Experimental autoimmune encephalomyelitis (EAE) is an animal model that reproduces many of the clinicaland pathological features of multiple sclerosis (MS). While it is well documented that myelin specific T cells,Th1 and Th17 cells are important for the initiation of the disease, the role of B cells and antibodies in thedisease process is not well understood. The development and the progression of EAE, like otherautoimmune diseases, results from the pathogenicity of effector T cells and the negative regulation imposedby regulatory T cells (Tregs). However, the lack of a reliable marker for regulatory T cells has made it difficultto study the interplay between myelin specific effector T cells and regulatory T cells. To study the effect ofantigen specific B cells in the generation of pathogenic T cells, we have established a mouse model(2D2xTH mice) in which both T and B cells are specific for the same myelin protein, myelin oligodendrocyteglycoprotein (MOG). The majority of 2D2xTH mice (about 59%) develop a very severe form of spontaneousEAE within 6 weeks of age that is similar to a sub-form of MS called Devic disease, characterized by thepresence of inflammatory foci restricted to the spinal cord and optic nerve. By gene expression profiling, wehave identified IL-22 as a cytokine differentially upregulated in the spinal cord of mice with Devic disease.We have also generated a Foxp3-EGFP knock-in mouse in order to track CD4+CD25+ Treg cells during thecourse of an ongoing immune response. With the help of l-Ab/MOG35-55 tetramer (developed incollaboration with Kai Wucherpfennig) we are able to track development and effector functions of MOGspecific pathogenic and regulatory T cells. Based on our results, we propose that antigen presentation byMOG-specific B cells generates highly pathogenic T cells and limits the generation and function of MOGspecific CD4+CD25+ regulatory T cells which results in the development of a very severe EAE. We will testwhether: 1) MOG specific B cells participate in disease progression by the secretion of MOG specificpathogenic antibodies and /or by preferential antigen presentation to MOG-specific T cells; 2) T cellsgenerated in the presence of cognate antigen specific B cells are more encephalitogenic and produce moreIL-17 and IL-22; 3) MOG specific B cells limit the expansion and/or function of regulatory T cells responsiblefor keeping pathogenic T cells under check. The role of IL-22 in generating highly pathogenic T cells anddevelopment of Devic-like disease in mice will be evaluated by using IL-22 deficient mice. The proposedstudies will allow us to better characterize the mechanism by which autoantigen specific B cells induceautopathogenic T cells and how they regulate the expansion and function of antigen specific regulatory Tcells. Furthermore, our proposed studies will allow us to study how antigen specific B cells might control thedevelopment of an organ specific T cell mediated autoimmune disease.
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