Current studies have indicated that antibodies directed against the stalk region of CD23 cause enhancement of IgE synthesis in both the human in vitro and mouse in vivo systems. CD23 transgenic mice, which overexpress CD23 on all lymphocytes and FDCs, exhibit drastically reduced IgE production in both helminth and alum/ag models. The data suggest a model where the role of CD23 is initially to serve as a component of innate immunity to signal for IgE production by becoming destabilized and cleaved and later by overexpressing at the cell surface and modulating IgE production. This continuation application proposes to investigate the mechanism of these effects.
Aim#1 examines the mouse system where the destabilizing mab 19G5 gives enhanced IgE synthesis in vivo. In the current funding, the metalloprotease, ADAM10 has been identified as the primary CD23 sheddase in mouse and humans. The role of ADAM10 in allergic disease will be modeled by making transgenic mouse that overexpress ADAM10 or dominant negative ADAM10. In addition, we will examine the mechanism for the 19G5-induced IgE production by investigating the association of CD23 with another negative signaling molecule, LAX, which has recently been shown to both modulate CD23 expression and regulate IgE levels.
Aim#2 will investigate the affect of CD23 overexpression and CD23 destabilization on the mouse asthma model with respect to both modulation and exacerbation of disease. We will utilize both IgE and the new ADAM10 transgenics in order to evaluate the mechanism of the suppression of eosinophilia as well as the capacity of CD23 to modulate the asthma phenotype.
Aim#3 will investigate the human in vitro IgE synthesis models with respect to the mechanisms involved in IgE synthesis enhancement, seen with anti-stalk antibodies and synthesis suppression, seen with certain anti-lectin mabs. The importance of ADAM10 in human CD23 cleavage and IgE production will also be explored as will the involvement of LAX. Finally, we will determine if IgE production by B cells obtained from normal and allergic subjects is affected differently by destabilization or stabilization of CD23. In summary, these studies examine the mechanism of action of a natural regulator of IgE production, CD23, with the objective of developing protocols to enhance CD23 expression and thereby regulate IgE, and by analogy, allergic disease in which IgE plays a dominant role.Project Narrative: This project examines mechanisms involved in control of IgE synthesis by a natural regulator. The latter is CD23, a low affinity receptor for IgE. Accumulated evidence indicates that cleavage of CD23 by the metalloprotease ADAM10 increases IgE production in both mouse and humans. This application proposes to study mechanisms involved in this regulation in order to develop new protocols to control allergic disease.
|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|
|Chaimowitz, Natalia S; Martin, Rebecca K; Cichy, Joanna et al. (2011) A disintegrin and metalloproteinase 10 regulates antibody production and maintenance of lymphoid architecture. J Immunol 187:5114-22|
|Creasy, Blaine M; McCoy, Kathleen L (2011) Cytokines regulate cysteine cathepsins during TLR responses. Cell Immunol 267:56-66|
|Schlosburg, Joel E; O'Neal, Scott T; Conrad, Daniel H et al. (2011) CB1 receptors mediate rimonabant-induced pruritic responses in mice: investigation of locus of action. Psychopharmacology (Berl) 216:323-31|
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