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Title: ADAM10 and Notch1 on murine dendritic cells control the development of type 2 immunity and IgE production

item DAMIE, SHEELA - Virginia Commonwealth University
item MARTIN, REBECCA - Virginia Commonwealth University
item COCKBURN, CHELSEA - Virginia Commonwealth University
item LOWNIK, JOSEPH - Virginia Commonwealth University
item CARLYON, JASON - Virginia Commonwealth University
item Smith, Allen
item CONRAD, DANIEL - Virginia Commonwealth University

Submitted to: Allergy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/21/2017
Publication Date: 8/31/2017
Citation: Damie, S.R., Martin, R.K., Cockburn, C.L., Lownik, J.C., Carlyon, J.A., Smith, A.D., Conrad, D.H. 2017. ADAM10 and Notch1 on murine dendritic cells control the development of type 2 immunity and IgE production. Allergy. 148(4):542-551.

Interpretive Summary: DCs are specialized immune cells, which initiate immune responses. Mice in which dendritic cells (DCs)lack ADAM10(ADAM10DC-/-), a protein that digests other proteins, were found to have a dramatic decrease in the type of immune response associated with allergies called TH2 immunity, using two models of lung inflammation. The first model uses an extract of house dust mites (HDM) to cause lung inflammation. The second model uses a protein called ovalbumin to induce active systemic anaphylaxis(ASA), a severe allergic reaction. With HDM, the ADAM10DC-/- mice had a reduced immune response compared to mice that had the ADAM10 protein in their dendritic cells. With the ASA model, ADAM10DC-/- mice did not have an allergic reaction to the ovalbumin. The loss of the allergic reaction in ADAM10DC-/- mice was found to be dependent on another protein called Notch 1. When Notch 1 levels were increased in ADAM10DC-/- mice, the severe allergic reaction called anaphylaxis once again occurred in ADAM10DC-/- mice. Two other types of immune responses called TH1 and TH17 were not changed in ADAM10DC-/- mice, although the immune response C. rodentium, a bacteria that infects the intestinal tract of mice, was decreased. Overall these results point to a mechanism requiring the Notch protein in dendritic cells for TH2 (allergic) responses and point to new approaches for modulating TH2 immune responses.

Technical Abstract: Mice in which dendritic cells (DCs)lack ADAM10 (ADAM10DC-/-) were found to have a dramatic decrease in TH2 immunity and IgE production, as measured by both lung inflammation to house dust mite (HDM) and active systemic anaphylaxis models (ASA). With HDM, the ADAM10DC-/- had significantly less airway resistance, less IgE, fewer eosinophils, and reduced TH2 lung cytokine expression than wildtype (WT). With ASA, ADAM10DC-/- mice were completely resistant and had barely detectable antigen-specific IgE. Notch receptor involvement was demonstrated by the restoration of anaphylaxis in ADAM10DC-/- that overexpress Notch1 intracellular domain. Using DC-specific Notch knockouts, Notch1 was more important than Notch2. Acquired immunity with both TH1 and TH17 was normal in ADAM10DC-/- mice although innate responses to C. rodentium were decreased. Overall these results point to a mechanism requiring Notch signaling in DCs for TH2 responses and point to a novel strategy for modulating TH2 immune responses and IgE production.