The goals of the CSGADP program are to understand the immune mechanisms that underlie autoimmune disease and the consequences of manipulation of the immune response in autoimmunity in order to apply this information to the prevention of autoimmunity in humans. This grant application addresses these goals with respect to understanding the mechanisms that regulate the fate and function of CD4 effector T cells and Treg. Specifically we address how alterations in the IL-2/STAT5 and IL-6/STAT3 cytokine signaling pathways contribute to the loss of this balance in individuals with T1D, MS and CD. These two pathways are known to have opposing influences on the function and development of Treg, and the development of potentially pathogenic CD4 effector cells. Genetic variants link the IL-2R/STAT5 pathway to T1D, MS and IBD, and the IL- 6/STAT3 pathway to MS and CD. In this grant, we pose the hypothesis that in autoimmune individuals enhanced phosphorylation of STAT3 and diminished phosphorylation of STAT5 establish a functional program biasing cytokine responses towards a skewed, pro-autoimmune profile. We will test this hypothesis by determining the extent to which signaling via STAT5 and STAT3 is altered in three autoimmune diseases;type 1 diabetes (T1D), multiple sclerosis (MS) and Crohn's Disease (CD). We will determine whether these alterations in phosphorylation, independently and in combination, lead to an imbalance between Treg and Th17 cells and/or enhance the resistance of effector T cells (Teff) to suppression. We will then determine the molecular mechanisms that lead to these alterations, using disease-associated genetic polymorphism as a guidepost.
Aim 1. We will address the hypothesis that blunted STAT5 signaling in response to IL-2 results in a diminished induction, function and stability of Treg in T1D, CD and MS. We will examine this question in the context of blood and then extend these studies to the tissue in the setting of CD. We will then determine the biochemical and genetic mechanisms that lead to the defect in IL-2R signaling in each disease.
Aim 2. We will address the hypothesis that enhanced phosphorylation of STAT3 in response to IL-6 leads to the development and persistence of pathogenic T cells in autoimmunity, by promoting the expression of ROR?t, restraining expression of FOXP3 and enhancing the resistance of effector T cells to suppression by Treg. We will examine this question using genotyped controls to address molecular mechanism and T1D, MS and CD patients to address disease phenotypes.
Aim 3. We will test the hypothesis that enhanced phosphorylation of STAT3 and diminished phosphorylation of STAT5 in combination reverse the balance of Treg and Teff functional profiles upon antigen challenge.
The GWAS have identified genetic variants and immunologic pathways that are shared between autoimmune diseases - giving us a tool to understand mechanisms that connect autoimmune diseases and to identify therapeutic targets with broad efficacy. In this grant, we will focus on two immune implicated by the GWAS as important in autoimmunity pathways (IL-2/STAT5 and IL-6/STAT3 signaling), across three diseases T1D, MS and Crohn's disease. Understanding the pathogenic mechanisms common to autoimmune diseases will help us address a large unmet need in the treatment of autoimmune diseases and the selection of therapies for the appropriate patients with the potential of preventing disease.
|Wight, Thomas N (2016) Provisional matrix: A role for versican and hyaluronan. Matrix Biol :|
|Kuipers, Hedwich F; Rieck, Mary; Gurevich, Irina et al. (2016) Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization. Proc Natl Acad Sci U S A 113:1339-44|
|Cao, Li; Qu, Yi; Zhang, Zhaorui et al. (2016) Intact glycopeptide characterization using mass spectrometry. Expert Rev Proteomics 13:513-22|
|Dam, Elizabeth M; Habib, Tania; Chen, Janice et al. (2016) The BANK1 SLE-risk variants are associated with alterations in peripheral B cell signaling and development in humans. Clin Immunol 173:171-180|
|Kuipers, H F; Nagy, N; Ruppert, S M et al. (2016) The pharmacokinetics and dosing of oral 4-methylumbelliferone for inhibition of hyaluronan synthesis in mice. Clin Exp Immunol 185:372-81|
|Hundhausen, Christian; Roth, Alena; Whalen, Elizabeth et al. (2016) Enhanced T cell responses to IL-6 in type 1 diabetes are associated with early clinical disease and increased IL-6 receptor expression. Sci Transl Med 8:356ra119|
|Sukka-Ganesh, B; Larkin 3rd, J (2016) Therapeutic Potential for Targeting the Suppressor of Cytokine Signalling-1 Pathway for the Treatment of SLE. Scand J Immunol 84:299-309|
|Nagy, Nadine; Kaber, Gernot; Johnson, Pamela Y et al. (2015) Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis. J Clin Invest 125:3928-40|
|Kang, Inkyung; Barth, Jeremy L; Sproul, Erin P et al. (2015) Expression of V3 Versican by Rat Arterial Smooth Muscle Cells Promotes Differentiated and Anti-inflammatory Phenotypes. J Biol Chem 290:21629-41|
|Hull, Rebecca L; Bogdani, Marika; Nagy, Nadine et al. (2015) Hyaluronan: A Mediator of Islet Dysfunction and Destruction in Diabetes? J Histochem Cytochem 63:592-603|
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