Antibodies can be a problem in MS..AAN 2019

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Intrathecal Injections of Primary Progressive Multiple Sclerosis Derived Antibodies Result in Motor Deficits and CNS Pathology in Mice Suggesting Leading Role of Antibodies in CSF Effects

Francesca Cali , Alexandra Tse, Jamie Wong, Jerry Lin , Saud Sadiq Objective: To investigate the effects of intrathecal administration of recombinant IgG1 antibodies (rAbs) derived from multiple sclerosis (MS) patients’ cerebrospinal fluid (CSF) on motor behavior and CNS pathology in mice. Background: The presence of CSF IgG oligoclonal bands as a diagnostic marker and the effectiveness of B-cell targeted therapies suggest an essential role of B-cells in MS. Previous studies in our laboratory showed that intrathecal delivery of primary progressive MS (PPMS) CSF in mice resulted in significant motor deficiencies, astrocyte activation, and axonal damage compared to control mice. Design/Methods: Following isolation of B-cells MS patient CSF samples, immunoglobulin variable regions were analyzed and rAbs were produced. In total, 53 mice received intrathecal injections under the dura mater at cervical levels 4 and 5. Control mice received injections with saline or rAbs from healthy, HTLV-1, or ALS patients. 6 PPMS and 1 RRMS antibodies were injected. Motor deficits were evaluated and spinal cords were stained with luxol fast blue, GFAP, Iba1, SMI-32, and anti-human IgG antibody. Results: 20 of 27 mice injected with PPMS antibodies exhibited motor deficits while only 1 of 12 RRMS and saline injected mice developed motor deficits. 4 of 6 injected PPMS rAbs displayed higher intensity GFAP and Iba1 immunostaining, providing evidence of both reactive astrogliosis and microglial activation. Similar SMI-32 immunostaining between groups reveals that axonal damage may not cause these observed motor deficits. Anti-human IgG immunostaining was only detected following PPMS rAb injections, suggesting possible rAb binding sites in the cervical spinal cord. Luxol fast blue staining revealed areas of demyelination in the cervical spinal cord following PPMS rAb injections, while no lesions were found in RRMS injected mice. Conclusions: Antibodies derived from PPMS patients likely contribute to motor deficits and spinal cord pathology in mice. Future investigations will seek to elucidate the pathogenic role of these CSF antibodies.

The concept of taking antobodies from people with MS and injecting them into the brain of mice and they get neurological signs is not new , it has been shown by a number of other groups. We have done this too. That is why I know there are pathogenic antibodies in the brains of people with MS. Some people respond to plasma exchange (removing antibodies from the blood) some don’t. Here people with PPMS had antibodies as did a person with RRMS, but may the level is different between individuals. I hope they dont show videos as it is not pleasant viewing. So there is clear autoimmunity in MS. However the problem is whether it is a primary problem or a secodary problem. As you get more damage you release more nerve proteins that can cause problems. What do they react to ? Not myelin basic protein;-)

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8 comments

  • If mice have an immune system susceptible to ground based pathogens and we are susceptible to air born pathogens among many other differences, please see following study, http://www.jimmunol.org/content/172/5/2731, I can’t wrap my head around why we insist of using time, money and energy of wasteful experiments?

    • Because they can and people continue to fund it.

      In many scientitists heads they are not bothered about MS, it is how the immune system works….I can rememebr Poly Matzinger (NIH Prof) giving an hour presentation about the “danger theory” about how the immune systme responds to danger and how Sir Peter Medawar got it wrong….then someone ask you give a transplant and it is kept for years and years and the inflammation associated with the transplant has all gone so there is not danger signal, you forget your transplant drugs and the transplant is rejected within a day or two. The answer is “I’m not interested in the clinical stuff”

  • “At
    present it is unclear whether these antibodies are harmful, protective, neither
    or both. It has been demonstrated that patients with RRMS and SPMS have
    antibodies directed towards oligodendrocyte precursor cell lines, but only the
    SPMS patients had antibodies directed towards a neuronal cell line.49 This
    supports the idea that the concept of epitope spreading is important in MS.”

    Joachim Burman

    https://uu.diva-portal.org/smash/get/diva2:714003/FULLTEXT01.pdf

      • Type I IFNs, which include IFN-β, elevate expression of B cell activation factor (BAFF), increase B cell activity and drive the production of autoantibody in systemic lupus erythematosus (SLE) and neuromyelitis optica (NMO), promoting inflammation(1–3). Inone sense, these are “type 1 IFN diseases” where B cell autoantibody production is clearly pathogenic. In RRMS IFN-β also increases serum levels of BAFF and B cell activity(4, 5), yet in a seeming paradox IFN-β reduces inflammation and decreases relapses(6

        10.4049/jimmunol.1402029

        🙂

  • Hi Drs, Prof G & team
    I’m hoping you can help and I apologise that my comment is little to do with the above or is it… I have RRMS (active MS in my eyes) – I’m not qualified medically, just a ‘Ph.D.’ from Dr. Google & friends! I’m frustrated with for all sorts of reasons with the disease or possible conditions that the man upstairs has landed me with & it doesn’t help with my constant and insatiable appetite to find out more info, research, cure & ultimately answer all my sometimes unusual questions! I’ll get straight to it & forgive my non-medical speak! I’m in constant pain, every day and it gets worse at night or when I’m resting. My whole body but especially my limbs, legs, and arms, are always cold & ache (dull, gnawing pain) through & also running up & down, with gnawing pains mostly whilst resting. I have unusual, stomach & toileting probs which make me stay near home or to ensure there are clean usable toilets wherever I go! My nerves tingle and feel like I’m heightened to noise & environmental factors, along with the weather. I also have a huge heavy, weighty feel about my body whenever I move. In short, I feel like my elderly Mother who has a walking frame in her 80s and need assistance, getting up and sitting down in a chair. These symptoms are I know linked and some are the common problems MS seems to cause. I get all of that, what I don’t get is why, when I put hot water bottles on my limbs (or heat pads, hot/warm water) or sit in the sunshine and allow the sun to burn on my skin that I feel relief from a lot of the aforementioned! I haven’t found or had the time to discuss this further with my Neuro (I do believe I have mentioned it but it was noted down on my record and the conversation wasn’t reciprocated & my next 2 chances have been scuppered by DMD probs) – If heat is healing to MS patients once the blood in the arms is warmed up – can this not be looked into further? If heat helps stop the pain – can this not be looked into forming a medication (it may already be out there) to help keep the blood warm and therefore stop the daily agony of pain I have to go through? If heat has such an impact – why is body so cold all the time & how can the circulatory system not be something that should be medically looked into as a link to MS and meds created (they might again, already exist) to help keep the body warm and the blood flow, flowing around the body which would help with pain, stiffness, heaviness, fatigue and general well being but most importantly give an MS person relief. This could then mean, that no extreme neuro pain meds, possible better well being, therefore, more inclined to have a life and not feel anxious, depressed & low mood. This also results in more medication and possible complications of low mobility, weight and accelerated aging.

    I understand also, and there seems to be a lot of misrepresentation with regard to the demise of an MS person. You can’t die of MS – you can die of heart failure or other diseases or illnesses that run alongside the disease and by being less of a person due to all the above – you can give up and start your own process of shutting yourself down. My Father had Alzheimer’s – he didn’t die of the disease, he stopped eating, then pushed away drinks – then the next was an inevitable shut-down of the body, which took a painful and slow demise of a once very fit and healthy human being. Basically, what I’m saying is that we must be able to help support people with neurological diseases in time, so that you don’t give up and to end your life like my Father’s was and should not have been so distressing for everyone, no more so, than himself!

    Any thoughts on the above, please do let me know.

    Thanks if you’ve read this – as I do go on a bit!
    xx

  • And another one again from Tisch

    Cerebrospinal Fluid of Primary Progressive MS Patients Impairs Remyelination in an Experimental Model of Multiple Sclerosis
    http://indexsmart.mirasmart.com/AAN2019/PDFfiles/AAN2019-000543.pdf

    Results:Only PPMS CSF-injected mice exhibited significantly impaired forelimb function and increased tail flaccidity compared to all other experimental groups. Luxol fast blue staining revealed a significantly greater extent of demyelination in PPMS CSF-injected mice as compared to controls, RRMS and SPMS CSF-injected mice. Immunostaining revealed significantly greater microglial activation (Iba1) and astrogliosis (GFAP) for PPMS CSF-injected mice as compared to RRMS and SPMS CSF-injected mice. No significant differences were found among groups for numbers of proliferating oligodendrocyte progenitor cells (NG2/Ki67) or mature oligodendrocytes (APC/Olig2). Conclusions:Intrathecal delivery of PPMS CSF, but not RRMS or SPMS CSF at the site of a lysolecithin-induced lesion yielded larger lesions, greater microglial activation and reactive astrogliosis, as compared to controls. This suggests that as yet unidentified factors present in PPMS CSF, but not RRMS or SPMS CSF can impede remyelination.

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