The rational for B-cell therapy in multiple sclerosis (MS) was presented during ECTRIMS 2019, with David Baker (Blizard Institute, Queen Mary University of London, UK) posing the question of why B-cell therapy could be key for MS treatment.
For many years it has been said that MS is mediated by CD4 Th17 (T helper) cells, began Professor Baker, yet the arrival of effective therapies that target CD20 (a protein primarily found on the surface of B cells) calls into question this theory. “If MS is a T-cell mediated disease, how and why do CD20 B-cell therapies work?” he questioned.
One argument is that T regulatory cells – i.e. suppressors of other cells in the immune system – are increased following anti-CD20 therapy, while another argument pertains to antigen presentation, he stressed: “T cells undergo auto-proliferation due to the action of B-cell presenting antigens to the T cell.” However, neither of these theories seem to pan out when looking closer at the data, said Professor Baker.
Or, he went on, perhaps the benefit comes from blocking B-cell follicles. “It has been suggested that that might be a factor associated with worsened disease progression,” he noted. “I will say, though, that CD20 is not expressed by plasmablasts or plasma cells. Antibodies are about 99% excluded from the central nervous system [CNS], and if you look shortly after B-cell therapy, it does not affect the oligoclonal bands [a key marker in MS] or the CNS B cells.”
He added: “But it may well be that if you could get more antibody into the CNS, you may be able to see an effect.”
Finally, Professor Baker postulated that direct B-cell inhibition could play a role. B cells produce cytokines and neurotoxic molecules, and are the forerunners in the production of antibodies. “We know that in MS, antibodies are there, they are in lesions, and we can see that they are activated because there is evidence of the membrane attack complex,” he said.
These antibodies, many of which are auto-antibodies, are also pathogenic, as Professor Baker described: “However, many of these auto-antibodies act against intracellular targets, suggesting that they are probably secondary to tissue destruction. Nevertheless, some people do seem to respond to plasma exchange, suggesting that there is some role for antibodies.”
As Professor Baker explained, B cells transition from pre- to immature to mature B-cells, enter the circulation and the secondary lymphoid tissue where they meet antigens, expand and become memory cells, differentiate into plasmablasts and plasma cells, before typically migrating back to the bone marrow.
“Now, the important thing is, when you have depletion, you have very rapid repopulation by the immature and mature cells,” he said. “That gives the impression that B cells go back to normal, masking the fact that there is a very slow repopulation of the memory B cell population. And it is this aspect which I would suggest is important in trying to explain MS therapy.
“If you understand that, you can understand how all MS therapies work. The reason being because every single therapy that works in MS has the functional activity of blocking memory B-cell response arriving in the CNS. The drugs that do that well are most effective at blocking relapsing disease, and those that don’t have lower efficacy. It fits perfectly, while T-cell immunology does not.”
Turning to what aspects of B-cell biology might further explain the therapeutic effect of B-cell treatments, Professor Baker explored the regeneration of memory B cells in more detail. With the knowledge that establishment of a memory B-cell pool in infants takes anywhere from 18 to 48 months from birth, the process is clearly slow. As is regeneration after depletion, he said: “Following CD20 depletion, in some non-MS conditions it may take five years for that pool to repopulate.”
He added that memory B cells have been found to be the dominant B-cell population in the CSF and perivascular area during relapse. “So the pathology fits … what about the genetics? Well, that fits too,” he said. Indeed, MS susceptibility genes with presumed T-cell function are present in, or act on, B cells, noted Professor Baker.
Lastly, he focused on the Epstein-Barr virus (EBV), which most people can expect to be infected with at some point in their lives. Crucially, while EBV may offer a survival advantage due to the creation of memory B cells, and therefore helps fight infections much quicker, it also increases the risk of B-cell cancers and autoimmune diseases.
“EBV affects essentially everyone with MS,” said Professor Baker. “The EBV proteins activate many of the autoimmune risk genes, and EBV makes memory B cells – it blocks differentiation to the plasma cell component.”
He added that EBV also impacts the genetic variants associated with MS susceptibility and the control of viral load, upregulates certain adhesion molecules and other adhesion-presenting molecules, and can make B cells more efficient for antigen presentation.
Offering his closing remarks for the audience, Professor Baker commented: “We can see that B cells are instrumental in targeting the drivers of active lesions which occur in relapsing and progressive MS.”
He concluded: “We started off with the question of why B-cell therapy, and now I think the question is why not?”
For more coverage from ECTRIMS 2019, please click here.