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.
|Banchereau, Romain; Hong, Seunghee; Cantarel, Brandi et al. (2016) Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients. Cell 165:551-65|
|Caielli, Simone; Athale, Shruti; Domic, Bojana et al. (2016) Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J Exp Med 213:697-713|
|Blanco, Patrick; Ueno, Hideki; Schmitt, Nathalie (2016) T follicular helper (Tfh) cells in lupus: Activation and involvement in SLE pathogenesis. Eur J Immunol 46:281-90|
|Schmitt, Nathalie; Liu, Yang; Bentebibel, Salah-Eddine et al. (2016) Molecular Mechanisms Regulating T Helper 1 versus T Follicular Helper Cell Differentiation in Humans. Cell Rep 16:1082-95|
|Ueno, Hideki; Banchereau, Jacques; Vinuesa, Carola G (2015) Pathophysiology of T follicular helper cells in humans and mice. Nat Immunol 16:142-52|
|Schmitt, Nathalie; Ueno, Hideki (2015) Regulation of human helper T cell subset differentiation by cytokines. Curr Opin Immunol 34:130-6|
|Turner, Jacob A; Bolen, Christopher R; Blankenship, Derek M (2015) Quantitative gene set analysis generalized for repeated measures, confounder adjustment, and continuous covariates. BMC Bioinformatics 16:272|
|Jacquemin, ClÃ©ment; Schmitt, Nathalie; Contin-Bordes, CÃ©cile et al. (2015) OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T Follicular Helper Response. Immunity 42:1159-70|
|Bentebibel, Salah-Eddine; Jacquemin, Clement; Schmitt, Nathalie et al. (2015) Analysis of human blood memory T follicular helper subsets. Methods Mol Biol 1291:187-97|
|Schmitt, Nathalie (2015) Role of T Follicular Helper cells in Multiple Sclerosis. J Nat Sci 1:e139|
Showing the most recent 10 out of 35 publications