Experimental autoimmune encephalomyelitis (EAE) is an animal model that reproduces most of the clinical and pathological features of multiple sclerosis (MS). The development and the progression of EAE, like other autoimmune diseases, result from the pathogenicity of effector T cells and the negative regulation imposed by regulatory T cells (Tregs). However, the role of B cells in MS pathogenesis and the interplay of myelin-specific B, T effector, and regulatory T cells is not well understood. Therefore, we have established a trangenic mouse model (2D2xTH mice) in which both T and B cells are specific for the myelin oligodendrocyte glycoprotein (MOG). The majority of the 2D2xTH mice (about 59%) develop a very severe form of spontaneous EAE characterized by the presence of ectopic lymphoid follicle like structures in the spinal cord of affected mice. By gene expression profiling we have identified Th17 cytokines differentially upregulated in the spinal cord of sick 2D2xTH vs. 2D2 mice. 2D2 TCR transgenic Thi7 cells were specifically found to induce autoimmune tissue inflammation characterized by formation of ectopic lymphoid follicles under the meninges of the recipients. The effector cytokine IL-17 and a cell surface molecule Podoplanin (PDPN) specifically expressed on Th17 cells were involved in the induction of ectopic follicles in the affected animals, since anti-PDPN antibody treatment suppressed development of ectopic lymphoid follicles in the CNS. CLEC-2, the ligand for PDPN, is predominantly expressed on DCs and B cells. We have recently generated/obtained PDPN and CLEC-2-deficient mice to address the role of this pathway in T:B ceir collaboration and induction of ectopic lymphoid follicles in autoimmune disease. Based on our results, we propose that antigen presentation by MOG-specific B cells results in the generation of highly pathogenic T cells and limits the generation and function of MOG specific CD4+CD25+ regulatory T cells. We will: 1) Study the mechanism by which B cells induce pathogenic Thi7 cells in vivo;2) Study the mechanism by which Th17 cells induce ectopic lymphoid follicles and germinal center formation and 3) Study the role of Foxp3+ Tregs in regulating ectopic lymphoid follicles and germinal center formation in the CNS. A better characterization of the role of auto-reactive T and B cells, pathogenic cytokines and their interactions during disease progression, as described in our proposal, will provide invaluable insight into the role of autoantigen-specific B cells in the generation of autopathogenic T cells.
; In multiple sclerosis, CNS myelin is target of immune attack. Although traditionally considered to be a T cell mediated autoimmune disease, remarkable efficacy of B cell depletion therapy in MS has forced us to rethink this premise. The grant proposal addresses the issue of role of B cells in this T cell mediated autoimmune disease and hypothesizes that B cell may play a critical role in inducing highly pathogenic Th17 cells.
|Farh, Kyle Kai-How; Marson, Alexander; Zhu, Jiang et al. (2015) Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518:337-43|
|Fletcher, Anne L; Elman, Jessica S; Astarita, Jillian et al. (2014) Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in high-mortality murine sepsis. Sci Transl Med 6:249ra109|
|Stern, Joel N H; Yaari, Gur; Vander Heiden, Jason A et al. (2014) B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med 6:248ra107|
|Manzel, Arndt; Muller, Dominik N; Hafler, David A et al. (2014) Role of "Western diet" in inflammatory autoimmune diseases. Curr Allergy Asthma Rep 14:404|
|Choudhuri, Kaushik; Llodrá, Jaime; Roth, Eric W et al. (2014) Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. Nature 507:118-23|
|Zhou, Penghui; Shaffer, Donald R; Alvarez Arias, Diana A et al. (2014) In vivo discovery of immunotherapy targets in the tumour microenvironment. Nature 506:52-7|
|Sollid, Ludvig M; Pos, Wouter; Wucherpfennig, Kai W (2014) Molecular mechanisms for contribution of MHC molecules to autoimmune diseases. Curr Opin Immunol 31:24-30|
|Elpek, Kutlu G; Cremasco, Viviana; Shen, Hua et al. (2014) The tumor microenvironment shapes lineage, transcriptional, and functional diversity of infiltrating myeloid cells. Cancer Immunol Res 2:655-67|
|Woodruff, Matthew C; Heesters, Balthasar A; Herndon, Caroline N et al. (2014) Trans-nodal migration of resident dendritic cells into medullary interfollicular regions initiates immunity to influenza vaccine. J Exp Med 211:1611-21|
|Kofler, David M; Marson, Alexander; Dominguez-Villar, Margarita et al. (2014) Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells. J Clin Invest 124:2513-22|
Showing the most recent 10 out of 84 publications