Juvenile dermatomyositis (JDM) is an autoimmune inflammatory myopathy disease. CD4+ T cells and B cells are most prevalent, and evidence of autoimmunity is frequent with high-titer autoantibodies observed in the sera of 60-80% of adult patients and up to 40% of pediatric patients. Results from clinical trials with anti-CD20 clearly suggest the role of B cells in the pathogenesis and clinical manifestations of DM. While autoantibody responses have been studied in DM, the CD4+ T cell subsets which might be associated with the differentiation of autoreactive B cells are not understood. In preliminary studies, we have found that the CXCR5+CD4+ T cell subsets in dermatomyositis are skewed towards CXCR3-CCR6- Th2 and CXCR3-CCR6+ Th17 cells when compared to age-matched healthy children, and other autoimmune diseases including psoriatic arthritis and systemic lupus erythematosus (SLE). These B-helper-T cells might be the main drivers of autoreactive B cells differentiation in DM thus contributing to disease pathogenesis. Therefore, their development and function in DM need to be established. We have further shown that differentiation of B-helper-T cells is mediated by a subset of myeloid dendritic cells (DCs) (interstitial DCs). IL-12 is the critical DC-derived factor that induces naTve CD4+ T cells to become IL-21-secreting B-helper-T cells. These results form the basis for our hypothesis: Alterations in CXCR5+ B helper T cells and IL-12 producing Antigen Presenting Cells contribute to autoreactive B cell development in juvenile/adult dermatomyositis.
AIM 1 will determine the phenotype and frequency of CXCR5+ B-helper-T cells in juvenile/adult DM patients.
AIM 2 will determine the function of blood CXCR5+CD4+ T cells from DM patients.
AIM 3 will determine the cytokine secretion pattern of Antigen Presenting Cells (APCs) from patients with DM. We expect that this comprehensive analysis of the phenotype and function of B-helper-T cells, B cells and APCs in DM patients will bring insights into the DM pathogenesis as well as help us establish novel disease biomarkers. It will be particularly informative in the group of patients in Clinical Trial Concept 1 where DM patients will receive IL1 blockade.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082715-04
Application #
8377375
Study Section
Special Emphasis Panel (ZAI1-QV-I)
Project Start
2012-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$204,267
Indirect Cost
$48,477
Name
Baylor Research Institute
Department
Type
DUNS #
145745022
City
Dallas
State
TX
Country
United States
Zip Code
75204
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