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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAI1-ALW-I (M2))
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Esch, Thomas R
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Benaroya Research Institute at Virginia Mason
United States
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Nagy, Nadine; de la Zerda, Adi; Kaber, Gernot et al. (2018) Hyaluronan content governs tissue stiffness in pancreatic islet inflammation. J Biol Chem 293:567-578
Lord, James D; Long, S Alice; Shows, Donna M et al. (2018) Circulating integrin alpha4/beta7+ lymphocytes targeted by vedolizumab have a pro-inflammatory phenotype. Clin Immunol 193:24-32
Wight, Thomas N (2018) A role for proteoglycans in vascular disease. Matrix Biol 71-72:396-420
St Clair, Joshua R; Ramirez, David; Passman, Samantha et al. (2018) Contrast-enhanced ultrasound measurement of pancreatic blood flow dynamics predicts type 1 diabetes progression in preclinical models. Nat Commun 9:1742
Gaucherand, Léa; Falk, Ben A; Evanko, Stephen P et al. (2017) Crosstalk Between T Lymphocytes and Lung Fibroblasts: Generation of a Hyaluronan-Enriched Extracellular Matrix Adhesive for Monocytes. J Cell Biochem 118:2118-2130
Johnson, Howard M; Larkin 3rd, Joseph (2017) Editorial: The Dynamic Role of Suppressor of Cytokine Signaling Proteins in the Regulation of Immune and Autoimmune Responses. Front Immunol 8:825
Gan, Ryan W; Demoruelle, M Kristen; Deane, Kevin D et al. (2017) Omega-3 fatty acids are associated with a lower prevalence of autoantibodies in shared epitope-positive subjects at risk for rheumatoid arthritis. Ann Rheum Dis 76:147-152
Ma, Hongyan; Delafield, Daniel G; Wang, Zhe et al. (2017) Finding Biomass Degrading Enzymes Through an Activity-Correlated Quantitative Proteomics Platform (ACPP). J Am Soc Mass Spectrom 28:655-663
Demoruelle, M Kristen; Harrall, Kylie K; Ho, Linh et al. (2017) Anti-Citrullinated Protein Antibodies Are Associated With Neutrophil Extracellular Traps in the Sputum in Relatives of Rheumatoid Arthritis Patients. Arthritis Rheumatol 69:1165-1175
Gan, Ryan W; Bemis, Elizabeth A; Demoruelle, M Kristen et al. (2017) The association between omega-3 fatty acid biomarkers and inflammatory arthritis in an anti-citrullinated protein antibody positive population. Rheumatology (Oxford) 56:2229-2236

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