Pathogenic events leading to rheumatoid arthritis (RA) are the result of a complex interaction between arthritogenic genes and yet unidentified environmental factors. T lymphocytes are postulated to be among the ultimate effector cells causing joint destruction as well as extra- articular manifestations of the disease. The investigators propose to test an abnormality in T cell homeostasis exemplified by the in vivo clonotypic expansion of CD4 T cells. They have been able to assign the expanded clonotypes to a T cell compartment which is characterized by the phenotype CD4+ CD7-CD28- and can consistently detect clonally expanded populations in this compartment in RA patients and infrequently in patients with nonrheumatoid inflammatory polyarthritis or age matched normal individuals. They propose that CD4+ CD7-CD28- T cells, by virtue of their functional profile, are disease relevant cells in RA. The first specific aim will be to determine functional characteristics of CD4+ CD7- CD28- cells and isolated expanded clonotypes. Specifically, the investigators will study cytokine profiles, the responsiveness of clones to apoptotic stimuli and the role of helper functions for rheumatoid factor producing B cells. The second specific aim will attempt to identify the antigens driving proliferation of expanded clonotypes building upon preliminary data that autologous adherent cells, but not autologous EBV blasts, support the growth of clonotypically expanded CD4 cells. The biological function of CD4+ CD7-CD28- cells in the inflammatory process in the joint will be explored directly by employing synovial tissue xenografts implanted into SCID mice in the third specific aim. The fourth specific aim will test the pathogenic role of clonally expanded CD4+ CD7-CD28- T cells by correlating the size and clonality of this cell compartment with the clinical features of the disease. RA patients stratified according to their clinical presentation and their therapeutic response will be studied for the contribution of the presumptive disease relevant T cell clonality in vivo. Mechanisms leading to the abnormal T cell homeostasis in RA patients will be addressed in Specific Aim 5. If RA patients and their unaffected siblings share the expression of multiple expanded CD4 clonotypes it will suggest the role of inherited factors in controlling clonal expansion or defective clonal downsizing in vivo. The genetic regulation of CD4 clonality will be confirmed and pedigrees of multiplex and simplex families studied to develop a model of inheritance. In combination, the above approaches will test the arthritogenicity of clonally expanded CD4+ CD7-CD28- T cells, determine whether they are under the control of a gene conferring risk to develop RA and to explore whether they provide a suitable target for immunotherapy of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR042527-06
Application #
2769603
Study Section
Special Emphasis Panel (ZRG2-EI (01))
Project Start
1993-09-30
Project End
2000-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
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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