Tuesday, 31 July 2018

Oligoclonal bands: what are they doing?

Oligoclonal bands (OB) are a characteristic hallmark of MS.

They occur from disease onset. But what are they doing?


Despite much wishful thinking by researchers that OB are producing the pathogenic antibody (which they may well do) it has to be said that people have looked and looked, but no consistent antibody has yet been found in MS.

However, do the antibodies in the OB have to be specific for a target in MS?

MD2 suggests not, but they may play a role in progressive damage.





Read the paper free of charge (for the next 50 days)

Click on this link
https://authors.elsevier.com/c/1XTgS7skoexb7E

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Pryce G, Baker D. Oligoclonal bands in multiple sclerosis; functional significance and therapeutic implications. Does the specificity matter?. Mult Scler Rel Disord 2018.DOI

Highlights



  • Immunoglobulins in oligoclonal bands secreted by plasma cells in the CNS can contribute to worsening pathology in MS
  • Secreted immunoglobulin can interact with microglial Fc receptors in an antigen non-specific manner.
  • Microglia and astrocytes may create a survival niche for long-term plasma cell survival.
  • Plasma cells, microglia and astrocytes may interact to establish a locally neurotoxic or dystrophic environment.
  • Bruton's tyrosine kinase inhibitors may be therapeutic agents for the potential elimination of plasma cells and OCB from the CNS in MS.

Since their discovery, the existence of secreted oligoclonal immunoglobulin in the central nervous system in people with multiple sclerosis has been the subject of scientific investigation and debate over several decades. Although autoantibodies can be detected in some individuals, probably secondary to release of neo-antigens after damage, evidence for a major, primary involvement of damaging antibodies is still relatively lacking. However it is possible to construct a working hypothesis that establishes the interaction of plasma cells, which are the source of oligoclonal bands, microglia and astrocytes to create a self-perpetuating activated phenotype. This may generate an environment conducive to long-term plasma cell survival and the initiation and perpetuation of neurotoxicity that may contribute to disease worsening in multiple sclerosis. Therapeutic strategies to re-establish a homeostatic environment conducive to repair/recovery are indicated to control progressive multiple sclerosis.

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Antibodies in the CNS tend to be targeting things within the cells (intracellular targets). This suggests that the antibodies are occurring after damage and the liberation of cellular proteins rather than being the primary problem themselves.

We know that antibodies in the CNS of people with MS are pathogenic (causing disease) just as some in the blood are potentially pathogenic if they can get in the brain. 


We know this because some people respond to plasmapheresis (
the removal, treatment, & return or exchange of blood plasma) and immunoadsorption (where immunoglobulins in the blood are removed). This indicates that the problem is caused by the antibodies in the periphery.

Likewise we can take the peripheral antibodies, and the antibodies in the CNS, and inject them into animals. There, they can cause neurological problems or augment the damage driven by T cells.


However, this is not a problem for all.


Maybe one thing that OB do is to juice-up microglia (which are believed to the central problem of progressive MS) and keep them in an activated state, such that damage caused by the immune response is perpetuated into a slow-burning neurodegeneration.

Antibodies simply bind to receptors on the microglia to activate them, and their specificity may well be irrelevant.


If this is true, targeting the plasma cell response within the CNS may be the linchpin to control progression by the glial responses and metabolic problems.


Bruton's tyrosine kinase (BTK) inhibitors can block plasma cell function, but they also inhibit microglial/macrophage function.  A number of companies have these drugs. 


Other treatments may be proteosome inhibitors, which have also been used to target B cell lymphomas/myelomas (plasma cell cancers) in the brain and will be tested in MS soon.


Yes, there many other conditions with OB that are not MS, but it does indicate a way that OB can contribute to MS and other conditions.

27 comments:

  1. at 11:40 Pender says Oligoclonal Bands are multiple mono-clonal B cell expansions induced by EBV virus.."driven by EBV clonal expansion."

    https://soundcloud.com/bioanalysis-zone/nctalks-at-aan-2017-michael-pender-on-a-new-multiple-sclerosis-treatment

    From 2003:
    "During primary infection, autoreactive B cells are infected by EBV, proliferate and become latently infected memory B cells, which are resistant to the apoptosis(cell death) that occurs during normal B-cell homeostasis because they express virus-encoded anti-apoptotic molecules."

    https://www.ncbi.nlm.nih.gov/pubmed/14596882

    ReplyDelete
    Replies
    1. Thanks for this and maybe I could go along with this, but the central hypothesis is that EBV creates memory B cells to present antigens to CD4 T cells.... Problem is perhpas response to therapy as CD4 depletion didn't do much. However the therapy is T cels against EBV

      Delete
  2. Thanks for presenting this and providing the link the paper. I guess publishing 'gold open access' (where anyone can download the results at any time) is to expensive for the NHS?

    If MS is one disease, as we hear repeatedly on the blog (and with which I concur, for what its worth) and only 95% of pwMS have OCB's, does that mean the other 5% are a distinct subset of pwMS who reportedly have slightly different symptoms/responses, or, are do the 5% have another disease?

    Is is possible to change from OCB+ive to OCB-ive, and if so do we know what causes this?

    I've been told from 2 lumbar puncture results that I'm OCB-ive but seem to be progressing just as fast as others with PPMS.... Maybe I'm the odd one out of the 5%?

    Wisdoms greatly appreciated.

    A. Nonny Moose.

    ReplyDelete
    Replies
    1. We do not routinely pay to publish such reviews as we would rather use our money to do work.

      This was not funded by anyone so there is no money to support gold access (open access for everyone). However we go green open access on all our papers (papers go open access after an embargo period set by the journal, so we submit the word processed mauscript to our library upon acceptance. We have three months to do this.

      MD2 will stick his papers on Research gate so you can access pdf copy papers therir

      However, MSARDS allow you to put copies on your own social media and importantly they give us the link that gives open access, which we can send to people. Thats why we stick it on the blog

      Delete
    2. Progression and CSF Inflammation after Eradication of Oligoclonal Bands in an MS Patient Treated with Allogeneic Hematopoietic Cell Transplantation for Follicular Lymphoma

      DOI: 10.1159/000339738

      Obrigado

      Delete
    3. "A handful of cases of MS patients treated with allo-HCT for malignant hematological disease have been published [1]. In two recent reports continued disease activity was observed after transplantation [9, 10]. In our patient allo-HCT was associated with the disappearance of IgG oligoclonal bands. This has also been observed in auto-HCT-treated MS patients [2]. However, serial CSF studies showed that even though IgG oligoclonal bands disappeared, CXCL13 and MMP-9 concentrations were increased. CXCL13 is expressed in perivascular infiltrates and within the brain parenchyma in MS, and CSF concentrations of CXCL13 are increased in secondary progressive MS [5, 11]. Secondary progressive MS patients with a more severe disease course harbor lymphoid follicle-like structures in the meninges, and CXCL13 may be involved in the generation of these structures [12]. MMP-9 in CSF has also been associated with disease activity in MS [13]. In an autopsy study it was observed that although lymphocytes and plasma cells were almost absent after auto-HCT, there was ongoing microglia activation, demyelination, and axonal pathology [14]. We hypothesize that CXCL13 and MMP-9 detected in the CSF of our patient may reflect ongoing, pathogenic, immune activation associated with continuing tissue damage even after the eradication of intrathecal IgG synthesis. This is consistent with the notion that progressive MS may depend more on innate than on adaptive immune activation"

      DOI: 10.1159/000339738

      Ps: I did´nt read your paper ...But i am going to

      :)

      Obrigado

      Delete
    4. Just read your paper

      You seem to be trying very hard to find a meaning or a culprid

      for those Abs produce by plasma cells within the cns

      If the next Btk dmd pipeline dugs, accomplished that will the

      patients get better?

      Obrigado

      Delete
    5. By the way congrats for your work :)

      Obrigado

      Delete
    6. BTK inhibitors are in trial at the moment in MS. I think there will be results announced at ECTRIMS but press releases suggest efficacy in stopping relapses. The question is have they looked at OCBs and whether they disappear? If they do we are in business.

      Delete
  3. A Nonny Moose - For what it's worth, I am also OCB negative and have had a progressively worsening disease path ever since diagnosis (actually from before diagnosis). I believe Dr. G has stated that he thinks OCB negative patients may not have ms.

    In my case, if I do have ms it is a highly atypical form, as I've only ever had to lesions (one big juicy monster right at the base of my brainstem, and a smaller much less significant one in the right Periventricular region) which haven't changed in any way at all since my first MRI images were done over 15 years ago. Despite this, and the lack of OCB's, I've gone from walking with a tiny limp in 2003 to having my entire right side paralyzed and my left on its way to join the right 15 years later.

    Would be nice to know if people like you and I do indeed suffer from some other malady… We are in such a minority, though, that not much attention is paid…

    ReplyDelete
  4. it is possible to go OCB+ to OCB-, this happened in a case of HSCT that I know of.
    Does it occur otherwise I dont know.

    As to progressing as fast as others, what would you be like if you were OCB++?
    We don't know.

    Thats for the info, we can build the lack of OCB into our head, however in our model OCB would be one route to maintaining microglial activity, there could be others

    ReplyDelete
    Replies
    1. DrBenj had said that you can go from OCB- to OCB+ too. Are there any data to support the theory that pwOCB- have better course than pwOCB+? Because from real life, ProfGs theory does not seem to be valid.
      Also the disappearence of OCBs under treatment (ex. Tysabri) does not prevent the progressive phase.
      The mechanism of microglia neurotoxicity probably needs a high callibrate manipulation that goes beyond OCBs.

      Delete
    2. Good points, the case of natizumab and OCB is not reproduced

      Delete
  5. "We know this because some people respond to plasmapheresis"

    Only some of those with severe relapses. Progressive patients see no benefit. Since they have ongoing inflammation too, you can't use plasmapheresis as an argument to support the statement that MS blood is generally pathogenic.

    It could be pathogenic if taken at a time of extreme relapse, but even then there is no proof that it will lead to a new case of MS.

    https://www.aan.com/PressRoom/Home/PressRelease/893
    "The guideline recommends doctors consider using plasma exchange as a secondary treatment for severe flares in relapsing forms of MS and related diseases. The treatment was not found to be effective for secondary progressive and chronic progressive forms of MS"

    ReplyDelete
    Replies
    1. plasmapheresis deals with whats in the blood and not the brain. As BBB leakage is less of an issue in progressive MS, antibodies in the blood will have limited activity. If there is a relapse antibodies leak from blood into CNS so plasmaphersis will be ore beneficicial.

      Delete
    2. "As BBB leakage is less of an issue in progressive MS"

      I'm afraid not:
      "In summary, abnormal tight junctions in both SPMS and PPMS are most frequent in active white matter lesions but persist in inactive lesions, particularly in PPMS. Abnormal tight junctions are also common in normal-appearing grey matter in SPMS. Persistent endothelial abnormality with leak (PEAL) is therefore widespread but variably expressed in MS and may contribute to disease progression."
      https://www.ncbi.nlm.nih.gov/pubmed/17239011

      It's not BBB leakage that dictates when plasmapheresis is effective and when not, but probably the degree of acute damage inflicted within the CNS.

      Delete
  6. Results from a first-in-human study assessing the safety and early activity of PRN2246 confirmed that the oral compound can reach into the brain and spinal cord.

    “Confirmation that PRN2246 crosses the blood-brain barrier in humans and achieves therapeutic levels in the CSF [cerebral spinal fluid] is an important milestone for this program,” Martin Babler, CEO of Principia Biopharma, said in a press release. “We now look forward to evaluating the potential additional benefit of modulating B-cells directly in both the periphery and the CNS in MS patients.”

    https://www.businesswire.com/news/home/20180726005830/en/Principia-Confirms-Human-CNS-Exposure-Good-Tolerability

    ReplyDelete
    Replies
    1. Sold to Sanofi Genzyme last year. Will they develop it?

      Delete
    2. Sanofi just has to run the trials and then push it through
      their MS distribution. Principia is focused on more therapies
      so they took the money and ran back to their labs.

      "Sanofi will pay Principia a $40 million upfront payment, future milestone payments that could total $765 million and royalties on product sales. Principia has the option to co-fund Phase 3 development, in exchange for either increased royalties on worldwide product sales or a profit and loss sharing arrangement in United States."

      “Sanofi is an ideal partner for PRN2246. The agreement allows Principia to maximize the BTK opportunity in neurology with a strong partner for PRN2246 while focusing internal resources on our lead BTK inhibitor in another therapeutic area.” said Martin Babler,CEO Principia Biopharma.

      https://www.principiabio.com/pipeline/

      Delete
    3. MS tirals are high risk and expensive and many companies with not enter this space, but prefer to partner with a company with the infrastructure to do trials in MS.

      There are many many companies with BTK inhibitors, Ely Lilly dropped their interest after their compound was not good enough in Lupus

      Delete
  7. Do more oligoclonal banding correlate with worsening of MS disease? Do less correlate with improvement of the disease? Do other diseases that damage brain like CVA, Parkinson's disease or Huntington's disease show up with oligoclonal banding, ie. how sensitive and specific is OB for MS?

    ReplyDelete
  8. "We know this because some people respond to plasmapheresis (the removal, treatment, & return or exchange of blood plasma) and immunoadsorption (where immunoglobulins in the blood are removed). This indicates that the problem is caused by the antibodies in the periphery."

    Only true for pattern II MS. Looks like we need to consider an heterogeneous pathogenesis.

    ReplyDelete
    Replies
    1. In SPMS pattern 3 & 4 are noot present, is it a staging process?

      Delete

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