Evidence for eosinophil involvement in various human diseases is increasing. The eosinophil is not a bystander cell, but rather an active participant in allergic and other inflammatory diseases. However, the mechanism of inflammatory mediator release from eosinophils at the inflammation sites, and the significance of eosinophil-derived mediators for disease pathophysiology are not clear. During the current funding period, our observations suggest that eosinophil degranulation involves antigen-specific IgG antibodies, but not IgE antibodies. Further, the attachment of the cells to their targets through adhesion molecules and the strong amplification of signals by endogenous platelet-activating factor (PAF) produced within the cells are complex phenomena. This application uses which knowledge and seeks to dissect critically the mechanisms and significance of eosinophil degranulation in human diseases. First, we will analyze the """"""""molecular mechanisms of eosinophil degranulation"""""""" in vitro. Specifically, we will address how PAR, in controls to other chemotactic factors, strongly stimulates release of inflammatory mediators from eosinophils. We hypothesize that eosinophils have intracellular as well as extracellular PAF receptors and that the degranulation response to PAR uses distinct receptor/signaling mechanisms from those used in chemotaxis. Second, we will examine the roles of antigen-specific IgG antibodies as """"""""triggers of eosinophil degranulation"""""""" at the inflammation sites.
This aim combines in vitro experiments to examine the roles of the complement system in eosinophil activation with analyzes of airway and skin disease specimens to investigate the presence of eosinophil-activating IgG antibodies. Subsequently, the roles of IgG antibodies in the pathophysiology of eosinophilic inflammation will be examine directly in IL-5 transgenic mice. Third, the observations in the first and second aims will be culminated in vivo studies examining the """"""""significance of eosinophil degranulation"""""""" in diseases using a mouse model of asthma. We will examine the following question. Is eosinophil major basic protein involved in the development of airway hyperreactivity? Does the induction of inhibition of eosinophil degranulation in the airway modulate airway physiology in these animals? The results of these experiments will provide a better understanding of the mechanisms of eosinophil degranulation in vitro and in vivo and clarify the roles of eosinophils and their granule proteins in the pathophysiology of human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI034486-09
Application #
6631936
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Plaut, Marshall
Project Start
1994-05-01
Project End
2005-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
9
Fiscal Year
2003
Total Cost
$285,317
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Anderson, E L; Kobayashi, T; Iijima, K et al. (2016) IL-33 mediates reactive eosinophilopoiesis in response to airborne allergen exposure. Allergy 71:977-88
Kobayashi, Takehito; Soma, Tomoyuki; Noguchi, Toru et al. (2015) ATP drives eosinophil effector responses through P2 purinergic receptors. Allergol Int 64 Suppl:S30-6
Drake, Li Yin; Iijima, Koji; Hara, Kenichiro et al. (2015) B cells play key roles in th2-type airway immune responses in mice exposed to natural airborne allergens. PLoS One 10:e0121660
Bartemes, Kathleen R; Kephart, Gail M; Fox, Stephanie J et al. (2014) Enhanced innate type 2 immune response in peripheral blood from patients with asthma. J Allergy Clin Immunol 134:671-678.e4
Iijima, Koji; Kobayashi, Takao; Hara, Kenichiro et al. (2014) IL-33 and thymic stromal lymphopoietin mediate immune pathology in response to chronic airborne allergen exposure. J Immunol 193:1549-59
Fujisawa, Daisuke; Kashiwakura, Jun-Ichi; Kita, Hirohito et al. (2014) Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria. J Allergy Clin Immunol 134:622-633.e9
Drake, L Y; Iijima, K; Kita, H (2014) Group 2 innate lymphoid cells and CD4+ T cells cooperate to mediate type 2 immune response in mice. Allergy 69:1300-7
Kita, Hirohito (2013) Eosinophils: multifunctional and distinctive properties. Int Arch Allergy Immunol 161 Suppl 2:3-9
Bartemes, Kathleen R; Iijima, Koji; Kobayashi, Takao et al. (2012) IL-33-responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J Immunol 188:1503-13
Matsuwaki, Yoshinori; Wada, Kota; White, Thomas et al. (2012) Alternaria fungus induces the production of GM-CSF, interleukin-6 and interleukin-8 and calcium signaling in human airway epithelium through protease-activated receptor 2. Int Arch Allergy Immunol 158 Suppl 1:19-29

Showing the most recent 10 out of 25 publications