Infections by parasites and allergic inflammatory diseases, including asthma, allergic rhinitis and food allergies afflict more than three billion people worldwide. Type 2 effector immune responses provide protection against these infections but can be pathologic, for example in response to allergens. We have discovered mice with knockout of a conserved protein phosphatase regulatory subunit called SAPS1 (Ppp6r1 gene) have an unanticipated increase in serum IgE compared to controls as well as increased numbers of eosinophils in the blood and IL-4 producing CD4 T cells in secondary lymphoid tissues. Our hypothesis is that SAPS1 and its partner phosphatase PP6 constrain CD4 T cells from inappropriate CD4 T-helper 2 (Th2) differentiation and overproduction of IL-4, and possibly also prevent B cells from inappropriate switching to IgE. This project involves the collaborative efforts of a team of experienced investigators with complementary expertise to study this interesting and innovative animal model. The project Specific Aims are: 1) Determine the cellular mechanisms that lead to high serum IgE and enhanced ?-switching of B cells in SAPS1-null mice. We will cross SAPS1f/f mice to appropriate Cre-producing mouse strains to determine if the increased IgE levels in SAPS1 deficient mice arises from changes intrinsic to T cells and/or B cells. 2) Elucidate alterations in cell signaling in T and B lymphocytes resulting from deletion of SAPS1. Because SAPS1supports PP6 phosphatase activity the hypothesis is that deletion of SAPS1 will result in an increase in phosphorylation and activation of signaling pathways leading to cytokine expression and IgE production. Initial candidates GATA3, STAT6 and NF-kB, as well as BCL6 and NFIL3, will be analyzed in cells from SAPS1-/- and control mice using immunoblotting and biochemical methods. Signaling pathways that link the SAPS1 subunit of PP6 to the production of IgE have clinical implications and potential impact on human health related to allergy, asthma and parasitic infections.
Allergic diseases, including asthma, allergic rhinitis and food allergies and infections by parasites afflict more than three billion people worldwide. Immune responses provide protection but can be pathologic and inflammatory. We have generated mice with conditional gene knockout that display an unanticipated increase in serum IgE, plus increased numbers of eosinophils and IL-4 producing CD4 T-helper 2 (Th2) cells. These mice have symptoms of a heightened allergic response. This project will study signaling pathways that give rise to this phenotype with clinical implications and potential impact on human health related to allergic diseases.
| Shah, Millie; Smolko, Christian M; Kinicki, Sarah et al. (2017) Profiling Subcellular Protein Phosphatase Responses to Coxsackievirus B3 Infection of Cardiomyocytes. Mol Cell Proteomics 16:S244-S262 |
| Ziembik, Magdalena A; Bender, Timothy P; Larner, James M et al. (2017) Functions of protein phosphatase-6 in NF-?B signaling and in lymphocytes. Biochem Soc Trans 45:693-701 |
