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.

Public Health Relevance

; 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI045757-16
Application #
8705344
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Urso, Katia; Alvarez, David; Cremasco, Viviana et al. (2016) IL4RA on lymphatic endothelial cells promotes T cell egress during sclerodermatous graft versus host disease. JCI Insight 1:
Adams, Jarrett J; Narayanan, Samanthi; Birnbaum, Michael E et al. (2016) Structural interplay between germline interactions and adaptive recognition determines the bandwidth of TCR-peptide-MHC cross-reactivity. Nat Immunol 17:87-94
Longbrake, Erin E; Hafler, David A (2016) Linking Genotype to Clinical Phenotype in Multiple Sclerosis: In Search of the Holy Grail. JAMA Neurol 73:777-8
Singer, Meromit; Wang, Chao; Cong, Le et al. (2016) A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells. Cell 166:1500-1511.e9
Fernandez-Carbonell, Cristina; Vargas-Lowy, David; Musallam, Alexander et al. (2016) Clinical and MRI phenotype of children with MOG antibodies. Mult Scler 22:174-84
Cao, Yonghao; Nylander, Alyssa; Ramanan, Sriram et al. (2016) CNS demyelination and enhanced myelin-reactive responses after ipilimumab treatment. Neurology 86:1553-6
Axisa, Pierre-Paul; Hafler, David A (2016) Multiple sclerosis: genetics, biomarkers, treatments. Curr Opin Neurol 29:345-53
Lowther, Daniel E; Goods, Brittany A; Lucca, Liliana E et al. (2016) PD-1 marks dysfunctional regulatory T cells in malignant gliomas. JCI Insight 1:
Chastre, Anne; Hafler, David A; O'Connor, Kevin C (2016) Evaluation of KIR4.1 as an Immune Target in Multiple Sclerosis. N Engl J Med 374:1495-6
Astarita, Jillian L; Cremasco, Viviana; Fu, Jianxin et al. (2015) The CLEC-2-podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture. Nat Immunol 16:75-84

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