Wednesday, 14 November 2012

Grand Challenges in MS (7): how do anti-B cell therapies work?

It is 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).

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).

"In my opinion 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.

"In my opinion 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. 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.

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." 

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

"This is an observation that I made years ago!" 

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 plasma blasts; 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?"



Other posts of interest:

Pathology:

07 Mar 2012
Barnett and Prineas. Ann Neurol. 2004 Apr;55(4):458-68. "I am reposting this for those of you have not had time to read all the posts on this blog." "This study really challenges our understanding of MS; it challenges the dogma ...
22 Dec 2011
Ectopic lymphoid follicles (place where antibody producing B cells are generated) are hallmarks of chronic autoimmune inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis, Sj√∂gren's syndrome, and ...
06 Jun 2011
The B cell that make the antibodies are found in structures called "ectopic lymphoid follicle-like structures" in the coverings of the brain and spinal cord; the covering are called the meninges. These ectopic follicles are not ...
05 Oct 2011
The immune system forms and maintains the ectopic B-cell follicles in the brain & spinal cord by producing a cocktail of immune messengers called cytokines. One of these messengers is called lymphotoxin; if you inhibit or ...


OCBs:

03 Nov 2012
Background: Recently, the disappearance of oligoclonal bands (OCBs) from the cerebrospinal fluid (CSF) of a few natalizumab-treated MSers has been reported. This is interesting since CSF-restricted OCB are believed to ...
13 Sep 2012
BACKGROUND: The use of oligoclonal bands (OCBs) and cerebrospinal fluid (CSF) parameters are established in the diagnosis of MS, but poorly as markers of disease. OBJECTIVE: To investigate the role of OCBs in ...
19 Nov 2011
Background: Intrathecal antibody production manifest as oligoclonal bands (OCBs) is a hallmark of multiple sclerosis (MS). Once present, OCBs can be detected in the cerebrospinal fluid that bathes the CNS throughout the ...
23 Jan 2012
Correct me if i am wrong, but this means that the OCBs in MS do not necessarily imply a reaction to some pathogen, but could very well be the aftermath of some kind of brain or spinal injury. ReplyDelete. Anonymous Monday ...

Ocrelizumab:
06 Nov 2011
Current Ocrelizumab Trials that are recruiting subjects. Study 1: A Study of Ocrelizumab in Patients With Primary Progressive Multiple Sclerosis (NCT01194570). Eligibility: Ages Eligible for Study: 18 Years to 55 Years ...
04 Jun 2011
Please note that Ocrelizumab is the follow-on compound of Rituximab; both these drugs are monoclonal antibodies that target a protein CD20 that is expressed on B cells. Exactly how these drugs work is not known. However ...
06 Nov 2011
At week 24, patients in the initial placebo, 600 mg ocrelizumab, and interferon beta-1a groups received ocrelizumab 600 mg; the 2000 mg group received 1000 mg. Our primary endpoint was the total number of ...
16 Oct 2010
Worryingly there was one death in the high dose Ocrelizumab group at 14 weeks, from "systemic inflammatory response syndrome". These very impressive results need to be tempered against the death that we must assume ...

Rituximab:

11 Nov 2012
Rituximab, a monoclonal antibody that depletes B cells by targeting the CD20 molecule, has been shown to effectively reduce disease activity in MSers with relapsing MS as a single agent. Our investigator-initiated phase II ...
04 May 2012
B cells (cells that produce antibodies) have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects. Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to ...
29 Jun 2011
The investigators should be complemented for trying Rituximab in SPMS. In the past this is how therapies evolved; you started with an idea or scientific rationale and you then test the drug in an individual with the disease.
08 Jun 2011
Rituximab is a monoclonal antibody that targets a surface protein on B cells called CD20. There is good phase 2 data on its effectiveness when given intravenously (i.e. via a peripheral vein) in RRMS and a subgroup of PPMS ...

CoI: multiple

21 comments:

  1. Prof G can you please tell us about anti-CD19 treatment? Is there any way of getting on to it?

    ReplyDelete
    Replies
    1. Posted: http://multiple-sclerosis-research.blogspot.co.uk/2012/11/anti-cd19-and-multiple-sclerosis.html

      Delete
  2. Are you participating in the MS Society's project to identify unanswered questions in MS in association with the James Lind Alliance? Maybe some of your Grand Challenges would be good questions to ask on that forum. Details are on MSS website - though hopefully you know about it already.

    ReplyDelete
    Replies
    1. Thanks for the advice. This is the first I have heard about this initiative. I will look into it. This is unrelated to our Grand Challenges; I thought I would start this section of the blog after reading about the grand research challenges initiative the NIH in the US launched for science in general. I did it to break up the endless research posts and generate a bit of debate. What I am really hoping for is for a fairy godmother or angel to fund one of these challenges.

      Delete
  3. - If the MS diagnosis was made years ago without doing an LP, is there any point in asking for one now? The MS has been aggressive and nobody doubts the diagnosis

    - With a drug that targets plasma cells too, will there be a high chance of serious infections?

    - I remember reading there is disagreement about ectopic B-cell follicles in MSers. Can you write more about that?

    ReplyDelete
    Replies
    1. There is indeed disagreement about B cell follicles. Many who have looked for them can't find them and I can't believe that they would not have been noticed before if they were a common feature.

      Delete
    2. yes a drug that takes out the whole B cell lineage may cause problems with immune suppression. The good thing about this is that it is easy to correct; all you need to do is give immunoglobulin therapy, a large number of people have this problem.

      Delete
  4. Can any kind of brain damage trauma, infarcts, infections - to the least degree metabolic anomalies cause the same spectrum of oligoclonal banding, i.e. immune reactions, as multiple sclerosis.? and are they seen as the same in the EAE model?
    Regards as always.

    ReplyDelete
    Replies
    1. No not in typical stroke. However, if the stroke is due to an vasculitis (inflammation in the blood vessel walls) or infection (varicella-zoster virus) then you can get OCBs. OCBs are non-specific an occur in a large number of inflammatory disorders of the brain and spinal cord. The conditions associated with OCBs are usually easy to diagnose and differentiate from MS. You also find OCBs in a small number of normal people; these people have presumably had a mild episode of encephalitis or they could be at risk of MS.

      Delete
    2. You say that most things that cause OCBs are easy to differentiate from MS. What sort of things are not so easy to differentiate? Sjogren's? Neurosarcoidosis?

      Delete
    3. Sjogren's and sarcoid are typically not associated with OCBs. I have written an article on this before. Paraneoplastic disorders and infections are the conditions associated with OCBs.

      Delete
    4. Why I'm taking an interest in 'O' bands is my wife's Neurologist waited for the results of the lumbar puncture before dx and seemed to deem her to have mild MS based on these, so I'm reading up on the significance.Sine reading I've come across an old paper and would like your thoughts ."Cellular immune response to myelin protein: Absence in MS and presence in cerebrovascular accidents,Youngchaiud U et al. 1974

      Delete
  5. Any idea (a timeline?) when some of these Grand Challenges will be resolved i.e. answered. It seems simple to keep generating questions, but much more difficult to answer them!

    I'm guessing the Charcot Project may answer the EBV question - or will it just generate more questions / more research?

    Any idea when will get more results from the B cell depleting trials? Why isn't Alemtuzumab called a B cell depleting therapy? (I thought it targetted B cells?).

    I'm really looking forward to the day when answers to these big questions will be posted on this blog. It's all taking far too long for those already with the disease.

    Hopefully 2013 will see some real progress, but I'm sure I hoped for this in 2012.

    I'm in two minds about attending the Research Event. Will I hear anything new? Anything to give me hope for the near future?

    Best of luck.

    ReplyDelete
    Replies
    1. 2012 is meant to be the year that alemtuzumab got a license for MS. It is the only drug one the near horizon that offers a potential for a cure. The others are cladribine and bone marrow transplantation. The latter is too dangerous to be a mainstream treatment.

      Delete
  6. Will I hear anything new? Anything to give me hope for the near future?

    Yes

    ReplyDelete
  7. Which? Something new (genuinely new and not been announced/covered elsewhere?) or just "yes" to anything to give hope for the future?

    ReplyDelete
  8. "It is clear that B cells play a central role in pathogenesis of MS:"

    from:
    B cells and autoantibodies: complex roles in CNS injury.
    http://www.ncbi.nlm.nih.gov/pubmed/20691635

    "Emerging data indicate that traumatic injury to the brain or spinal cord activates B lymphocytes, culminating in the production of antibodies specific for antigens found within and outside the central nervous system (CNS)."

    A lesion is an injury of some kind. B-cell presence is, once again, the result, not the cause. The antibodies produced do not point to the damaging agent, they are just the "system scan" initiated by the injury.

    ReplyDelete
    Replies
    1. So in MS what would be the "traumatic injury" triggering a B cell response? I think I already know what your answer is going to be but who knows you may surprise me.

      Delete
    2. That's for researchers like you to find out. The study shows that a different explanation for the antibody presence is possible. Since you (researchers) had no luck yet in pinpointing the target or the trigger of the immune response, why don't you try studying the problem from a different perspective. You claim to have an open mind.

      Delete
    3. We (researchers) have found plenty of targets

      May have an open mind but but don't have bottom less pockets, ideas may grow on trees but unfortunately investigating them doesn't

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.