Asthma, inflammation, eosinophils and bronchial hyperresponsiveness

Asthmatics can have a blood eosinophilia which in some studies correlates with the severity of the disease. However, an increased number and percentage of activated eosinophils can be present in the blood without asthma. The eosinophils that contribute to asthma will be those in the lung. In the BAL fluids collected from asthmatics there is usually no change in total cell number, but there are changes in the differential cell count. A consistent finding is an increase in percentage of mast cells and eosinophils with a tendency for an increase in lymphocytes and epithelial cells and a decrease in percentage of macrophages. As with the blood eosinophilia, an increase in number of eosinophils can be present in BAL fluids without asthma. The site of localization and activation of the eosinophils in the lung may be critical. In bronchial biopsies, taken from asthmatics, increased number of mast cells, eosinophils and lymphocytes have been demonstrated in the bronchial mucosa together with shedding of columnar epithelial cells. However these changes have not been found, or have not reached significance, in all studies. An increase in number of activated eosinophils and T-lymphocytes has been demonstrated but an increase in number of degranulating mast cells has been disputed. A consistent finding has been thickening below the basement membrane. Attempts to correlate the changes in the BAL or lung biopsies with the severity of asthma, lung airways function or bronchial responsiveness have given inconsistent results. Treatment of asthmatics with inhaled steroids can reduce the cellular infiltration in the bronchial biopsies to normal levels but this produces a trivial reduction in bronchial responsiveness. It is possible that infiltration of inflammatory cells into the bronchial mucosa is intermittent, at least in mild asthma, but this produces changes leading to a long lasting bronchial hyperresponsiveness.     

Siglec-8 on human eosinophils and mast cells, and Siglec-F on murine eosinophils, are functionally related inhibitory receptors

Siglecs (sialic acid‐binding, Ig‐like lectins) are a family of single‐pass transmembrane cell surface proteins found predominantly on leucocytes. Their unique structural characteristics include an N‐terminal carbohydrate‐binding (‘lectin’) domain that binds sialic acid, followed by a variable number of Ig‐like domains, hence these structures are a subset of the Ig gene superfamily. Another unique feature of Siglecs is that most, but not all, possess so‐called immunoreceptor tyrosine‐based inhibitory motifs in their cytoplasmic domains, suggesting that these molecules function in an inhibitory capacity. Siglec‐8, the eighth member identified at the time, was discovered as part of an effort initiated almost a decade ago to identify novel human eosinophil and mast cell proteins. Since that time, its selective expression on human eosinophils and mast cells has been confirmed. On eosinophils, Siglec‐8 engagement results in apoptosis, whereas on mast cells, inhibition of Fc?RI‐dependent mediator release, without apoptosis, is seen. It has subsequently been determined that the closest functional paralog in the mouse is Siglec‐F, selectively expressed by eosinophils but not expressed on mast cells. Despite only modest homology, both Siglec‐8 and Siglec‐F preferentially recognize a sulphated glycan ligand closely related to sialyl Lewis X, a common ligand for the selectin family of adhesion molecules. Murine experiments in normal, Siglec‐F‐deficient mice and hypereosinophilic mice have resulted in similar conclusions that Siglec‐F, like Siglec‐8, plays a distinctive and important role in regulating eosinophil accumulation and survival in vivo. Given the resurgent interest in eosinophil‐directed therapies for a variety of disorders, plus its unique additional ability to also target the mast cell, therapies focusing on Siglec‐8 could some day prove to be a useful adjunct to our current armamentarium for the treatment of asthma, allergies and related disorders where overproduction and overactivity of eosinophils and mast cells is occurring.     

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.     

The trials and tribulations of IL-5, eosinophils, and allergic asthma

Eosinophils have been suggested to be part of the pathologic process that characterizes asthma, and their recruitment into the upper or lower airways appears to be essential for the clinical manifestations of allergen inhalation. IL-5 is a cytokine necessary for the development, differentiation, recruitment, activation, and survival of eosinophils. Allergen inhalation increases the production of IL-5 in the airways as measured in bronchoalveolar lavage cells and induced sputum. The relationship between IL-5 and the development of airway eosinophilia has been firmly established in IL-5 transgenic mice, with allergen challenge models in IL-5-deficient mice, and in mice treated with blocking anti-IL-5 antibodies. In addition, an accumulation of evidence suggests that treating mice with anti-IL-5 blocking antibodies prevents allergen-induced airway hyperresponsiveness. A recently reported study examined the effects of treatment with a humanized anti-IL-5 mAb (SB-240563) on allergen-induced airway responses and inflammation in atopic subjects. The authors of the study concluded that their results call into question the role of eosinophils in mediating the allergen-induced late asthmatic response and airway hyperresponsiveness; however, because of methodologic limitations, the study cannot be used either to support or to refute the concept of an important role for eosinophils in causing allergen-induced changes in airway function.     

Induction, isolation and surface marker studies on bovine eosinophils.

A crude extract from Ascaris suum was infused into the teat canal of heifers to serve as an irritant or an antigens. The cells present in the mammary gland following such stimulation were assessed over a period of 2 weeks. Prior to stimulation there were few cells, predominantly macrophages, however, by 12 h post-stimulation a larger number of eosinophils and neutrophils were present. The eosinophils, which represented approximately 50% of the total population, could be purified by Ficoll-Hypaque flotation and nylon or glass wool column filtration to yield a population consisting of over 90% eosinophils. Surface marker studies on the purified eosinophils revealed that they contained both Fc and complement receptors.     

Role of secretory IgA, secretory component, and eosinophils in mucosal inflammation

Eosinophils and their products are important in the pathophysiology of allergic inflammation in mucosal tissues. Secretory component (SC) bound to IgA mediates transepithelial transport of IgA. As another biological activity of SC, we have reported that secretory IgA (sIgA) and SC preferentially activate human eosinophils. When eosinophils were stimulated with immobilized sIgA, degranulation and superoxide production were greater than when stimulated with serum IgA. In contrast, neutrophils responded similarly to sIgA and serum IgA. Superoxide production by eosinophils stimulated with cytokines was enhanced synergistically by immobilized SC, while SC showed no effect on neutrophil activation. Eosinophil superoxide production stimulated with sIgA was abolished by anti-CD18 mAb, suggesting that beta2 integrins might be crucial for this reaction. There are several reports that SC and sIgA may play important roles in regulating eosinophil functions in vivo in diseases associated with mucosal eosinophilia and in various allergic diseases. It is speculated that eosinophils in the mucosa are activated by SC or sIgA, and that subsequent degranulation and superoxide production are induced.