This project focuses on defining the role of transmethylation in the innate and adaptive immune responses relevant to systemic autoimmunity. This is a new area of immunological research that is based on recent studies by us and others showing that inhibition of transmethylation affects normal immune and autoimmune responses. We hypothesize that transmethylation is critical for inflammation and immune responses and that blockade of this post-translational process can curtail systemic autoimmunity. In support of this, we have specifically documented in published and preliminary studies that inhibition of S-adenosyl-L-homocysteine hydrolase (SAHase), a major enzyme involved in transmethylation, leads to immunosuppression by reducing phosphorylation/activation of several key proteins involved in TCR signaling. Strikingly, this effect was noted in CD4, but not CD8 T cells, and correlated with reduced arginine methylation of Vav1. We also documented that stimulation by diverse TLR ligands and the consequent production of inflammatory cytokines was significantly reduced by inhibition of transmethylation. More importantly, treatment of an organ-specific autoimmune mouse model (EAE) and lupus mouse models (MRL-Faslpr and BXSB) with a reversible SAHase inhibitor markedly reduced the incidence, severity, and progression of disease. Here, we propose to perform mechanistic studies to further define the specificity and pathways by which protein methylation affects normal and autoimmune responses with the following three specific aims: 1) determine what PRMT (protein arginine methyltransferase) members are present in T cells, identify the specific PRMT(s) that methylates Vav1 in CD4 T cells, and determine the role of specific PRMTs in T cell, B cell, and macrophage function;2) define the molecular pathways by which transmethylation inhibition interferes with TLR-dependent and TLR-independent induction of inflammatory mediators by nucleic acids and complexes thereof, thought to be involved in lupus pathogenesis;and 3) characterize the cellular and functional changes that occur due to transmethylation inhibition during disease progression in lupus models. These studies should significantly advance our knowledge of how post-translational modifications affect normal and abnormal immune responses, and have the potential for identifying novel targets for the treatment of autoimmune diseases.

Public Health Relevance

Post-translational modifications such as transmethylation greatly expand the functional repertoire of proteins and have critical effects on immune cell function. Our preliminary studies indicate that transmethylation is required for the full activation of T cells, B cells and macrophages and, importantly, is necessary for the progression of both organ-specific and systemic autoimmune diseases. In this application, we propose to further define the mechanisms by which transmethylation promotes immune cell activation and lupus-like systemic autoimmunity. This work has the potential of identifying novel therapeutic targets for this and other autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI076396-04
Application #
8286993
Study Section
Special Emphasis Panel (ZRG1-IMM-G (02))
Program Officer
Esch, Thomas R
Project Start
2009-07-01
Project End
2013-12-30
Budget Start
2012-07-01
Budget End
2013-12-30
Support Year
4
Fiscal Year
2012
Total Cost
$465,302
Indirect Cost
$220,277
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Tardif, Virginie; Manenkova, Yulia; Berger, Michael et al. (2013) Critical role of transmethylation in TLR signaling and systemic lupus erythematosus. Clin Immunol 147:133-43
Lawson, Brian R; Eleftheriadis, Theodoros; Tardif, Virginie et al. (2012) Transmethylation in immunity and autoimmunity. Clin Immunol 143:8-21