PROVIDED. This is a continuation application to study the structure and function of the low affinity receptor for IgE (FceRII/CD23). A soluble chimeric CD23 that is predicted to form a trimeric molecule similar to membrane CD23 has been produced and shown to interact in a dual manner with IgE. This molecule has a modified leucine zipper at the amino terminus (Iz-CD23). The capacity of Iz-CD23 to induce inflammatory mediator release and to interact with cell surface ligands will be determined. In addition, the current studies have indicated two strategies to improve the capacity of CD23 to control IgE-mediated activities: increase the stability of the stalk region and inhibit the cell surface proteolysis. Both aspects are part of the renewal application. As studies have indicated that the current chimera becomes increasingly unstable at 37?C, additional studies to further stabilize the molecule are presented and the newly produced chimeric molecules will also be examined for both inhibition of binding of IgE to the FceRI, inflammatory mediator release and influence on B cell activation, especially IgE production. These studies will be performed both in vitro and in vivo using transgenic animals. A number of studies have indicated that induction of increased cell surface CD23 results in inhibition of IgE synthesis in both mouse and human models. An antibody that blocks CD23 degradation will be produced in order to inhibit the cell surface degradation that classically occurs. The capacity of this antibody to inhibit IgE production in both IgE high and low responder mice will be compared. In addition, the mechanism via which cross-linking CD23 in an Fc dependent manner influences CD40 induced cell proliferation will be examined. Finally, the current grant period has indicated that mouse CD23b is produced in intestinal epithelial cells and the parameters regulating this expression will be explored.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI018697-27
Application #
7169888
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Minnicozzi, Michael
Project Start
1989-05-01
Project End
2008-03-14
Budget Start
2007-01-01
Budget End
2008-03-14
Support Year
27
Fiscal Year
2007
Total Cost
$347,031
Indirect Cost
Name
Virginia Commonwealth University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Martin, Rebecca K; Damle, Sheela R; Valentine, Yolander A et al. (2018) B1 Cell IgE Impedes Mast Cell-Mediated Enhancement of Parasite Expulsion through B2 IgE Blockade. Cell Rep 22:1824-1834
Damle, S R; Martin, R K; Cockburn, C L et al. (2018) ADAM10 and Notch1 on murine dendritic cells control the development of type 2 immunity and IgE production. Allergy 73:125-136
Damle, Sheela R; Martin, Rebecca K; Cross, Janet V et al. (2017) Macrophage migration inhibitory factor deficiency enhances immune response to Nippostrongylus brasiliensis. Mucosal Immunol 10:205-214
Lownik, Joseph C; Luker, Andrea J; Damle, Sheela R et al. (2017) ADAM10-Mediated ICOS Ligand Shedding on B Cells Is Necessary for Proper T Cell ICOS Regulation and T Follicular Helper Responses. J Immunol 199:2305-2315
Cooley, Lauren Folgosa; El Shikh, Mohey Eldin; Li, Wei et al. (2016) Impaired immunological synapse in sperm associated antigen 6 (SPAG6) deficient mice. Sci Rep 6:25840
Cooley, Lauren Folgosa; Martin, Rebecca K; Zellner, Hannah B et al. (2015) Increased B Cell ADAM10 in Allergic Patients and Th2 Prone Mice. PLoS One 10:e0124331
Martin, Rebecca K; Brooks, Keith B; Henningsson, Frida et al. (2014) Antigen transfer from exosomes to dendritic cells as an explanation for the immune enhancement seen by IgE immune complexes. PLoS One 9:e110609
Martin, Rebecca K; Saleem, Sheinei J; Folgosa, Lauren et al. (2014) Mast cell histamine promotes the immunoregulatory activity of myeloid-derived suppressor cells. J Leukoc Biol 96:151-9
Folgosa, Lauren; Zellner, Hannah B; El Shikh, Mohey Eldin et al. (2013) Disturbed follicular architecture in B cell A disintegrin and metalloproteinase (ADAM)10 knockouts is mediated by compensatory increases in ADAM17 and TNF-? shedding. J Immunol 191:5951-8
Gibb, David R; Saleem, Sheinei J; Chaimowitz, Natalia S et al. (2011) The emergence of ADAM10 as a regulator of lymphocyte development and autoimmunity. Mol Immunol 48:1319-27

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