#ResearchSpeak: grand challenges in MS (7.1) - working out how anti-B cell therapies work

How do B cell depleting agents work? Will they prevent SPMS? #ResearchSpeak #MSBlog #MSResearch

"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. 

MSers who don't have these oligoclonal bands have a more benign course; this applies to MSers with relapse-onset MS and PPMS.

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.

3. B-cell follicles, were the B-cells mature and become antibody factories or plasma cells, are found in CNS of MSers. These are ectopic follicles as they are normally found in lymph nodes and the spleen. These follicles appear to be more common in progressive MSers and may result in cortical or gray matter pathology that drives progressive disease. These follicles also contain plasma cells that don't express CD20 the antigen targeted by ocrelizumab. 

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. 

4. Pathological studies show immunoglobulin deposits in the brains of MSers and complement activation. Complement is one of the molecules that certain classes of immunoglobulins use to damage or kill target cells and organisms. Interestingly in the, now famous, Barnett and Prineus lesion immunoglubluin deposition was seen without the classic T cell infiltrates. Many of us now consider this to be the earliest relapse-causing lesion and based on the observations in these lesions immunoglobulins seem to be is very important inflammatory mediators.

5. B cells are the cells were EBV, the virus that is causally linked to MS, resides.

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.  

6. Most if not all highly effective MS DMTs target B cells.

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.  

7. Targeted anti-B cell therapies (anti-CD20 - rituximab, ocrelizumab, ofatumumab) are among the most promising emerging MS therapies. There superior efficacy was not expected given the current dogma that MS is T-cell driven disease.

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? 


CoI: multiple

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