B cells for MS, what evidence smashes the idea?

We asked you (steve S is very quiet and so is Mr T!) to see if you can find papers that mash the idea that B cells are the beasts that drive MS.

Sadly not much traffic on this one. 

So maybe we are not talking nonsense or maybe you can't be bothered:-( 

However, we have had a challenger.

As I have said we can walk through these and maybe Mr Karl Pooper will be right and we will disprove the hypothesis and we will move on
Who is Karl Popper have a listen (click here)

Although we had said that there is not a 10-20% depletion of T cells because about 10-20% of T cells express low levels of CD20

Palanichamy A, Jahn S, Nickles D, Derstine M, Abounasr A, Hauser SL, Baranzini SE, Leppert D, von B├╝dingen HC.Rituximab efficiently depletes increased CD20-expressing T cells in multiple sclerosis patients. J Immunol. 2014;193(2):580-6.
We didn't think that was enough as CD4 depleting antibodies had failed in MS and had depleted more than this

However, a referee who was quite smug and said that following rituximab 

There is actually 55% T cell depletion by rituximab (Cross et al. 2006) and this is why anti-CD20 works because it is killing T cells.

Cross AH, Stark JL, Lauber J, Ramsbottom MJ, Lyons JA. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol. 2006; 180:63-70.

Holy c**p has the bubble burst already, You can see for yourself T cells down from 600 and a bit down to 300 T cells in the CSF.

So how do we counter old smuggola?

First thing first read the paper, not someone's interpretation of the paper.

So now the abstract

Effects of B cell depletion by rituximab, a monoclonal antibody to CD20, were studied in patients with relapsing MS that had not responded optimally to standard immunomodulatory therapies. Flow cytometry demonstrated reduced cerebrospinal fluid (CSF) B cells and T cells in most patients at 6 months post-treatment. ELISAs demonstrated modest reductions in serum antibodies to myelin oligodendrocyte glycoprotein and myelin basic protein in some subjects. Beta-interferon neutralizing antibodies were reduced in three subjects, but developed anew after treatment in three others, suggesting caution in considering rituximab as a means to eliminate NABs. In summary, rituximab depleted B cells from CSF at 24 weeks after initial treatment, and this B cell depletion was associated with a reduction in CSF T cells as well.

There you see it, rituximab is dropping T cells and this is the headline 

But look. This is at 6 months after the injection of rituximab!
What can we say?
  • Depletion of T cells, by CD4-depleting antibodies, by about 70% was not enough to stop MS. So is 55% depletion enough.
  • Our Animal studies say No.
  • If you inject rituximab into the cerebrospinal fluid it does not remove B cells from the CSF, it leaks out and kills cells in the blood, so shortly after injection into the blood rituximab isn't killing B cells in the CSF, but 6 months later they are gone (see picture above)
  • If you inject rituximab in the blood it depletes B cells from the blood and importantly stops attacks in MS for at least 6 months.
  • In 6 months this is ample time for inflammation which is under control due to the rituximab to subside and what would we expect if inflammation is inhibited.
  • Yep..less B cells and less T cells in the brain and what do we find 6 months after rituximab....less T cells and less B cells in the brain.
I say keep trying! .....Four

Editorial: Lymphocytes in MS and EAE: More Than Just a CD4+ World.Rangachari M, Kerfoot SM, Arbour N, Alvarez JI.
Front Immunol. 2017 Feb;8:133.