Experimental autoimmune encephalomyelitis (EAE) is a CD4 T cell-dependent model for the human disease multiple (MS). Several antigen presenting cells (APCs) coordinate and regulate CD4 T cell function during immune responses. B cells likely have multiple roles in the pathogenesis of MS, with their capacity to function as APCs and drive auto-reactive CD4 T cell responses gaining more recognition. However, questions remain as to the importance of antigen presentation in the role for B cells in EAE and MS. We have designed a new tool in which individual subsets of APCs are capable of conditionally expressing MHCII in vivo. We successfully targeted a stop sequence flanked by loxP sites to the MHCII ? chain locus in mice in order to utilize the Cre/loxP system for conditional expression of MHCII. Successful conditional manipulation was achieved using B lineage-specific Cre mice, restricting expression of MHCII to B cells. B cell expression of MHCII alone was sufficient to support inflammatory demyelination of the central nervous system (CNS) mediated by encephalitogenic CD4 T cells, but only when B cells were highly efficient at recognizing target antigen. Based on these observations, we hypothesize that the process by which B cells coordinate antigen- specific CD4 T cell autoimmune destruction of myelin is dependent upon B cell localization to the CNS and efficient capture of target antigen during the propagation of EAE.
We aim to: 1) Determine the requirement for antigen-specific humoral responses during EAE mediated by B cell antigen presentation;2) Determine the requirement for B cell antigen presentation in the CNS compartment during EAE;and 3) Determine the effect of B cell depletion on dendritic cell (DC) antigen presentation in EAE and MS. While the proposal herein utilizes a novel system to explore the role of B cell antigen presentation during EAE, this powerful murine genetic system is optimally designed to investigate the cellular contributions by various APCs in different models of immunity and autoimmunity. Furthermore, studies pursuing functional alterations in DCs from MS patients receiving B cell depletion therapy will bring into context the relation between antigen specific B cell regulation of CD4 T cell function and B cell therapies used to treat patients with MS. These studies will provide mechanistic understanding of immune regulation by B cells in MS and offer potential for future design of optimal B cell and CD4 T cell therapeutics.

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In this proposal, we will explore the mechanisms by which B cell antigen presentation regulates neuro- inflammation in multiple sclerosis (MS). Using an animal model of MS, we will define the processes by which B cells modulate auto-reactive CD4 T cells. Further, we will examine immune cells from MS patients treated with B cell depletion therapy to gain further understanding of optimal treatment strategies targeting B cells in MS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Utz, Ursula
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Washington University
Schools of Medicine
Saint Louis
United States
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Lin, Chih-Chung; Bradstreet, Tara R; Schwarzkopf, Elizabeth A et al. (2016) IL-1-induced Bhlhe40 identifies pathogenic T helper cells in a model of autoimmune neuroinflammation. J Exp Med 213:251-71
Parker Harp, Chelsea R; Archambault, Angela S; Sim, Julia et al. (2015) B cell antigen presentation is sufficient to drive neuroinflammation in an animal model of multiple sclerosis. J Immunol 194:5077-84
Shin, Soomin; Walz, Katharine A; Archambault, Angela S et al. (2014) Apolipoprotein E mediation of neuro-inflammation in a murine model of multiple sclerosis. J Neuroimmunol 271:8-17