We have identified three gene expression signatures in peripheral blood mononuclear cells (PBMC) from children with recent-onset polyarticular and oligoarticular juvenile idiopathic arthritis (JIA) that identify subsets of patients with apparent differences in pathobiology and clinical outcomes. These signatures include: 1) a "Monocyte Signature" that is predominantly expressed by older (a6 years) patients with polyarthritis, and is associated with greater disease severity and more frequent treatment with anti-TNF biologies;2) a "T Cell Signature" that is also predominantly expressed by older polyarthritis patients, contains genes that implicate T cell exposure to TGFp and other pro-apoptotic influences, is associated with chronically active arthritis, and is associated with increased expression of several putative genetic markers of JIA susceptibility {IGF1R, JMJD1C and PTPN2);and 3) a "B Cell Signature" that is expressed by younger (<6 years) patients with either oligoarthritis or polyarthritis, and implicates similar pathology between these two JIA subtypes. Our over-arching hypothesis is that these PBMC signatures detect cells that have entered the circulation after being influenced by arthritic inflammatory milieus, and therefore reflect pathological activity at sites of arthritis. Specifically, we hypothesize that 1) the Monocyte Signature detects circulating monocytes that have participated in and/or responded to joint tissue damage;2) the T Cell Signature detects circulating T cells that have been exposed to endogenous mechanisms in arthritic joints that are aimed at suppressing joint inflammation, such as regulatory T cell activity;and 3) the B Cell Signature detects circulating B cells with abnormal activity in the context of the developing B cell repertoires in children under age 6. We will test these hypotheses in our Specific Aims: 1) Identify differences in isolated PBMC subsets that correspond to differential expression of total PBMC gene expression signatures, 2) assess relationships of PBMC gene expression signatures to synovial fluid pathology, and 3) identify gene expression biomarker surrogates of PBMC signatures in whole blood. In the long-term, we believe that improved understanding of pathobiology associated with these PBMC signatures will lead to novel molecular tools for assessing and predicting arthritis activity that will advance clinical management of oligoarticular and polyarticular JIA.

Public Health Relevance

We have identified differences in expression of sets of genes in blood cells among sub-groups of children with juvenile arthritis. These differences appear to reflect specific disease processes that are only active in subsets of patients. We further hypothesize that these sets of genes can be used as biomarkers to assess arthritis activity in the present, and predict outcomes, such as response to particular medications, in the future, which ultimately will help improve the outcomes of children with juvenile arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR048929-09
Application #
8727963
Study Section
Special Emphasis Panel (ZAR1-HL)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
9
Fiscal Year
2014
Total Cost
$152,302
Indirect Cost
$70,532
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Prahalad, Sampath; McCracken, Courtney E; Ponder, Lori A et al. (2016) Familial autoimmunity in the Childhood Arthritis and Rheumatology Research Alliance registry. Pediatr Rheumatol Online J 14:14
Clement, Cristina C; Moncrieffe, Halima; Lele, Aditi et al. (2016) Autoimmune response to transthyretin in juvenile idiopathic arthritis. JCI Insight 1:
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Schulert, Grant S; Bove, Kevin; McMasters, Richard et al. (2015) 11-Month-Old Infant With Periodic Fevers, Recurrent Liver Dysfunction, and Perforin Gene Polymorphism. Arthritis Care Res (Hoboken) 67:1173-9
Cutler, David J; Zwick, Michael E; Okou, David T et al. (2015) Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping. PLoS One 10:e0128074
Schulert, Grant S; Grom, Alexei A (2015) Pathogenesis of macrophage activation syndrome and potential for cytokine- directed therapies. Annu Rev Med 66:145-59
Schulert, Grant S; Grom, Alexei A (2014) Macrophage activation syndrome and cytokine-directed therapies. Best Pract Res Clin Rheumatol 28:277-92
Moncrieffe, Halima; Prahalad, Sampath; Thompson, Susan D (2014) Genetics of juvenile idiopathic arthritis: new tools bring new approaches. Curr Opin Rheumatol 26:579-84

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