“It is now clear that B cells play a central role in pathogenesis of MS:
1. MS has not be seen in people who don’t make immunoglobulins due to rare genetic disorders (agammaglobulinaemia).
This observation is based on a literature review and my own personal experience. If anyone reading this post has seen a case of MS occurring in a patient with agammaglobulinaemia please let me know.
2. Oligoclonal IgG bands are invariably found in the cerebrospinal fluid (CSF) and brain/spinal tissues of MSers. These immunoglobulin bands have been highly selected; in other words whatever is driving their production is getting help from other cells (antigen presenting cells and T cells). This selection process is typically seen with infections or foreign antigens (proteins).
I have always hypothesised that if we can uncover what these bands are reacting with we will uncover, or pin down, the cause of MS.
OCB-negative MSers don’t have ‘classic MS’ and should be given a separate diagnosis or the diagnosis of definitive MS should be delayed; this is particularly important when diagnosing PPMS! This is another reason why lumbar punctures and spinal fluid analysis should be done in all MSers. Please note to get into the ocrelizumab PPMS trial (Oratorio Trial) you had to have OCBs. The latter may be the reason why the trial was positive.”
You only get one chance not to make the diagnosis of MS and that is in the beginning or the diagnostic phase of the disease. Spinal fluid analysis helps you exclude other conditions and tells you if you have OCBs or not.
The lack of targeting of plasma cells may prove to be the achilles heel of the anti-CD20 therapies. Killing plasma cells may be very important to prevent the SPMS. We will need to wait and see what happens with the long term follow-up of the ocrelizumab trial cohorts.
Could the B cell be the Trojan horse that takes EBV into the brain and spinal cord? Unfortunately, the evidence on this topic is rather mixed at present, but I suspect the B-cell is the cell that EBV hitches a ride in. This may be the mechanism of how ocrelizumab works.
This is an observation that I made years ago! The one exception to that rule is daclizumab (anti-CD25). This is why we need to study the immunological effects of daclizumab in great detail in MS. We need to know exactly how it is working and what its effects are on B cell function. I have hypothesised in the past that the expansion of CD56-bright NK cells, that occurs with daclizumab, may be working via an antiviral mechanism.
It is a pity that anti-CD20 therapies do not target plasma cells or plasmablasts; these are the immunoglobulin factory cells and are also part of immunoglobulin pathway. May be the newer anti-CD19 agents that target plasma blasts will be more effective than anti-CD20?
The Grand Challenge: Are B cells the pivotal cell in the pathogenesis of MS? How do anti-B cell therapies work in MS? Do anti-B cell therapies work as anti-EBV agents? How do we reconcile the immunological effects of daclizumab with the B cell hypothesis?