Type I interferon (IFN) production by plasmacytoid dendritic cells (pDC) and increased expression of IFN-? inducible genes are argued to be central to the pathogenesis of systemic lupus erythematosus (SLE). The type I IFN gene signature is associated with more severe disease in SLE and several other systemic and organ- specific autoimmune diseases. This suggests that there are significant disease subgroups in which less severe disease may be due to type I IFN independent mechanisms. The scarcity of experimental data on the mechanisms of type I IFN independent autoimmunity is a significant barrier to our understanding of the totality of the autoimmune disease process and its treatment. Our studies of the systemic autoimmunity resulting from exposure to mercury reveal the mild disease in this model to be independent of type I IFN. Mercury exposure in humans also results in a mild expression of systemic autoimmunity. Less fulminant systemic disease has also been observed with other xenobiotics and drugs. Thus mercury-induced autoimmunity may offer a suitable animal model to study type I IFN independent autoimmunity, the mechanisms of which may be applicable to multiple environmental agents. Based on our preliminary studies we hypothesize that in type I IFN independent autoimmunity innate immune responses are mediated by endosomal TLRs via NF-?B activation leading to proinflammatory cytokine production and NF-?B dependent synergy with IFN-? resulting in enhanced expression of IFN-? induced genes. We propose to address this hypothesis in four specific aims:- Aim 1) Are dendritic cells (DCs) essential for type I IFN independent autoimmunity?, Aim 2) Do endosomal Toll-like Receptor (TLR) signaling pathways mediate type I IFN-independent autoimmunity?, Aim 3) Is proinflammatory cytokine expression in type I IFN independent autoimmunity regulated by NF-?B?, and Aim 4) Is proinflammatory IL-1? required for IFN-? dependence of type I IFN independent autoimmunity? Answers to these questions will provide insight into the multiplicity of pathogenic pathways leading to systemic autoimmunity and broaden the conceptual foundation upon which autoimmune disease research is based.

Public Health Relevance

Studies suggest that severe systemic autoimmunity is due to increased expression of type I IFN inducible genes, however the contribution that type I IFN independent mechanisms play in disease expression is poorly understood. In this application we propose to determine the mechanism of type I IFN independent systemic autoimmunity and thereby broaden the conceptual foundation upon which autoimmune disease research is based.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES022625-02
Application #
8788352
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (90))
Program Officer
Humble, Michael C
Project Start
2014-01-01
Project End
2018-10-31
Budget Start
2014-11-01
Budget End
2015-10-31
Support Year
2
Fiscal Year
2015
Total Cost
$383,737
Indirect Cost
$181,237
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Pollard, K Michael; Escalante, Gabriela M; Huang, Hua et al. (2017) Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN. J Immunol 199:3739-3747
Cauvi, David M; Cauvi, Gabrielle; Toomey, Christopher B et al. (2017) From the Cover: Interplay Between IFN-? and IL-6 Impacts the Inflammatory Response and Expression of Interferon-Regulated Genes in Environmental-Induced Autoimmunity. Toxicol Sci 158:227-239
Maine, Christian J; Marquardt, Kristi; Scatizzi, John C et al. (2015) The effect of the autoimmunity-associated gene, PTPN22, on a BXSB-derived model of lupus. Clin Immunol 156:65-73
Pollard, Kenneth Michael (2015) Environment, autoantibodies, and autoimmunity. Front Immunol 6:60
Pollard, K Michael; Kono, Dwight H (2014) Requirements for ""Fire and ICE"" differ between animal models of autoimmunity: comment on the article by Kahlenberg et al. Arthritis Rheumatol 66:2310-1
Toomey, Christopher B; Cauvi, David M; Hamel, John C et al. (2014) Cathepsin B regulates the appearance and severity of mercury-induced inflammation and autoimmunity. Toxicol Sci 142:339-49