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 follicular dendritic cells, 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 its overexpression at the cell surface to downmodulate IgE production. This project will investigate the mechanism(s) of these effects.
Aim#1 examines the mouse system where the destabilizing mAb 19G5 gives enhanced IgE synthesis in vivo. Importantly, 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 mice that overexpress ADAM10 or make a dominant negative ADAM10. In addition, we will examine the mechanism for the 19G5-dependent enhancement of 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 to evaluate the mechanism(s) of the suppression of eosinophilia as well as the capacity of CD23 to modulate the asthma phenotype. In addition, Lyn deficient mice will be used to evaluate the capacity of CD23 to modulate the extreme 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 diminish IgE production, and, by analogy, allergic diseases such as asthma in which IgE plays a dominant role.
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|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|
|Liang, Jie; Nagahashi, Masayuki; Kim, Eugene Y et al. (2013) Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell 23:107-20|
|Nagahashi, Masayuki; Kim, Eugene Y; Yamada, Akimitsu et al. (2013) Spns2, a transporter of phosphorylated sphingoid bases, regulates their blood and lymph levels, and the lymphatic network. FASEB J 27:1001-11|
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