Whether B cells, plasma cells and antibody (Ab) play a role in the pathogenesis of MS or its animal model, experimental autoimmune encephalomyelitis (EAE) is controversial. Myelin-specific T cells can transfer EAE to naive recipients, whereas neither B cells nor Abs can transfer EAE. Ab-producing cells are extremely numerous in most active MS lesions and increased amounts of Abs in the spinal fluid are a relatively diagnostic feature of MS. Our data indicate a critical role for B cells in EAE induced by active immunization with the extracellular 120 amino acids of myelin oligodendrocyte glycoprotein (rMOG), but not when disease is induced by a short encephalitogenic peptide (MOG35-55) in C57BL/6 (B6) mice. The hypothesis to be tested is that myelin-specific B cells and their products are critical in the pathogenesis of this model of CNS inflammatory demyelination via a role in antigen processing and presentation that focuses the immune response toward encephalitogenic epitopes of MOG. ? ? Our studies indicate that rMOG-primed wild-type (WT) B6 T cell lines do not induce EAE in B cell deficient (B-/-) B6 mice, nor do B-/- T cell lines initiated with rMOG-primed T cells transfer EAE to WT or B-/- recipients. These data suggest a complex role for B cells and their products during both the initiation and effector stages of disease. We will determine the mechanisms by which B cells act in rMOG-induced EAE, and whether B cells or Ab or both are involved. Our preliminary data indicate that B-/- mice have a broader response to rMOG, as they recognize an additional MOG-epitope by proliferation and cytokine production that WT mice do not recognize. This seems to indicate that B cells or Abs affect MOG processing and presentation to T cells. Guided by these preliminary data, the foremost candidate mechanism to be tested is whether there is a differential processing of MOG by B cells vs other APCs, and whether B cells or their products focus the immune response toward encephalitogenic epitopes of MOG. Experiments will utilize WT B6 mice, B-/- mice on a B6 background, and mice with normal B cells that do not elaborate Ab (""""""""B6/APC"""""""").
In Aim 1, the stage(s) of EAE in which B cells play a role will be fully determined. Whether B cells play a critical role in MOG processing and presentation to activate encephalitogenic T cells, using B cells specific for myelin or irrelevant antigens, will be examined in Aim 2a, and whether myelin-specific Abs or non-specific Abs alter MOG processing will be determined in Aim 2b. The remainder of Aim 2 will focus on effects of B cells on other APCs, especially dendritic cells, and on effects of B cells on cytokine and chemokine expression. Methods to alter in humans the number and function of B cells and Abs already exist, making our results potentially applicable to MS therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040504-02
Application #
6642027
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Utz, Ursula
Project Start
2002-08-15
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$327,038
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Lyons, Jeri A; Riter, Melissa M; Almatrook, Alaa M et al. (2016) Amelioration of EAE by a cryptic epitope of myelin oligodendrocyte glycoprotein. J Neuroimmunol 300:66-73
Lyons, Jeri-Anne; Ramsbottom, Michael J; Mikesell, Robert J et al. (2008) B cells limit epitope spreading and reduce severity of EAE induced with PLP peptide in BALB/c mice. J Autoimmun 31:149-55