Systemic juvenile idiopathic arthritis (SJIA) is a disease of unknown etiology characterized by a combination of systemic features and arthritis that can result in severe disability. Our previous kpcr-validated microarray results show monocyte activation as a characteristic of SJIA. We hypothesize that dysregulation of monocyte activation represents a key aspect of the pathobiology of SJIA. We propose to investigate how SJIA monocytes are altered, and how this activated state may interfere with regulatory T cell function. Some related defects in T lymphocyte populations also will be investigated. Based on our preliminary data, our specific aims are:
Aim 1 : To investigate the interferon 3, GMCSF, IL-6 and IL-1 signaling pathways in circulating immune cells in SJIA subjects, determine the mechanistic basis of altered signaling and investigate the specificity of these findings for SJIA cells.
Aim 2 : To determine whether the dysregulated state of immune cells is associated with monocyte resistance and lymphocyte susceptibility to apoptosis and whether these defects are SJIA-specific.
Aim 3 : To test whether the SJIA monocytes down-regulate the inhibitory function of Treg and whether this property is SJIA-specific. By comparison with Kawasaki disease (KD) and polyarticular JIA (PolyJIA), we will differentiate between factors unique to SJIA and factors associated with systemic inflammation (common to SJIA and KD) and arthritis (common to SJIA and PolyJIA). Understanding regulation of monocyte activation in these diseases may shed light on other inflammatory conditions and autoimmune responses. Narrative: Systemic juvenile idiopathic arthritis (SJIA) is a childhood disease whose cause is presently unknown. In our previous studies examining cells from the blood of children with SJIA, we found that their monocytes are activated, especially during periods of disease activity, and resist normal pathways of cell death, whereas their T cells are highly susceptible to cell death. These observations led us to propose that in SJIA, immune cell activation is not properly controlled, We propose to investigate which specific cellular paths are activated in SJIA monocytes, and if and how monocyte activation may interfere with the function of T cell populations that regulate cell activation. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI075254-01A1
Application #
7393039
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Peyman, John A
Project Start
2008-01-01
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
1
Fiscal Year
2008
Total Cost
$197,500
Indirect Cost
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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