Eosinophil Secretory Functions
Eosinophils release highly cationic proteins (eosinophil granule major basic protein 1, eosinophil cationic protein) that can cause airway hyperresponsiveness (AHR). The effects of cationic proteins are not limited to those proteins released from eosinophils, suggesting a redundant role and introducing the concept of total cationic protein burden. Neutralization of cationic charge abrogates the cationic protein-induced AHR and illustrates the receptor-independent nature of this unique effector mechanism. However, cationic proteins cause AHR by a complex mechanism that involves the generation of bradykinin, tachykinin peptides, altered airway permeability, and a reduction of an epithelial-derived relaxing factor. The principal site of signaling is the apical aspect of the airway epithelium due to the presence of glycosaminoglycans and other structural elements composing the anionic barrier. Cationic proteins in the context of other mechanisms lead to catastrophic results, strongly implicating a key role for cationic proteins and the eosinophil in severe forms of asthma.
Eosinophils in Human Disease
The human eosinophil contains some unique proteins shared only with primates. These are eosinophil cationic protein and eosinophil-derived neurotoxin/RNase2, two potent multifunctional secretory proteins likely to have a great impact on the biology of eosinophils in disease. This is illustrated by the close associations of genetic polymorphisms in these two genes with allergy and parasitic disease. The study of the proteome of human eosinophils has revealed intriguing differences in molecular forms of several proteins between healthy and allergic subjects. Some proteins, such as the heat shock cognate protein 70, were only detected in eosinophils of allergic individuals and other proteins, such as eosinophil peroxidase, showed dramatic molecular alterations in the allergic population. The study of the proteome of human eosinophils and of genetic polymorphisms of the major secretory molecules should, together with assaying eosinophil proteins in biological fluids, provide us with decisive knowledge on the role of eosinophils in health and disease.
Eosinophil-associated gastrointestinal disorders (EGID)
PROINFLAMMATORY ROLE OF EOSINOPHILS IN EGID
In vitro, the granule constituents of eosinophils are toxic to many tissues, including intestinal epithelium. The eosinophil cationic proteins major basic protein (MBP), eosinophil peroxidase (EPO), and eosinophil cationic protein (ECP) are cytotoxic to epithelium at concentrations similar to those found in biological fluids from patients with eosinophilia. ECP can render cell membranes porous, facilitating the entry of other toxic molecules. MBP increases smooth muscle reactivity by affecting vagal muscarinic M2 receptors and triggers mast cell and basophil degranulation. Eosinophils can generate a wide range of inflammatory cytokines, indicating that they could modulate multiple aspects of the immune response involving epithelial growth, fibrosis, and tissue remodeling. Other toxic products include hydrogen peroxide, halide acids, and the leukotrienes LTC4, LTD4 and LTE4, which increase vascular permeability and mucus secretion and stimulate smooth muscle contraction. In patients with eosinophilic gastroenteritis, MBP and ECP are deposited extracellularly in the small bowel, and ultrastructural changes in eosinophil secondary granules (indicating degranulation and mediator release) are found in duodenal biopsies. Furthermore, Charcot–Leyden crystals are commonly found in feces, and disease severity correlates with mucosal eosinophil numbers.