Looking for autoimmunity, is it flogging a dead horse

L

On saturday I talked about a Jan Klein moment and today I am wondering if we need another one.

Should we say…Schtop…you are all wasting your time!

One, reader thought the story written on my phone on the tube, was written like a “soap”. But is it Sainsbury’s own brand, Imperial leather or is it not soap but a bit of “head and shoulders” Hope you enjoy what we write today, after all we are “EastEnders”

We are led to believe MS is autoimmune, but when you ask…. what is the autoimmune target? You don’t get a coherent answer.

We have been hunting for this as long as I have been studying MS and whilst we get a new one every so often, they are never really been replicated.

For many years we had and still have myelin basic protein (MBP)…In my opinion this is not a good candidate as it is in peripheral nerves, not usually affected in MS and is used because it is easy to purify, water soluble and so easy for the T cell immunologists to use.

They have been peddling immune mechanisms for ever. Have we been sold a pup. We had a potassium, Kir4.1, channel for a while and besides a lab in Germany, essentially no one could find evidence to support that. Last year we had RASGRP2, which is not really expressed in the CNS, according to RNA expression data bases when asked why should we get MS…the answer was I don,t know. In this new study we get some new ones.

RASPGR2 expression

Do they occur in the CNS, sort of, however, they do not occur in most individuals and if fact it occurs in few individuals. Had this study we done by a big swinger we would all be lapping it up or would we.?

The T cell immunologists have struggled to convince themselves that anything other than MBP and myelin oligodendrocyte glycoprotein (MOG) are important.

Other people go hunting for antibodies. Antibodies are made from two proteins, heavy and light immunogobulin molecules. and together they create the specificity of the antibody. There are ways to make these using viruses that infect bacteria and you can get them to make human proteins.

You get brain tissue take the protein making molecules (messenger RNA) and you convert it back into DNA (the building blocks of protein), you get the bacteria viruses to make the brain protein. Then you get Brain derived B cells and you make heavy and light chains from the B cells using other virus-infecting bacteria. You then make the antibodies. They also tested bloods and spinal fluid and antibody fragments and do a search.Past studies have shown the same results, so now we are in the territory of beating non-living equines.

What did they find. Antibodies to a few proteins that we have largely never heard of.

There is no accumulation of anti-Kir 4.1 nor alpha B crystallin nor other stuff.

Last week I was at the Charcot meeting and Dr. X said B cells are the dominant cell type in MS and 5 minutes later Dr Y said B cells are a minor population and I asked who is right, Dr Z didn’t understand the question. There was no debate. Couldn’t they see or care that some one had shown a result 180 degrees opposite of their work and they did not question each other. It makes you think neither are confident about their position, don’t listen to other people and I am now dubious about believing any other of their stuff. Past history has shown that very little of the pathological mechanisms turn out to be replicated, supporting my view. However, some ideas become common knowledge or is that myth.

The claims of biopsies have largely been questioned. Indeed people have been questioning whether shadow plaques are really remyelination. I have never seen such a poor answer to this question as given by one of the demi-god pathologists. No wonder science progresses slowly, because it seems we are basing our ideas on quick sand. Anyway I disgress.

In this study they did not find an antigen that everyone or even a large number of people reacted to. This suggests there is no single autoantigen in healthy brain. Secondly they found reactivity to proteins that are largely inside cells and suggests to me that the antibody response is created secondary to damage. Once a cell dies and liberates its contents this is when antibodies form.Therefore, it is not the primary target, suggesting there is not an major autoantigen. So maybe we are chasing our tails.

We have been looking for causative antigens in MS, are we chasing our tails?

Maybe MD2 is right in that we do not need for these antibodies to be specific for one thing. It is simpler than that.

Identification of novel non-myelin biomarkers in multiple sclerosis using an improved phage-display approach. Cortini A, Bembich S, Marson L, Cocco E, Edomi P. PLoS One. 2019 Dec 5;14(12):e0226162. 

Although the aetiology of multiple sclerosis is not yet understood, it is accepted that its pathogenesis involves both autoimmune and neurodegenerative processes, in which the role of autoreactive T-cells has been elucidated. Instead, the contribution of humoral response is still unclear, even if the presence of intrathecal antibodies and B-cells follicle-like structures in meninges of patients has been demonstrated. Several myelin and non-myelin antigens have been identified, but none has been validated as humoral biomarker. In particular autoantibodies against myelin proteins have been found also in healthy individuals, whereas non-myelin antigens have been implicated in neurodegenerative phase of the disease. To provide further putative autoantigens of multiple sclerosis, we investigated the antigen specificity of immunoglobulins present both in sera and in cerebrospinal fluid of patients. A human brain cDNA library was constructed and enriched for open-read-frame fragments. This library was selected against pooled and purified immunoglobulins from cerebrospinal fluid and sera of multiple sclerosis patients. The antigen library was also screened against an antibody scFv library obtained from RNA of B cells purified from the cerebrospinal fluid of two relapsing remitting patients. From all biopanning a complex of 14 antigens were identified; in particular, one of these antigens, corresponding to DDX24 protein, was present in all selections. The ability of more frequently isolated antigens to discriminate between sera from patients with multiple sclerosis or other neurological diseases was investigated. The more promising novel candidate autoantigens were DDX24 and TCERG1. Both are implicated in RNA modification and regulation which can be altered in neurodegenerative processes. Therefore, we propose that they could be a marker of a particular disease activity state.

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16 comments

Leave a Reply to Luís fernando Cancel reply

  • Perhaps an ignorant question:

    “the antibody response is created secondary to damage. Once a cell dies and liberates its contents this is when antibodies form.”

    So there is neurodegeneration for *some reason*. The relapse activity is the (damaging) immunological response to this damage.

    Is the really important question not: What is the *some reason*? Crack that and you crack progressive MS, all MS?

    • Brilliant question Anonymous! That seems to be the answer for all forms of MS.

      Do you believe, MD, that all current neuroinflammatory therapies are aimed at a downstream reaction created by our peripheral adaptive nervous system in response to the frontline war that is taking place in our innate immunity (hot microglia, A1 astrocytes, neurons with associated myelin) triggered by some virus(es)?

      This would explain why immunosuppressant therapies are a “bandaid solution” and will never address the real MS and it will continue to progress. They will possibly limit the damage if given early enough but never completely halt or cure MS.
      .

  • “the antibody response is created secondary to damage. Once a cell dies and liberates its contents this is when antibodies form

    So basically any type of, brain injured (tbi, stroke)
    Would cause an antibodie response
    It’s what we see in that kind of scenario?

    Stroke survivors have autoantibodies?

  • Sadly, it is becoming very clear to me that a real therapy for MS, including progressive MS, is not going to come from the Barts team.

    • “Sadly, it is becoming very clear to me that a real therapy for MS, including progressive MS, is not going to come from the Barts team.”

      This was harsh, grumpy and uncalled for. I take it back. Should have had a cup of tea first.

  • Re: RASGRP2, I wonder if what’s going on is this: the Jelcic et al. 2018 paper was all about B and T cells that “auto”proliferated in a Petri dish. It was written up as if this proliferation was in response to nothing, but it was probably in response to the release of antigens by dead/dying fellow cells in the Petri dish. (They were serum-free.) RASGRP2 seems to be present in B cells, so maybe that really was the trigger in some instances. It wasn’t a large % of the cells in the dish that proliferated (on the order of 1%). So that suggests that in people with established MS, the immune repertoire is enriched somewhat for autoreactive cells that specifically go after antigens associated with cell death/damage, maybe specifically that of lymphocytes. So you could imagine a model in which round 1 of damage is caused by CNS-specific (perhaps EBV-infected) cells, then successive rounds of further damage are caused by cells specific to various antigens exposed by prior rounds of attack. This might include neoantigens formed by oxidative damage caused by iron (as in “Communication of CD8+ T cells with mononuclear phagocytes in multiple sclerosis” Sabolek et al.).

    • Maybe. I wondered if they found autoproliferation and when they went to publish it the referee said what’s the antigen…a desparate search and B cells express RASGRP2…then they had to find it in the CNS and I believe dogey staining is the name of the day. However, why look for a new antigen and do the hard stuff. They could have gone to the literature, the most abundant immunogenic antigen in the inflammed CNS in MS is HSPB5 or alpha B crystallin. B cells infected with EBV or CMV express HSPB5 and present it to T cells and everyone on has HSPB5 reactive T cells and you get autoproliferation.

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