Rheumatoid arthritis (RA) is a quintessential autoimmune syndrome with tissue-destructive chronic inflammatory lesions attacking the synovium and a wide spectrum of extra-articular organs. Mounting evidence emphasizes that RA patients not only generate autoreactive immune responses but have broadly diminished immune competence, manifesting as increased susceptibility to infection, lymphoma, and cardiovascular disease. Over the last decade, this project has been devoted to dissecting the contribution of T cells to RA pathogenesis. Our studies have led to the discovery that patients with RA have premature aging of the immune system. Remodeling of the T cell pool, characterized by shrinkage of T cell diversity and accumulation of end-differentiated memory T cells biased toward pro-inflammatory effector functions, revealed a defect in T cell generation that imposes proliferative stress and causes accelerated T cell aging. The current application will investigate this defect in T cell homeostasis and builds on our preliminary data, demonstrating a striking impairment in the survival of na?ve CD4 T cells from RA patients when undergoing antigen-driven clonal burst. In search of the underlying molecular defect, we have found that RA patients fail to induce sufficient telomerase during the priming response of na?ve CD4 T cells. Here, we will investigate the mechanistic links between malfunctioning of the telomere repair apparatus and mitochondrial apoptosis pathways, rendering na?ve CD4 T cells highly sensitive to apoptosis and undermining T cell replenishment.
In Specific Aim 1 we will knock-down telomerase in na?ve CD4 T cells from RA patients and controls and study the impact on T cell expansion after antigen-driven priming. We will repair the defective induction of hTERT in RA CD4 T cells with the intention of readjusting their apoptosis sensitivity.
Specific Aim 2 is centered on molecular mechanisms mediating na?ve CD4 T cell death with special emphasis on BCL-2 family members that function as survival proteins, pro-apoptotic executioners, or regulators. Guided by preliminary data, we will focus on the death sentinel NOXA which transmits extracellular signals controlling recovery during the CD4 priming response. Experiments have been designed to test whether the survival defect in RA T cells relates to NOXA induction and, in particular, is dependent on the p53 pathway.
In Specific Aim 3, we will explore how competition for glucose affects CD4 T cell survival during priming. Specifically, we will examine how insufficient induction of the regulatory enzyme 6-phospofructo-2-kinase/fructose-2,6- biphosphatase in RA CD4 T cells reduces glycolytic flux and renders T cells apoptosis sensitive.
Specific Aim 4 will connect the molecular studies on T cell homeostasis with the clinically important question as to what extent defective induction of telomerase and impaired survival of CD4 T cells compromise immunocompetence in RA patients and weaken their anti-microbial immune protection.
This specific aim will make use of yearly influenza vaccinations to delineate CD4 T cell expansion and contraction in vivo in a cohort of RA patients. PUBLIC HEALTH REVELANCE. Despite the development of powerful immunosuppressive agents, we have not succeeded yet in curing patients with RA. Indeed, patients treated with effective anti-cytokine biologics are now found to have increased risk for infections and tumors. Evidence has accumulated that the immune system of RA patients has a principal defect and that the chronic inflammation destroying joints and other organs systems may signify diminished and not enhanced immune function. Specifically, patients with RA have premature aging of the immune system, easily diagnosed by the shortening of telomeres in T cells. Here, we will examine how RA patients regenerate T cells in their immune system and why their T cells fail to survive when they are driven by antigen. The studies will include vaccinating RA patients with an influenza vaccine to test whether they can build sufficient T cells to be protected from infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR042527-18
Application #
8080918
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mao, Su-Yau
Project Start
1993-09-30
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
18
Fiscal Year
2011
Total Cost
$334,541
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Weyand, Cornelia M; Goronzy, Jörg J (2018) A Mitochondrial Checkpoint in Autoimmune Disease. Cell Metab 28:185-186
Ye, Zhongde; Li, Guangjin; Kim, Chulwoo et al. (2018) Regulation of miR-181a expression in T cell aging. Nat Commun 9:3060
Zhang, Hui; Watanabe, Ryu; Berry, Gerald J et al. (2018) Inhibition of JAK-STAT Signaling Suppresses Pathogenic Immune Responses in Medium and Large Vessel Vasculitis. Circulation 137:1934-1948
Uribe, Jorge A; Aggarwal, Ishita; Witthayaweerasak, Juthamat et al. (2018) Refractory Giant Cell Arteritis Complicated by Vision Loss From Optic Atrophy and Maculopathy Associated With Pachymeningitis. J Neuroophthalmol 38:17-23
Gustafson, Claire E; Cavanagh, Mary M; Jin, Jun et al. (2018) Functional pathways regulated by microRNA networks in CD8 T-cell aging. Aging Cell :e12879
Li, Yinyin; Goronzy, Jörg J; Weyand, Cornelia M (2018) DNA damage, metabolism and aging in pro-inflammatory T cells: Rheumatoid arthritis as a model system. Exp Gerontol 105:118-127
Goronzy, Jörg J; Hu, Bin; Kim, Chulwoo et al. (2018) Epigenetics of T cell aging. J Leukoc Biol 104:691-699
Kim, Chulwoo; Hu, Bin; Jadhav, Rohit R et al. (2018) Activation of miR-21-Regulated Pathways in Immune Aging Selects against Signatures Characteristic of Memory T Cells. Cell Rep 25:2148-2162.e5
Watanabe, Ryu; Maeda, Toshihisa; Zhang, Hui et al. (2018) MMP (Matrix Metalloprotease)-9-Producing Monocytes Enable T Cells to Invade the Vessel Wall and Cause Vasculitis. Circ Res 123:700-715
Weyand, Cornelia M; Shen, Yi; Goronzy, Jorg J (2018) Redox-sensitive signaling in inflammatory T cells and in autoimmune disease. Free Radic Biol Med 125:36-43

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