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.
|Weng, Leiyun; Mitoma, Hiroki; Trichot, Coline et al. (2014) The E3 ubiquitin ligase tripartite motif 33 is essential for cytosolic RNA-induced NLRP3 inflammasome activation. J Immunol 193:3676-82|
|Rodriguez-Pla, Alicia; Patel, Pinakeen; Maecker, Holden T et al. (2014) IFN priming is necessary but not sufficient to turn on a migratory dendritic cell program in lupus monocytes. J Immunol 192:5586-98|
|Lu, Hongbo; Lu, Ning; Weng, Leiyun et al. (2014) DHX15 senses double-stranded RNA in myeloid dendritic cells. J Immunol 193:1364-72|
|Chiche, Laurent; Jourde-Chiche, Noémie; Whalen, Elizabeth et al. (2014) Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures. Arthritis Rheumatol 66:1583-95|
|Schmitt, Nathalie; Bentebibel, Salah-Eddine; Ueno, Hideki (2014) Phenotype and functions of memory Tfh cells in human blood. Trends Immunol 35:436-42|
|Schmitt, Nathalie; Liu, Yang; Bentebibel, Salah-Eddine et al. (2014) The cytokine TGF-? co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells. Nat Immunol 15:856-65|
|Banchereau, Romain; Cepika, Alma-Martina; Pascual, Virginia (2013) Systems approaches to human autoimmune diseases. Curr Opin Immunol 25:598-605|
|Bentebibel, Salah-Eddine; Lopez, Santiago; Obermoser, Gerlinde et al. (2013) Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination. Sci Transl Med 5:176ra32|
|Schmitt, Nathalie; Bustamante, Jacinta; Bourdery, Laure et al. (2013) IL-12 receptor ?1 deficiency alters in vivo T follicular helper cell response in humans. Blood 121:3375-85|
|Schmitt, Nathalie; Ueno, Hideki (2013) Human T follicular helper cells: development and subsets. Adv Exp Med Biol 785:87-94|
Showing the most recent 10 out of 18 publications