Abstract

Granzymes, found in the cytoplasmic granules of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, are known to be critical for inducing target cell apoptosis during granule exocytosis-induced cytotoxicity. The observation that granzyme B can specifically cleave known sutoantigens has broad implications for its possible role in mediating the bypass of tolerance to autoantigens, and the subsequent development of autoinmune disease. It is hypothesized that granzymes- specifically granzyme B - are required for the initiation and propagation of autoimmune disease. This proposal outlines four Specific Aims designed to address the precise role of these proteases in the development of the autoimmune disease systemic lupus erythematosus (SLE). Immunological and biochemical methods, as well as animal models will be utilized to.test the hypothesis. Observations made in the SLE model system have the potential to be translated.to other autoimmune conditions for which changes induced during apoptosis are believed to contribute to the pathogenesis of disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31AI010663-01
Application #
6313276
Study Section
Special Emphasis Panel (ZRG1-MDCN-7 (02))
Program Officer
Hernandez, Milton J
Project Start
2001-09-30
Project End
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
1
Fiscal Year
2001
Total Cost
$41,355
Indirect Cost

  Institution

Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305

  Publications

Burchill, M A; Golden-Mason, L; Wind-Rotolo, M et al. (2015) Memory re-differentiation and reduced lymphocyte activation in chronic HCV-infected patients receiving direct-acting antivirals. J Viral Hepat 22:983-91
Golden-Mason, Lucy; Waasdorp Hurtado, Christine E; Cheng, Linling et al. (2015) Hepatitis C viral infection is associated with activated cytolytic natural killer cells expressing high levels of T cell immunoglobulin- and mucin-domain-containing molecule-3. Clin Immunol 158:114-25
Mitchell, Angela M; Stone, Amy E L; Cheng, Linling et al. (2015) Transmitted/founder hepatitis C viruses induce cell-type- and genotype-specific differences in innate signaling within the liver. MBio 6:e02510
Giugliano, Silvia; Kriss, Michael; Golden-Mason, Lucy et al. (2015) Hepatitis C virus infection induces autocrine interferon signaling by human liver endothelial cells and release of exosomes, which inhibits viral replication. Gastroenterology 148:392-402.e13
Stone, Amy E L; Mitchell, Angela; Brownell, Jessica et al. (2014) Hepatitis C virus core protein inhibits interferon production by a human plasmacytoid dendritic cell line and dysregulates interferon regulatory factor-7 and signal transducer and activator of transcription (STAT) 1 protein expression. PLoS One 9:e95627
Golden-Mason, Lucy; Rosen, Hugo R (2013) Natural killer cells: multifaceted players with key roles in hepatitis C immunity. Immunol Rev 255:68-81
McMahan, Rachel H; Wang, Xiaoxin X; Cheng, Lin Ling et al. (2013) Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem 288:11761-70
Stone, Amy E L; Giugliano, Silvia; Schnell, Gretja et al. (2013) Hepatitis C virus pathogen associated molecular pattern (PAMP) triggers production of lambda-interferons by human plasmacytoid dendritic cells. PLoS Pathog 9:e1003316
Golden-Mason, Lucy; McMahan, Rachel H; Strong, Michael et al. (2013) Galectin-9 functionally impairs natural killer cells in humans and mice. J Virol 87:4835-45
Yanagisawa, K; Yue, S; van der Vliet, H J et al. (2013) Ex vivo analysis of resident hepatic pro-inflammatory CD1d-reactive T cells and hepatocyte surface CD1d expression in hepatitis C. J Viral Hepat 20:556-65

Showing the most recent 10 out of 19 publications