalloid granules of eosinophils

Eosinophils are considered late-phase cells of the host immune response (Rothenberg and Hogan, Reference Rothenberg and Hogan2006) . They originate and develop from pluripotent stem cells in the bone marrow. The regulation of eosinophil expansion is controlled by eosinophilopoietins, interleukin-1 (IL-1), IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) (Yang et al., Reference Yang, Sellins, Weber and Mccall2001; Rothenberg and Hogan, Reference Rothenberg and Hogan2006). Primitive stem cells become eosinophilic precursor myeloblasts in the presence of IL-1, IL-3, and GM-CSF (Yan and Shaffer, Reference Yan and Shaffer2009). IL-1, IL-3, and GM-CSF play a major role in eosinophil development, whereas IL-5, which is produced by mast cells, is the major cytokine that regulates the migration of eosinophils from bone marrow to blood circulation (Latimer and Prasse, Reference Latimer, Prasse, Latimer, Mahaffey and Prasse2003). Eosinophils cross the endothelium into target tissues by the regulation of chemokine eotaxin-1, eosinophil adhesion molecules, and adhesion receptors on the endothelium (Fig. 2). Because eosinophils are predominantly tissue-dwelling cells, only a small number of eosinophils can be found in the circulation. The major target organ of eosinophils in dogs is the GI tract (Khan, Reference Khan2005; Rothenberg and Hogan, Reference Rothenberg and Hogan2006; Tizard, Reference Tizard and Tizerd2009; Young and Meadows, Reference Young, Meadows, Weiss and Wardrop2010).

Fig. 2.

The development, migration, and activation of eosinophils. IL-1, IL-3, and GM-CSF stimulate the generation of eosinophil colony-stimulating units from stem cells in the bone marrow. Antigen-presenting cells present the antigen to Th2 cells. Th2 cells release IL-5, which stimulates eosinophil differentiation and proliferation. IL-4 from Th2 cells promotes the accumulation of eosinophils and IgE production from B cells. Th2 cells and activated mast cells produce IL-13 and TNF to promote local inflammation.

Activation of eosinophils

Various changes in cell morphology, cell surface characteristics, and functional activities occur during eosinophil activation. Eosinophilic mobilization is orchestrated by T helper 2 (Th2) cells, mast cells, and eotaxins. Once antigen-presenting cells (APCs) present the antigen to Th2 cells, the activated Th2 cells produce IL-4, IL-5, and tumor necrosis factor (TNF) (Yan and Shaffer, Reference Yan and Shaffer2009). IL-4 stimulates eosinophilic accumulation and an immunoglobulin E (IgE) response from B cells. IL-5 is important for the termination of differentiation and proliferation of eosinophils (Yan and Shaffer, Reference Yan and Shaffer2009). In addition, mast cells release IL-13 and TNF, which play a role in promoting the local inflammation (Yan and Shaffer, Reference Yan and Shaffer2009) (Fig. 2).

Eotaxins are chemokines that act as eosinophilic chemoattractants to the mast cell degranulation site. CCR3 is a receptor on eosinophils for eotaxins. Gurish et al. (Reference Gurish, Humbles, Tao, Finkelstein, Boyce, Gerard, Friend and Austen2002) found that a low abundance of CCR3 was associated with a decreased response of eosinophil recruitment in mice during parasitic infestation. In addition, activated eosinophils can express MHC class II and immunosuppressive enzymes. The mobilization of eosinophils to the site of mast cell degranulation and the activation of eosinophils increase their ability to kill and respond to the inflammation of other eosinophils (Young and Meadows, Reference Young, Meadows, Weiss and Wardrop2010).

Eosinophil degranulation and mediators

Eosinophils can destroy small particles through exocytosis and large particles through extracellular destruction. Exocytosis is regulated by the formation of a docking complex that consists of the soluble N-ethylmaleimide-sensitive factor attachment protein and its receptor (SNARE) on the vesicle and the target membrane (Blackshaw and Levison, Reference Blackshaw and Levison1986). Eosinophil sombrero vesicle (EoSV), a unique vesicular compartment of eosinophils, migrates to the docking site on the plasma membrane to release protein mediators during eosinophil activation. This piecemeal degranulation plays a role in the elimination of large parasitic infections. Eosinophils degranulate in response to IgE, chemokines, C5a, and platelet-activating factor (PAF) (Rothenberg and Hogan, Reference Rothenberg and Hogan2006; Young and Meadows, Reference Young, Meadows, Weiss and Wardrop2010). Lipid mediators, such as prostaglandins, leukotrienes, and thromboxane A2, are produced and released from eosinophils to play a role in the host defense mechanism; however, prostaglandins may also down regulate eosinophil functions.

Eosinophils also release inflammatory and toxic mediators, such as ECP, MBP, and EOP. Interestingly, EOP selectively generates reactive brominating reagents (OBr⁻) when chloride concentrations are higher than bromide concentrations (100 mM Cl⁻, 20–150 μM Br⁻, and 0.1–0.6 μM I⁻) (Shen et al., Reference Shen, Mitra, Wu, Chen, Yang, Qin and Hazen2001). Superoxide and hydrogen peroxide that are generated during the respiratory burst of eosinophils react with EOP to produce HOBr through an EPO–H₂O₂–halide system (Fig. 3) (Weiss et al., Reference Weiss, Test, Eckmann, Roos and Regiani1986; Senthilmohan and Kettle, Reference Senthilmohan and Kettle2006). HOBr is a highly potent non-stable oxidizing agent that is generated by eosinophils (Mayeno et al., Reference Mayeno, Curran, Roberts and Foote1989; van Dalen and Kettle, Reference van Dalen and Kettle2001). It has activities against various microorganisms, such as viruses, bacteria, fungi, and parasites (Mayeno et al., Reference Mayeno, Curran, Roberts and Foote1989), and will react with tyrosine in physiological conditions (Weiss et al., Reference Weiss, Test, Eckmann, Roos and Regiani1986; van Dalen and Kettle, Reference van Dalen and Kettle2001). The reaction of HOBr and tyrosine generates 3-bromotyrosine, which is a stable cytotoxic product that marks the activation of eosinophils (Weiss et al., Reference Weiss, Test, Eckmann, Roos and Regiani1986; van Dalen and Kettle, Reference van Dalen and Kettle2001). Eosinophils also release an array of cytokines: IL-1, IL-2, TNFα, TNFβ, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-16, IL-18, TGFα/β, and CCL5 (Blackshaw and Levison, Reference Blackshaw and Levison1986).

Fig. 3.

The generation of an EPO–H₂O₂–halide system during an eosinophil respiratory burst. Superoxide is formed during the respiratory burst of eosinophils and generates hydrogen peroxide in the presence of superoxide dismutase. Hydrogen peroxide then reacts with EPO to produce HOBr through the EPO–H₂O₂–halide system. HOBr is toxic to microorganisms, which will be destroyed.

The release of granule proteins, lipid mediators, and cytokines during eosinophil degranulation not only can eliminate bacterial and parasitic infections, but can also harm the cell or surrounding tissues. Mast cells and eosinophils coordinate with each other during allergic reactions. In contrast, the uncontrolled or excessive release of inflammatory mediators from mast cells and eosinophils leads to type I hypersensitivity (Abbas et al., Reference Abbas, Lichtman, Pillai, Abbas, Lichtman and Pillai2007; Tizard, Reference Tizard and Tizerd2009).

Eosinophilic esophagitis

Eosinophilic esophagitis, also called idiopathic eosinophilic esophagitis, is the most common eosinophil-associated GI tract disorder in human patients (Blanchard and Rothenberg, Reference Blanchard and Rothenberg2008). Eosinophilic esophagitis manifests itself as a chronic immune-mediated disease characterized by esophageal dysfunction with a predominantly eosinophilic inflammation (Liacouras et al., Reference Liacouras, Furuta, Hirano, Atkins, Attwood, Bonis, Burks, Chehade, Collins, Dellon, Dohil, Falk, Gonsalves, Gupta, Katzka, Lucendo, Markowitz, Noel, Odze, Putnam, Richter, Romero, Ruchelli, Sampson, Schoepfer, Shaheen, Sicherer, Spechler, Spergel, Straumann, Wershil, Rothenberg and Aceves2011). Young male adults appear predisposed to eosinophilic esophagitis, which is also commonly associated with allergic diseases (Liacouras et al., Reference Liacouras, Furuta, Hirano, Atkins, Attwood, Bonis, Burks, Chehade, Collins, Dellon, Dohil, Falk, Gonsalves, Gupta, Katzka, Lucendo, Markowitz, Noel, Odze, Putnam, Richter, Romero, Ruchelli, Sampson, Schoepfer, Shaheen, Sicherer, Spechler, Spergel, Straumann, Wershil, Rothenberg and Aceves2011). Eosinophilic esophagitis is characterized by an infiltration of eosinophils into the esophagus. Normally, eosinophils are not present in the mucosa of the esophagus. Therefore, the presence of eosinophils in the esophageal mucosa is diagnostic for eosinophilic esophagitis (Rothenberg et al., Reference Rothenberg, Mishra, Collins and Putnam2001). In people, eosinophilic esophagitis can be diagnosed by the exclusion of other causes of esophageal disease, such as parasites or neoplasia, and by the presence of ⩾15 eosinophils per high power field (hpf) in mucosal biopsy specimens (Hogan, Reference Hogan2009; Liacouras et al., Reference Liacouras, Furuta, Hirano, Atkins, Attwood, Bonis, Burks, Chehade, Collins, Dellon, Dohil, Falk, Gonsalves, Gupta, Katzka, Lucendo, Markowitz, Noel, Odze, Putnam, Richter, Romero, Ruchelli, Sampson, Schoepfer, Shaheen, Sicherer, Spechler, Spergel, Straumann, Wershil, Rothenberg and Aceves2011).

Canine eosinophilic esophagitis was apparently first reportedly in 2009 (Mazzei et al., Reference Mazzei, Bissett, Murphy, Hunter and Neel2009). The dog reported had a history of allergic skin disease. The underlying cause of eosinophilic esophagitis in this instance was believed to be food allergy (Mazzei et al., Reference Mazzei, Bissett, Murphy, Hunter and Neel2009). The dog had clinical signs of esophageal disease, such as regurgitation, coughing, and dysphagia. The dog was unresponsive to anti-reflux therapy, but responded well to corticosteroid therapy and an elimination diet. In this case, the diagnosis of eosinophilic esophagitis was based on clinical signs, endoscopic and histopathologic findings, failure of prokinetic and gastric protectant drug therapy, and response to corticosteroid administration and allergen restriction (Mazzei et al., Reference Mazzei, Bissett, Murphy, Hunter and Neel2009). Other diseases associated with eosinophilic infiltration, such as spirocercosis, must also be ruled out before eosinophilic esophagitis can be diagnosed (Van der Merwe et al., Reference Van Der Merwe, Kirberger, Clift, Williams, Keller and Naidoo2008).

Eosinophilic gastritis

Gastritis and duodenitis often occur concurrently, which may be related to the close anatomical and physiological relationship between the stomach and small intestine (Lidbury et al., Reference Lidbury, Suchodolski and Steiner2009). Lymphocytic–plasmacytic gastritis is the most common form of canine gastritis (Lidbury et al., Reference Lidbury, Suchodolski and Steiner2009; Simpson, Reference Simpson, Washabau and Day2013). Eosinophilic gastritis has also been reported, but occurs less frequently (Lidbury et al., Reference Lidbury, Suchodolski and Steiner2009). The eosinophilic infiltration is mainly limited to the gastric mucosa and rarely extends into the muscularis or serosa of the stomach wall. The infiltration can cause hypertrophy of the rugal folds as well as an ulcerated mucosa (Neiger, Reference Neiger and Steiner2008). In severe cases, eosinophilia may also be present in the blood. Eosinophilic gastritis is more common in dogs under 5 years of age (van der Gaag, Reference Van Der Gaag1988b). Eosinophilic gastritis can be associated with urticaria and allergic skin lesions (Neiger, Reference Neiger and Steiner2008). The cause of eosinophilic gastritis remains unknown; however, several factors, such as a genetic predisposition and diet, are likely involved in its pathogenesis.

In contrast to the esophagus, eosinophils can normally be found in the stomach and intestines. Therefore, the diagnosis of eosinophilic gastritis is more complicated than that of eosinophilic esophagitis. In human medicine, there is no ‘gold standard’ for diagnosis of eosinophilic gastritis, but combinations of clinical and histopathological findings are usually used to diagnose the disease. An increase in eosinophils found in gastric biopsies that are characterized by the infiltration of eosinophils into the gastric glands combined with the exclusion of other causes of eosinophilia, such as infection, support a diagnosis of eosinophilic gastroenteritis (Rothenberg, Reference Rothenberg2004).

In dogs, a diagnosis of eosinophilic gastritis requires the exclusion of other causes of eosinophilic infiltration into the gastric mucosa. These other causes include parasitic infections of the stomach that are caused by Physaloptera spp., Ollulanustricuspis, Gnathostoma spp., and Spirocerca spp., can also cause an infiltration of a dog's stomach wall by eosinophils (Neiger, Reference Neiger and Steiner2008; Simpson, Reference Simpson, Ettinger and Feldman2010). The major clinical sign of eosinophilic gastritis is chronic, persistent, or intermittent vomiting. Delayed gastric emptying, anorexia, and weight loss can also be found in dogs with chronic gastritis (Neiger, Reference Neiger and Steiner2008). Because the clinical signs of eosinophilic gastritis cannot be distinguished from other forms of gastritis, a gastric biopsy is the only diagnostic tool to identify eosinophilic gastritis. The International GI Standardization Group of the World Small Animal Veterinary Association (WSAVA) has provided guidelines for the normal histology of the stomach (Washabau et al., Reference Washabau, Day, Willard, Hall, Jergens, Mansell, Minami and Bilzer2010). The mucosa of the normal gastric body and gastric antrum may have 0–2 (mean: 0.5) and 0–6 (mean: 2.7) eosinophils per 10,000 μm², respectively (Fig. 4A). Eosinophil counts above these levels would suggest eosinophilic gastritis.

Fig. 4.

Histopathological appearance of the canine gastrointestinal tract infiltrated with eosinophils (arrows). (A) Stomach: mild eosinophilic infiltration of the gastric antrum. (B) Duodenum: moderate eosinophilic duodenitis. (C) Ileum: moderate eosinophilic ileitis. (D) Ileum: severe eosinophilic enteritis. (E) Colon: severe eosinophilic colitis. (F) Colon: moderate eosinophilic colitis (stain: H&E).

Eosinophilic enteritis

Eosinophilic enteritis includes eosinophilic duodenitis, eosinophilic jejunitis, and eosinophilic ileitis. In human patients, the causes of IBD and eosinophilic enteritis remain unknown. However, it is widely hypothesized that these disorders are due to a loss of one's tolerance to luminal antigens. Disruption of the mucosal barrier, dysregulation of the immune system, disturbances in the intestinal microbiota, or a combination of these factors is thought to cause the loss of tolerance seen in this condition (Elson et al., Reference Elson, Cong, Brandwein, Weaver, Mccabe, Mähler, Sundberg and Leiter1998). Eosinophilic enteritis is uncommon and found more frequently in men than in women (1.4:1) (Edelman, Reference Edelman1998). Eosinophilic enteritis is considered an idiopathic disease. Histopathological findings associated with eosinophilic enteritis include increased numbers of eosinophils, hyperplastic crypts, villous atrophy, and epithelial cell necrosis (Collins, Reference Collins2009). Peripheral eosinophilia is reported in 75% of patients with eosinophilic enteritis; thus, peripheral eosinophilia is not a reliable indicator of the disease (Talley et al., Reference Talley, Shorter, Phillips and Zinsmeister1990).

Ancylostoma caninum, a canine hookworm, can cause eosinophilic enteritis and peripheral eosinophilia in dogs and, on rare occasions, in people (Walker et al., Reference Walker, Croese, Clouston, Parry, Loukas and Prociv1995). Primary eosinophilic enteritis has been reported to cause small intestinal obstruction in humans without peripheral eosinophilia (Uenishi et al., Reference Uenishi, Sakata, Tanaka, Yamamoto, Shuto, Hirohashi, Kubo and Kinoshita2003; Yun et al., Reference Yun, Cho, Park, Choi, Kim, Shin and Kim2007). Eosinophils infiltrate the muscularis layer of the small intestinal mucosa. This infiltration leads to thickening of the intestinal wall and obstruction of the intestinal lumen (Yun et al., Reference Yun, Cho, Park, Choi, Kim, Shin and Kim2007).

In dogs, eosinophilic enteritis is the second most commonly diagnosed form of IBD, while LPE is most common (Hall and German, Reference Hall, German and Steiner2008). Parasitic infection and food allergy must be excluded before making a diagnosis of eosinophilic IBD. Eosinophilic enteritis may be associated with HES. Diarrhea, weight loss, and abdominal pain are the most common clinical signs of eosinophilic enteritis. Peripheral eosinophilia can also be found in patients with eosinophilic enteritis (Quigley and Henry, Reference Quigley and Henry1981). Chronic and often bloody diarrhea are commonly found in dogs with eosinophilic enteritis (O'Brien, Reference O'brien1989), and mucosal erosion and ulceration can also be found in this disorder (van der Gaag et al., Reference Van Der Gaag, Happe and Wolvekamp1983). Hypoalbuminemia may also be associated with chronic eosinophilic enteritis due to protein-losing enteropathy.

Eosinophilia is not pathognomonic of eosinophilic enteritis, so intestinal biopsies are needed for diagnosis (Yang et al., Reference Yang, Sellins, Weber and Mccall2001; Yan and Shaffer, Reference Yan and Shaffer2009). Biopsies of both the duodenum and ileum should be evaluated for a diagnosis of small intestinal inflammation (Dossin et al., Reference Dossin, Tesseydre, Concordet and Raymond2007). The intestinal mucosa may contain a small number of eosinophils physiologically; thus it is important to perform the intestinal histopathological interpretation based on the WSAVA standardization guidelines (Washabau et al., Reference Washabau, Day, Willard, Hall, Jergens, Mansell, Minami and Bilzer2010). In an adult dog, the normal eosinophilic count in the cryptal lamina propria, villous lamina propria, and tip of the villi are 9.8±7.5, 3.7±3.5, and 3.8±6.1 per 10,000 μm², respectively (Washabau et al., Reference Washabau, Day, Willard, Hall, Jergens, Mansell, Minami and Bilzer2010) (Fig. 4B–D).

Eosinophilic colitis

Eosinophilic colitis is the least common of human eosinophilic GI diseases (Alfadda et al., Reference Alfadda, Storr and Shaffer2011; Yen and Pardi, Reference Yen and Pardi2012). The cause of primary eosinophilic colitis, which mainly affects infants and young children, is unknown (Yen and Pardi, Reference Yen and Pardi2012). Secondary eosinophilic colitis may result from an IgE-mediated food allergy, drug-induced eosinophilic colitis, or IBD (Tortora et al., Reference Tortora, Purchiaroni, Scarpellini, Ojetti, Gabrielli, Vitale, Giovanni and Gasbarrini2012; Yen and Pardi, Reference Yen and Pardi2012). Non-IgE-associated eosinophilic colitis is mainly found in adults (Yen and Pardi, Reference Yen and Pardi2012). The clinical signs of eosinophilic colitis include abdominal pain, bloody or non-bloody diarrhea, and weight loss. The diagnosis of eosinophilic colitis in human patients is based on increased numbers of mucosal eosinophils and other abnormalities, such as architectural changes in crypts, Paneth cell metaplasia in the distal colon, basal lymphoid aggregates, diffuse plasmacytosis, and eosinophils in the muscularis mucosa (Collins, Reference Collins2009).

Eosinophilic colitis (eosinophilic ulcerative colitis) is considered to be a form of IBD in dogs that is characterized by eosinophilic infiltration of the colon (van der Gaag et al., Reference Van Der Gaag, Van Der Linde-Sipman, Van Sluys and Wolvekamp1990; Leib, Reference Leib and Steiner2008). Eosinophilic colitis is rare in dogs, while atrophic colitis, diffuse colitis, and canine HUC are more common (van der Gaag, Reference Van Der Gaag1988a). The cause of eosinophilic colitis is still unclear, but the average age of dogs diagnosed was 3.9 years (van der Gaag and van der Linde-Sipman, Reference Van Der Gaag and Van Der Linde-Sipman1987). van der Gaag and van der Linde-Sipman (Reference Van Der Gaag and Van Der Linde-Sipman1987) reported a case of eosinophilic ulcerative colitis in a 3-year-old dog. The dog presented with hemorrhagic diarrhea, anorexia, weight loss, hypoalbuminemia, and anemia. However, eosinophilia was not present. Before diagnosing eosinophilic colitis, one should eliminate other causes of eosinophilia in the colon, such as endoparasites, autoimmune disease, and hypersensitivity. A colonoscopy and biopsy should be performed to diagnose eosinophilic colitis (van der Gaag et al., Reference Van Der Gaag, Van Der Linde-Sipman, Van Sluys and Wolvekamp1990). The WSAVA guidelines suggest that the physiologic count of eosinophils in the lamina propria between the basal crypts of the colon is 3.8±3.7 cells per 10,000 μm² (Washabau et al., Reference Washabau, Day, Willard, Hall, Jergens, Mansell, Minami and Bilzer2010) (Fig. 4E, F).

Eosinophilic gastroenteritis and eosinophilic gastroenterocolitis

Eosinophilia in more than one segment of the GI tract of dogs has been reported in several publications (Van Der Gaag et al., Reference Van Der Gaag, Happe and Wolvekamp1983; Rodriguez et al., Reference Rodriguez, Rodriguez, Pena, Flores, Gonzalez and Castano1995; McTavish, Reference Mctavish2002; Brellou et al., Reference Brellou, Kleinschmidt, Meneses, Nolte and Hewicker-Trautwein2006; Fonseca-Alves et al., Reference Fonseca-Alves, Correa and Elias2012). Eosinophilic gastroenteritis has been reported in a German shepherd, a Basset hound, a Siberian husky, and a mixed-breed dog (Van Der Gaag et al., Reference Van Der Gaag, Happe and Wolvekamp1983; Rodriguez et al., Reference Rodriguez, Rodriguez, Pena, Flores, Gonzalez and Castano1995; McTavish, Reference Mctavish2002; Brellou et al., Reference Brellou, Kleinschmidt, Meneses, Nolte and Hewicker-Trautwein2006; Fonseca-Alves et al., Reference Fonseca-Alves, Correa and Elias2012). Several studies have attempted to identify the cause of eosinophilic gastroenteritis/colitis in dogs. Kleinschmidt et al. (Reference Kleinschmidt, Meneses, Nolte and Hewicker-Trautwein2007) found an increased abundance of mast cells in the area of the eosinophilic gastroenterocolitis, and concluded that a type I hypersensitivity reaction was involved in eosinophilic gastroenterocolitis. Mast cell tumors and lymphomas also release cytokines that secrete eosinophil polymorphonuclear leukocyte chemotaxis factors (Marchetti et al., Reference Marchetti, Benetti, Citi and Taccini2005; Ozaki et al., Reference Ozaki, Yamagami, Nomura and Narama2006; Tomiyasu et al., Reference Tomiyasu, Fujino, Ugai, Goto-Koshino, Ide, Takahashi, Ohno, Uchida, Nakayam and Tsujimoto2010). The factors responsible for this stimulation include IL-5, IL-3, GM-CSF, and eotaxin. These tumors result in paraneoplastic eosinophilia and eosinophilic infiltrates in GI tract.

The clinical signs of eosinophilic gastroenterocolitis are chronic GI signs, such as vomiting, hematemesis, inappetence, weight loss, abdominal pain, melena, and bloody diarrhea (van der Gaag et al., Reference Van Der Gaag, Happe and Wolvekamp1983; Rodriguez et al., Reference Rodriguez, Rodriguez, Pena, Flores, Gonzalez and Castano1995; McTavish, Reference Mctavish2002; Brellou et al., Reference Brellou, Kleinschmidt, Meneses, Nolte and Hewicker-Trautwein2006; Mazzei et al., Reference Mazzei, Bissett, Murphy, Hunter and Neel2009; Fonseca-Alves et al., Reference Fonseca-Alves, Correa and Elias2012). Hematemesis, hematochezia, melena, weight loss, and regenerative anemia are thought to be due to GI ulceration (McTavish, Reference Mctavish2002). However, peripheral eosinophilia is not always present in these cases (Fonseca-Alves et al., Reference Fonseca-Alves, Correa and Elias2012). Thickening of the gastric and intestinal wall can also be found in eosinophilic gastroenterocolitis (van der Gaag et al., Reference Van Der Gaag, Happe and Wolvekamp1983; Fonseca-Alves et al., Reference Fonseca-Alves, Correa and Elias2012). The diagnosis of eosinophilic gastroenteritis and gastroentrocolitis in dogs is based on clinical signs along with histopathological findings in the GI tract (McTavish, Reference Mctavish2002).

Currently, there is no non-invasive marker for eosinophil activity available. However, the development of such a non-invasive biomarker for the diagnosis of GI eosinophilia would significantly advance the diagnostic capabilities for eosinophilic gastroenteritis as well as other eosinophilic diseases.