Gastrointestinal eosinophils

Summary: The gut‐associated lymphoid tissue (GALT) is composed of lymphocytes residing in Peyer's patches, lamina propria, and intraepithelial compartments. In addition to these features which distinguish GALT from other peripheral sites of the immune system, the gastrointestinal immune system is also composed of resident eosinophils. Eosinophils are generally considered to be peripheral blood leukocytes that have an important pro‐inflammatory role in various immune disorders. Although most research concerning this cell has focused on understanding its trafficking and function in the blood and lung, recent studies have also started to elucidate its regulation and function in the gastrointestinal tract. Interestingly, eosinophil numbers in the gastrointestinal tract are substantially higher than in other tissues. At baseline (healthy conditions), most eosinophils reside in the lamina propria in the stomach and intestine. Eosinophil homing to these sites occurs during embryonic development and their levels in perinatal mice are comparable to those in adults, indicating that their homing is not dependent upon the presence of intestinal flora. Furthermore, eosinophil localization to the lamina propria at baseline is critically regulated by eotaxin, a chemokine constitutively expressed throughout the gastrointestinal tract. Although eotaxin is required for eosinophil homing, its expression in the esophagus is not sufficient for eosinophil accumulation, since this organ is devoid of eosinophils at baseline. During Th2‐associated inflammatory conditions (e.g. interleukin (IL)‐5 overexpression or oral allergen challenge), marked increases of eosinophils occur not only in the lamina propria but also in Peyer's patches. The accumulation of Peyer's patch eosinophils, which mainly occurs in the outer cortex and interfollicular regions, is critically regulated by IL‐5 and less significantly by eotaxin, suggesting the involvement of other eosinophil chemokines in this lymphoid compartment. Preliminary investigations have shown that gastrointestinal eosinophils express the α4β7 integrin and that this molecule is responsible, in part, for eosinophil homing. In summary, eosinophils are resident cells of the gastrointestinal immune system whose levels can be induced by antigen exposure under Th2 conditions, in a manner that is critically regulated by eotaxin and IL‐5. We propose that eosinophils are integral members of the gastrointestinal immune system and are likely to be important in innate, regulatory and inflammatory immune responses. This work was supported in part by the National Health Medical Research Council (Australia) C.J. Martin Post‐doctoral Fellowship (S.P.H.), the Jaffe Family Fund of the American Academy of Allergy, Asthma, and Immunology (S.P.H.), NIH grant R01 AI45898 (M.E.R.) and the Human Frontier Science Program (M.E.R.). The authors wish to thank Drs. K. Frank Austen, Mitchell Cohen, Paul Foster, Glenn Furuta, and Nives Zimmermann for helpful discussions, as well as numerous other colleagues.     

GM-CSF regulation in eosinophils

Allergic asthma is characterized by a temporally and quantitatively inappropriate immunologic response. One of the hallmarks of this response is the accumulation of eosinophils in the airway and lung parenchyma, which results in broncho-constriction, lung damage and, ultimately, fibrosis. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a pivotal role in this process by modulating eosinophil function and survival. In this review, we discuss the effects and molecular regulation of GM-CSF secretion by eosinophils. Recent data demonstrate that activated eosinophils release small amounts of anti-apoptotic GM-CSF by stabilizing its coding mRNA.     

Hypodense eosinophils are much labeled with 32P than normodense eosinophils]

Peripheral blood eosinophils from the patients with atopic dermatitis were isolated on a Percoll gradient and incubated with H3(32)PO4. After stopping the reaction, SDS/PAG electrophoresis was performed and autoradiographs were prepared to determine the incorporation of 32P into proteins. Eosinophils developed at least 14 protein bands below 66.2 K by SDS/PAG electrophoresis and the differences of the staining patterns between hypodense and normodense eosinophils were observed. In the autoradiographs 5 distinct radioactive bands were observed below 31 K. 32P incorporation into the bands of hypodense eosinophils were stronger than that of normodense eosinophils, suggesting possible involvement of protein phosphorylation in the activation process of eosinophils.     

Intraepithelial eosinophils in esophagitis

Red blood cell alloantibody production was studied in 90 neonates who received a mean of 14.1 transfusions (range 2-35) from an average of 8.9 donors during the first three months after birth. Standard antibody detection procedures were done with the use of a selected red blood cell panel. No unexpected alloantibodies were detected. These findings suggest, at a 99% confidence level, that neonates do not make red blood cell alloantibodies in response to transfusion, indicating that repeated compatibility testing is probably unnecessary. Thus, following initial antibody screening and compatibility tests, further compatibility testing can be eliminated.     

Degranulating eosinophils in human endometriosis

Degranulating eosinophils have been described in most endometrial cancers. We hypothesized that endometriosis (ectopic, nonneoplastic endometrial tissue) would be an appropriate model system for determining whether eosinophil degranulation is part of a specific immune response to endometrial cancer or if it is related to the more general phenomenon of tissue remodeling (wound healing) that is common to both disorders. To test this hypothesis, we performed immunohistochemistry and Western blotting to evaluate the presence of eosinophil peroxidase (a marker of eosinophil degranulation) in normal endometrium (n = 20) and endometriosis samples (n = 24) and to define the coexpression of three eosinophil chemoattractants: interleukin-5 (IL-5), eotaxin, and regulated on activator-normal T cell expressed and secreted (RANTES). There was focally intense deposition of eosinophil peroxidase in the fibrotic connective tissue and blood vessels of 21 of 24 human endometriosis specimens; two samples showed weak staining, and only one tissue was negative for eosinophil degranulation. None of the 10 normal proliferative endometrial specimens had evidence of eosinophil degranulation, and four of 10 secretory tissues stained only weakly for eosinophil peroxidase. The presence of degranulating eosinophils was also associated with the presence of eotaxin and IL-5 in some samples and with RANTES in others. We conclude that the abundant presence of degranulating eosinophils in the fibrous regions of endometriosis supports the interpretation that eosinophils are involved in general tissue remodeling and wound healing rather than a tissue-directed immune response.     

Pattern-recognition receptors in human eosinophils

The pattern-recognition receptor (PRR) family includes Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD) -like receptors (NLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs) and the receptor for advanced glycation end products (RAGE). They recognize various microbial signatures or host-derived danger signals and trigger an immune response. Eosinophils are multifunctional leucocytes involved in the pathogenesis of several inflammatory processes, including parasitic helminth infection, allergic diseases, tissue injury and tumour immunity. Human eosinophils express several PRRs, including TLR1-5, TLR7, TLR9, NOD1, NOD2, Dectin-1 and RAGE. Receptor stimulation induces survival, oxidative burst, activation of the adhesion system and release of cytokines (interleukin-1β, interleukin-6, tumour necrosis factor-α and granulocyte-macrophage colony-stimulating factor), chemokines (interleukin-8 and growth-related oncogene-α) and cytotoxic granule proteins (eosinophil cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase and major basic protein). It is also evident that eosinophils play an immunomodulatory role by interacting with surrounding cells. The presence of a broad range of PRRs in eosinophils indicates that they are not only involved in defence against parasitic helminths, but also against bacteria, viruses and fungi. From a clinical perspective, eosinophilic PRRs seem to be involved in both allergic and malignant diseases by causing exacerbations and affecting tumour growth, respectively.