't Hart BA, Jagessar SA, Haanstra K, Verschoor E, Laman JD, Kap YS. The Primate EAE Model Points at EBV-Infected B Cells as a Preferential Therapy Target in Multiple Sclerosis. Front Immunol. 2013 Jun 13;4:145
The remarkable clinical efficacy of anti-CD20 monoclonal antibodies (mAb) in relapsing-remitting multiple sclerosis points at the critical involvement of B cells in the disease. However, the exact pathogenic contribution of B cells is poorly understood. In this publication we review new data on the role of CD20+ B cells in a unique experimental autoimmune encephalomyelitis (EAE) model in common marmosets (Callithrix jacchus), a small-bodied neotropical primate. We will also discuss the relevance of these data for MS. Different from rodent EAE models, but similar to MS, disease progression in marmosets can develop independent of autoantibodies. Progressive disease is mediated by MHC class Ib (Caja-E) restricted cytotoxic T cells, which are activated by γ-herpesvirus-infected B cells and cause widespread demyelination of cortical gray matter. B-cell directed monoclonal antibody therapies (anti-CD20 versus anti-BLyS and anti-APRIL) have a variable effect on EAE progression, which we found associated with variable depletion of the Epstein Barr virus (EBV)-like γ-herpesvirus CalHV3 from lymphoid organs. These findings support an important pathogenic role of CD20+ B cell in MS, especially of the subset infected with EBV.
MS is a uniquely human disease, but we have been modeling it in animals for years. Anti-CD20 antibodies made people stop and think. We have reported that anti-CD20 and all effective agents deplete memory B cells. This could be depleting the viral reservoir of MS as EBV infects CD21 expressing B cells and this virus drives then down the memory cell lineage.
EBV is largely unique to humans but there are some non-human primates that have a similar herpes virus, one such animal is the marmoset, which I first encountered when it was being used in Burkitt's Lymphoma-related research. Indeed marmosets have their own EBV-like virus.
What does it do in the marmosets? Is it pathogenic or is co-evolved.
Do marmosets get spontaneous MS?
I don't think they do, but stand to be corrected, but they do get EAE.
For many, many years the TH1/Th17 CD4 brigade had ruled the roost, shaping ideas on MS pathology and treatment. However, looking at MS and the response to therapy did not support this view. Both rodent relapsing EAE and the Marmoset treated late questioned the importance of IL12/IL23, but the T cell brigade ploughed on did the trial in MS which failed. In our hands CD20 in rodents doesn't do too much, in marmosets it is much more effective and dropped the Marmoset-EBV virus. Blocking APRIL (B cell growth factor) increased the virus but also blocked EAE, however in MS blocking APRIL, made MS worse. Was this because it made more virus or memory cells?
To date it suggested that EBV-infected B cells present antigen to T cells and CD8 drive progressive disease. Will this drive a trial of CD8 depletion? Will this work or will it make MS worse, as Prof Pender has shown anti-viral CD8 T cells are being used to treat MS.