The eosinophil paradox: Eosinophil migration in immunologic and infectious disease
Eosinophils comprise 3-8% of circulating leukocytes and populate tissues that interact with the environment. Eosinophilia is unique to a characteristic set of diseases including atopy and helminth infection. In both diseases, there is an increase in circulating and tissue eosinophils, which undergo a targeted migration. The work presented in this thesis examines the mechanisms by which eosinophils migrate to specific targets occurs in two different diseases.
Airway hyperreactivity is associated with prejunctional M2 receptor dysfunction mediated by major basic protein (MBP) released by eosinophils clustered at airway nerves. We hypothesized eotaxin, well associated with allergic disease, is produced by parasympathetic neurons, and that signaling via CCR3 mediates eosinophil migration to airway nerves. Guinea pigs sensitized and challenged with OVA were treated with an antagonist to CCR3, GW701897B. While OVA-challenged animals demonstrated increased bronchospasm with vagal stimulation, those treated with the CCR3 antagonist did not. M2R function was lost in antigen-challenged animals, but not in those that received the CCR3 antagonist. Histologic examination revealed decreased antigen-induced clustering of eosinophils along the nerves after CCR3 antagonist treatment.
Eosinophils immune function against Strongyloides stercoralis and Onchocerca volvulus is dependent on eosinophil-nematode interaction. We determined if an extract of S. stercoralis triggered eosinophil chemotaxis, and compared the intracellular mechanisms to those mechanisms triggered by host chemoattractants. Eosinophils demonstrated both chemotaxis and chemokinesis to soluble parasite extract in transwell plates. Pretreatment with inhibitors of chemokine induced intracellular second messengers including a G-protein coupled receptors, PI3K, tyrosine kinase, p38, and p44/42 inhibited migration of the eosinophils to the parasite extract. CCR3, CXCR4 or CXCR2 antagonists inhibited eosinophil chemotaxis to the parasite extract. Biochemical characterization of the parasite extract revealed that molecules attracting eosinophils were present in several fractions, with molecules greater than 30 kDa being the most potent, comprised of both chitin and protein.
These data demonstrate eosinophil targets in two dissimilar diseases release molecules that stimulate receptors on the eosinophil resulting in directed migration. In airway hyperreactivity, migration is due to the stimulation of a single receptor. Parasitic infection stimulates multiple receptors on the eosinophil.