B cells may have multiple roles in pathogenesis of CNS autoimmune disease. While data indicate that myelin-specific antibodies (Ab) promote demyelination in experimental autoimmune encephalomyelitis (EAE) and MS, the role of B cells in antigen (Ag) presentation in CNS autoimmune disease is not clear. When compared to other APC populations, B cells are efficient APC in presentation of protein Ag when they express the B cell receptor (BCR) specific for the Ag recognized by responding T cells. We hypothesize that B cells, in particular, myelin-specific B cells have an important role as APC in activation of myelin-specific T cells. We propose (1) to evaluate the contribution of myelin-specific B cells as APC in EAE and distinguish this function from the role of myelin-specific Ab in EAE. We are creating two transgenic (Tg) models, one containing B cells that express membrane MOG-specific BCR only, and one containing B cells that express membrane MOG-specific BCR and can secrete MOG-specific IgM. We will compare EAE susceptibility in these mice to B cell-deficient and MOG-specific BCR knock-in mice that can secrete all Ig isotypes. We propose (2) to examine the roles of B cell MHC II expression and myelin BCR specificity in presentation of myelin Ag in EAE. We hypothesize that B cells, in particular myelin-specific B cells, have a key role as APC in MHC II-restricted Ag presentation and activation of myelin-specific T cells in EAE and MS. (a) We will test the role of MHC II-restricted B cell Ag presentation to T cells by creating mixed bm chimera mice in which the B cell compartment is selectively deficient in MHC II expression, and compare activation of MOG-specific T cells and EAE susceptibility to bm chimera mice containing B cells that express MHC II molecules. (b) To clarify the role of BCR specificity in MHC II-restricted Ag presentation in EAE, we will examine mixed bm chimera mice in which B cells express either the MOG-specific BCR or nitrophenyl (NP)-specific BCR and do, or do not, express MHC II molecules. Recent clinical results suggest that anti-CD20 B cell depletion may be effective in MS treatment. Our preliminary data suggest that B cell depletion is beneficial in rMOG-induced EAE, but exacerbates MOG p35- 55-induced EAE. We hypothesize that the clinical benefit in rMOG-induced EAE results from reduced B cell Ag presentation or decreased secretion of myelin-specific Ab. We also hypothesize that exacerbation of MOG p35-55-induced EAE, a model that is less dependent upon B cells and Ab, represents loss of regulatory B cell function. In order to evaluate these possibilities, we will (3) examine how anti-CD20 B cell depletion influences MOG-specific T cell responses in the periphery and in the CNS in acute and chronic EAE, and examine whether MOG-specific Ab responses correlate with clinical improvement in anti-CD20 B cell-depleted mice. These studies should provide mechanistic insight regarding B cell depletion in CNS autoimmunity and address questions regarding B cell depletion that are not easily approached in MS clinical trials.

Public Health Relevance

B lymphocytes may have multiple roles in the pathogenesis of multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Our studies in experimental autoimmune encephalomyelitis (EAE), the murine MS model, will evaluate and distinguish potentially pathogenic roles of B cells in CNS autoimmunity. Our research program will also evaluate how anti-CD20 B cell depletion, a therapeutic approach being investigated in MS clinical trials, may influence immune regulation. Page 5

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI073737-04
Application #
8205036
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Esch, Thomas R
Project Start
2009-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$377,676
Indirect Cost
$128,731
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Varrin-Doyer, Michel; Zamvil, Scott S; Schulze-Topphoff, Ulf (2014) Laquinimod, an up-and-coming immunomodulatory agent for treatment of multiple sclerosis. Exp Neurol 262 Pt A:66-71
Schulze-Topphoff, Ulf; Casazza, Simona; Varrin-Doyer, Michel et al. (2013) Tob1 plays a critical role in the activation of encephalitogenic T cells in CNS autoimmunity. J Exp Med 210:1301-9
Schulze-Topphoff, Ulf; Shetty, Aparna; Varrin-Doyer, Michel et al. (2012) Laquinimod, a quinoline-3-carboxamide, induces type II myeloid cells that modulate central nervous system autoimmunity. PLoS One 7:e33797
Kim, Susan S; Richman, David P; Zamvil, Scott S et al. (2011) Accelerated central nervous system autoimmunity in BAFF-receptor-deficient mice. J Neurol Sci 306:9-15
Lalive, Patrice H; Neuhaus, Oliver; Benkhoucha, Mahdia et al. (2011) Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action. CNS Drugs 25:401-14
Li, Lihua; Zhang, Hua; Varrin-Doyer, Michel et al. (2011) Proinflammatory role of aquaporin-4 in autoimmune neuroinflammation. FASEB J 25:1556-66
Cravens, Petra D; Hussain, Rehana Z; Zacharias, Tresa E et al. (2011) Lymph node-derived donor encephalitogenic CD4+ T cells in C57BL/6 mice adoptive transfer experimental autoimmune encephalomyelitis highly express GM-CSF and T-bet. J Neuroinflammation 8:73
Nelson, Patricia A; Khodadoust, Mojgan; Prodhomme, Thomas et al. (2010) Immunodominant T cell determinants of aquaporin-4, the autoantigen associated with neuromyelitis optica. PLoS One 5:e15050
Steinman, Lawrence; Zamvil, Scott S (2010) Delivery of myelin peptides through the first line of defense, skin, to counter autoimmunity in multiple sclerosis. Ann Neurol 68:567-9
Newell, M K; Tobin, R P; Cabrera, J H et al. (2010) TLR-mediated B cell activation results in ectopic CLIP expression that promotes B cell-dependent inflammation. J Leukoc Biol 88:779-89

Showing the most recent 10 out of 13 publications