The Plasma cell story – how MS begins and ends

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Heinrich Wilhelm Gottfried von Waldeyer-Hartz - Wikipedia

In 1875, a famous German scientist; Wilhelm Gottfried Waldeyer Hertz, described an immune cell with a large cytoplasm (the space within the cell aside from the nucleus), he was the first to name it the “plasma cell”. We now know that this large cytoplasm hosts a production line that is solely dedicated to antibody formation (up to 10,000 molecules per second per cell).

They account for less than 1% of all immune cells, and largely reside in the bone marrow, spleen, lymph nodes, mucous tissue as well as chronically inflamed tissues in disease conditions (such as the central nervous system compartment in multiple sclerosis). Nowadays, scientists use cell surface proteins (markers) to identify plasma cells rather than the morphological appearance. Among these markers are the CD138 and CD38, whilst losing the famous B-cell markers CD19 and CD20 expression. They are for all intents and purposes the grandmother or grandfather of the immune world overseeing immune responses at several levels in the human body.

Some of the plasma cells can live for a lifetime – the so called long-lived plasma cells; responsible for the long-lasting antibody response to different pathogens, vaccinations, as well as antibody mediated autoimmune diseases. Imagine a plasma cell that never forgets that you have MS?

Plasma cell under light microscope. Large dark violet nucleus is encircled by lighter colored relatively abundant cytoplasm. Source: Wikipedia

How do plasma cells develop?

Plasma cells form from differentiated B-cells.

B cells originate from the bone marrow stem cells, once ready, these B cells travel to their duty watch point at lymph nodes and mucosal surfaces awaiting a potential invasion from a foreign pathogen which triggers B cell activation and differentiation into either plasma cell or a memory B cell.

Not all plasma cells are born equal. Some B cells quickly change into plasma cells that act like ‘rapid deployment troops’ and engage with invading organisms early. However, these plasma cells are short lived and fight only using IgM antibodies. More specialized plasma cells take days to fully develop but attack smarter and more specifically. What is impressive about these plasma cells is that they can survive for a life time. We have long standing immunity to many viruses and bacteria thanks to these long-lived plasma cells.

The Jobbing Plasma cell

The plasma cell sits at the end of the line in immune cell differentiation. Short living plasma cells undergo cell death within days, whilst long lived plasma cells have the capacity to survive and maintain their antibody production for a lifetime. Cells that are destined to survive migrate and settle primarily in the bone marrow, as well as secondary lymphoid tissues or mucosa, where they reside within a supporting survival niche.

Not surprisingly, survival niches can also occur in chronically inflamed tissues during infection but also in autoimmune diseases, such as MS. In MS, long lived plasma cells have been documented in the meninges and even within the brain/spinal cord parenchyma.

Problematic Plasma cells

Aberrant antibody production is a core feature of autoimmune diseases. Studies of different autoimmune conditions have shown that short and long lived plasma cells both contribute to organ injury.

Evidence for a prominent role of plasma cells in the pathology of multiple sclerosis is clear from earliest immunopathological studies, where plasma cells have noted within the brain of MS patients. In fact, one of the most characteristic phenomena that happens in nearly all MS is the oligoclional bands (OCBs) – ‘olig’ meaning few (see Figure below). When bands are seen exclusively in the CSF compartment as opposed to blood they are termed ‘intrathecal oligoclonal bands’, with the antibody production occurring exclusively in the CNS compartment. This antibody production is evidence that plasma cells do reside within the nervous system compartment and actively participate in the ongoing inflammation and tissue destruction. Specific IgM oligoclonal bands have also been noted with faster disease progression.

Each band represent a specific antibody response in either the serum or the cerebrospinal fluid. MS is well characterised by presence of multiple bands that appear in the CSF but not the serum. Source: https://mstrust.org.uk/a-z/lumbar-puncture

A congregation of B cells and plasma cell niches have been noted in the meninges coinciding with worse disability. These congregation can support a continuous long lasting damage, and encourage plasma cells to self potentiate setting up nodal points in the brain close to the activity.

Sites where B cell, T cells and plasma cell congregates (follicles) are usually found withing the brain covering. Source M. Haugen et al 2013

How can plasma cells be targeted?

Lets not beat around the bush, there have been treatments for targeting plasma cells for more than two decades. That’s because there is a cancer of plasma cells which is deadly called Multiple Myeloma. The figure below shows how sophisticated these treatments really are.

Hemato | Free Full-Text | Why Immunotherapy Fails in Multiple Myeloma | HTML

We now have established targeted therapies for B cells in MS, ones targeting the plasma cells that play such a fundamental role is maintaining autoimmunity is long overdue.

About the author

Dr Wafa

29 comments

  • If we knock out plasma cells wouldn’t we then need a way for them to be regenerated? And in such a way that they don’t “remember” how to attack brain, but do remember how to attack things we’ve been vaccinated against / developed immunity to? Or do we start from scratch and have to be re-vaccinated against everything?

    Errant plasma cells could be the missing link in “smouldering” MS. If so that’s not good news as knocking out the plasma cells is a pretty radical thing to do… (mind you if it gets rid of the MS then the objective has been achieved…)

    • I totally agree that knocknig out any immune cells you would need to have them back because they do exist for a certain need. And that is really one of the most concerning points in immune treatments.
      An ideal immune treatment would be intervening in a cruicial step in disease process without interfering with the rest of immune function.
      If we deplete the whole plasma cell armamentarium we would be erasing the antibody memory of all the viruses/vaccines we have went through in our life, which is something we definitely want to happen.
      However, interrupting the “smuldering process” you briliantly mentioned that takes place in MS without a complete washout to the plasma cells may be a good treatment target. Whoe knows! it might be this level of plasma cells targeting may halt the slowly ongoing damage to the brain and the spinal cord and ultimately disease progression.

  • Sorry dumb question – I thought we haven’t found a single antibody that’s responsible for MS damages. What are these plasma cells producing (OCB) in MS then?

    • Well this is a very smart question really!
      While we can not say the MS is an antibody mediated disease, the antibody related damage do exist obviously in MS. Oligoclonal bands is an outstandign example, specially because the antibodies that form the oligoclonal bands developed from plasma cells that has grown up within the nervous system.
      Immune cells work together and talk together. When certain cell has a job, every other cell help, and on the other hand, if we interrupt a function of a certain cell, many other cells would be interrupted as well.

  • To prevent plasma cells from returning you need Anti-CD20 or memory b cells targeted therapy ( cladribine) to clear the bad memory b cells that can differentiate and evolve to plasma cells. so on top of targeting plasma cells you need to target b cells.
    If we think of a drug that has bbb penetrance and needs to kill just a “few” plasma cells then we don’t need to wipe out all the plasma cells in the body.
    Plasma cells will anyway come back as soon as anti cd20 is discontinued and immunization process naturally reoccurs or through vaccines if required. Chance is that they will come back normal.
    Also you don’t need a specific antibody to do the damage. You can have 1000s different doing the damage or just one. If the antibody target is heterogeneous but still in brain you won’t find a specific one but a spectrum. But… it is not sure you need specificity to have killing… activation of immune cell could be sufficient

  • Imagining if EBV treatment could knock out MS before we need to start destroying the immune system, component by component.

    • Actually this could help not only with MS, alot more disease conditions are linked to EBV.

      To my knowledge it is still difficult to get an EBV vaccine so far.

      • “To my knowledge it is still difficult to get an EBV vaccine so far.”
        Moderna has done EBV and more.

        “Moderna currently has nine development candidates in its prophylactic vaccines modality, including:Vaccines against serious infections transmitted from mother to baby

        Cytomegalovirus (CMV) vaccine (mRNA-1647)
        Zika vaccine (mRNA-1893)
        Vaccines against common viral infections with high unmet need

        Epstein-Barr virus (EBV) vaccine (mRNA-1189)
        https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-progress-prophylactic-vaccines-modality-cmv

        “help not only with MS, alot more disease conditions are linked to EBV.”

        Pender tells us:

        “CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn’s disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves’ disease, Hashimoto’s thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection”

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270541/

        • Thanks for sharing these information really,..

          I hope there would be an available vaccine to be run into clinical trials and licensing very soon.

          • “Thanks for sharing these information really,..”

            No problem…EBV vaccine can’t help us cause we already have it..but can the antibodies from the vaccine lead to EBV therapies..?

            ..also they find high EBV antibodies in mental illness so now Pender has EBV theory in Bipolar Disorder..maybe connected to ms depression.

            https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133420/

  • 10,00 molecules per second per cell

    You forgot one zero 🙂 ….Its 10 000

    One of the “Mavens” of plasma cells biology in autoimmune diseases is Prof: Andreas Radbruch

    From Charité
    Which i have the pleasure to listen in its presentation from 2019 Aidwp

    You can listen to

  • Aaaaand I forgot one fundamental question! This looks your first post on this blog… I would be happy to know a bit more about blog authors 🙂 Thank you for this post!

    • This comment indicates that you are a very good reader to the blog, which makes me really happy.
      It is my very first post indeed and I am a clinical research fellow in Barts MS team.

      Thanks for your nice feedback 🙂

      • “It is my very first post indeed”

        Welcome….just what this place needs fresh blood…if those are your cartoon drawings..very nice job.

  • I am far from a blood scientist so forgive me if I sound completely dense. Just a regular, everyday person with tons of health issues. So let me ask, are you maybe leading to saying that perhaps Plasmapheresis could help MS? I only know of Plasmapheresis because I worked many many years in US States for the company that makes the machines to do the Plasmapheresis.

    • Plasma exchange is a way of washing out offending antibodies from the blood. This helps with conditions such as neuromyelitis optica where the incriminated antibody circulates in the blood.
      In MS there is a considerable part of the story take place within the central nervous system rather than the circulating blood.

      There has been contradictory evidence for benefit of plasma exchange in MS patients and is not currently recommended as a line of therapy indeed.

  • This sounds like a case for hsct – remove all the diseased cells from the bone marrow and start fresh.
    Are you suggesting the same cure for multiple myeloma would cure ms too?

    • It would be the ideal plan is to be able to remove the plasma cells within the central nervous system doing the ongoing damage and leave the bone marrow plasma cells intact which hold immunity against all the organisms that we were exposed to through our life.

    • Immune cells with memory are usually lost with ablation. This includes memory B cells and plasma cells of course. New cells will show up in time if there are stem cells present in the marrow, but not necessarily keeping the same memory of their predecessors.

      Our body may needs to forget about MS, but of course need to remember evil organisms and virusus and keep them in check.

    • My understanding is that myeloablative HSCT does this more effectively but with more risk to the individual, with non myeloablative many ppl retain their childhood vaccinations…

  • What a great in-depth and simple explanation of such a complex topic, you have a real talent, thank you!

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