Going round the guts to get to the brain.

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MAdCAM-1-Mediated Intestinal Lymphocyte Homing Is Critical for the Development of Active Experimental Autoimmune Encephalomyelitis.

Kuhbandner K, Hammer A, Haase S, Terbrack E, Hoffmann A, Schippers A, Wagner N, Hussain RZ, Miller-Little WA, Koh AY, Stoolman JS, Segal BM, Linker RA, Stüve O. Front Immunol. 2019;10:903

Lymphocyte homing into the intestine is mediated by binding of leukocytes to mucosal addressin cell adhesion molecule 1 (MAdCAM-1), expressed on endothelial cells. Currently, the immune system of the gut is considered a major modulator not only of inflammatory bowel disease, but also of extra-intestinal autoimmune disorders, including multiple sclerosis (MS). Despite intense research in this field, the exact role of the intestine in the pathogenesis of (neuro-)inflammatory disease conditions remains to be clarified. This prompted us to investigate the role of MAdCAM-1 in immunological processes in the intestine during T cell-mediated autoimmunity of the central nervous system (CNS). Using the experimental autoimmune encephalomyelitis model of MS, we show that MAdCAM-1-deficient (MAdCAM-1-KO) mice are less susceptible to actively MOG35-55-induced disease. Protection from disease was accompanied by decreased numbers of immune cells in the lamina propria and Peyer’s patches as well as reduced immune cell infiltration into the spinal cord. MOG35-55-recall responses were intact in other secondary lymphoid organs of MAdCAM-1-KO mice. The composition of specific bacterial groups within the microbiome did not differ between MAdCAM-1-KO mice and controls, while MAdCAM-1-deficiency severely impaired migration of MOG35-55-activated lymphocytes to the gut. Our data indicate a critical role of MAdCAM-1 in the development of CNS inflammation by regulating lymphocyte homing to the intestine, and may suggest a role for the intestinal tract in educating lymphocytes to become encephalitogenic.

You can read the paper if interested.

Inhibition of migration of immune cells into the CNS inhibits relapsing MS. This was first done with natalizmab, which blocks alpha 4 integrin binding to vascular cell adhesion molecule-one on inflamed blood vessls in the brain.

Many years ago we showed that inflammed blood vessles in the CNS sometime express the mucosal (intentinal) addresin also known as MadCAM-1.

Expression of vascular addressins and ICAM-1 by endothelial cells in the spinal cord during chronic relapsing experimental allergic encephalomyelitis in the Biozzi AB/H mouse. O’Neill JK, Butter C, Baker D, Gschmeissner SE, Kraal G, Butcher EC, Turk JL. Immunology. 1991;72(4):520-5.

This is involved in homing of lymphocytes into the gut lymphoid tissues. So it is not suroprising that MAdCAM-1 deficient mice have reduced cells in their intestine as shown in the current paper.

The authors suggest a critical role of MAdCAM-1 in homing into the CNS, but look at the data…Not exactly compelling

I have to say…”critical”…sounds abit melodramatic, because if it was critical and you get rid of it there would be no disease. But look at D above and there eventually was disease, although E suggests it is different. These two graphs seem at odds with each other.

Now the reason I picked this paper to comment on, is that it talks about our work, but the authors suggest that the disease forming cells pass through the gut, so is this why microbiome is important. Is this stretching an idea abit too far? The whole world is microbiome mad at the moment, so is this why lymphocytes are affected by microbiome becaus ethey all migrate through the gut on their way to the brain.

However other authors suggested that disease cell go through the lung and their they get programmed to go to the brain.

T cells become licensed in the lung to enter the central nervous system.Odoardi F, Sie C, Streyl K, Ulaganathan VK, Schläger C, Lodygin D, Heckelsmiller K, Nietfeld W, Ellwart J, Klinkert WE, Lottaz C, Nosov M, Brinkmann V, Spang R, Lehrach H, Vingron M, Wekerle H, Flügel-Koch C, Flügel A. Nature. 2012 Aug 30;488(7413):675-9.

Did Odoardi et al. look in the gut…No. Did Kuhbandner et al. look in the lung….Em No. So they are both right?

Perhaps they did not try to disprove that they were wrong and here lies the rub.

So when you inject lymphocytes they go on a tour of the body and have to stop off in the gut and lung? I have to ask is this all way too complicated for biology?

What would be the advantage of such a tour? If you have an infection you don’t want your lymphocytes to go on a “Tour de France” before it gets to Paris.

I was brought up to think that cells come from the thymus and circulate round the body and the naive T cells go into lymph glans via specialised blood vessles called high endothelial venules. In peripheral lymph gland they use L-selectin and MECA-79 in the lymph glands ans and MAdCAM (MECA-367) to get into the gut lymphoid tissue. On seeing their target- antigen they differentiate into memory/primed cells and down regulate L-selectin and up-regulate CD49 (alpha4 , beta 1 integrin) and CD44.

So they can enter tissue (gut and brain) through interaction with vascular cell adhesion one and hyaluronic acid that is depositied in vessels during inflammation. So now the primed cells travel round the body and go everywhere, like the lung and the gut and even the brain, but especially into inflammated tissue. If they don’t see what they are interested in the either die or leave and go elsewhere until they find what they are designed to find. If you lookin the lung you will find lables cells as they are being circulated round the body in the blood. Would you find them in the gut…sure you would.

In the interval since our early discoveries we have moved on as natalizumab has hit the scence and the issues about blocking lymphocytes into the brain and the risk of PML made us look elsewhere…. I suppose for every gene there is a knockout mouse and and EAE knockout mouse study or three of four or five.

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MouseDoctor

10 comments

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  • “The whole world is microbiome mad at the moment”

    Agreed! I have started drinking kefir daily for some reason… the only objective evidence I have noticed so far is the £1.45 going out of my account every day.

  • I can’t comment on this paper, but I find that you tend to be far too dismissive of microbiome research MD.

    • Dang rumbled….yes I am rather sceptical, just as I was sceptical about CCSVI and about using worms to treat MS etc. There is alot of science behind microbiome, but to think it is the wonder cure……I will wait for the endless set of trials that (you) have (been) funded, will be funded, and then time will tell.

      Nostradamus is riduculed but if you dont make predictions you can’t say I told you so, nor can you say I was wrong. I am sometimes wrong.

      I predicted the faecal transplant would become a cottage industry years ago. However academia is going mad on it and will fuel the cottage industry. Am I going to say the work is ace….if it is yes……but if it is following dogma without any thought and the same old sausage factory stuff, it is right to ask questions. Millions of dollars are being ploughed into this, every disease has an interest in microbiome, there are loads of trials. What happened to all those vitamin D (the previous science fad) trials. Was the effect any better than a good DMT..I haven’t seen that data.

      What about the WORMS/WIRMS studies, they must have finished years ago, or maybe they couldn’t recruit because people were not convinced.
      A piece of the jigsaw.

      • Well, I’m just going by my gut feeling (no pun intended). I have absolute sympathy for your scepticism regarding worms and CCSVI, but I think, from what I have come to understand about just how vital symbiosis is in so many organisms (even lichen, for goodness sake), how interwoven biological systems are (e.g. Peter Wohlleben’s writing on forest ecosystems) that we cannot afford to be arrogant about things we as yet simply do not understand. A reductionist outlook in science may not always be the answer. Whilst I tend to scorn the esoteric, I do not follow with a “simple” approach of finding some drug to do “something”. I feel my PPMS needs a multifaceted approach with exercise, lifestyle, diet – and hence microbiome – being powerful and crucial factors. I have much more hope in such things, as opposed to any drug. Especially given how little is yet known about progressive MS.

          • Is it arrogant to ask questions? Or religion is you accept with blind faith?.

            What is the selective advantage of sending cells round the houses when you know where the problem is? I would except them going every where has advantage this is “seek and destroy”, but going to sequential places is surely not that logical?

            There are already 720 studies on microbiome at clinical trials gov, 238 on faecal transplant in conditions such as Irritable Bowel Syndrome, Obsessive-compulsive Disorder (MIO), prosiasis, colitis, etc etc etc. Five trials in arthritis, two trials in MS (I bet there are more) one n=30 the othere is n=40, surely these are going to be underpowered if we look at an average pharma trial is 15-20 enough? Probably they will give a wishy-washy answer that needs another trial….Time wasted.

            Does every disease need to do a trial? Pick the one with the quickest read out, do it properly and definativiely and move on. However this probably would not be in MS. Would you be happy with that?

          • “symbiosis is one can’t do without the other”

            Absolutely. We certainly could not live without gut flora, albeit not in terms of one particular sp. of bacterium.

          • My opinions on the current state of MS research are somewhat conflicted. For example, i think overall it could benefit from a more focused approach. That is, we must thoroughly test one hypothesis before moving to the next (instead of running hundreds of small and underpowered studies). However, I also understand that medical breakthroughs often come via unexpected avenues. Then there is big pharma with it’s endless cycle of me too drugs. But without these drugs patient outcomes would be far worse than they are today. I don’t know what the answer is but the fact that we landed people on the moon in the 1960’s supported by the same computing power held in a mobile phone shows the power of a unified vision and approach. A further example is the Manhattan Project. I think it’s going to take this level of focus and commitment to provide patients the cure they are so desperately looking for.

        • “Is it arrogant to ask questions? Or religion is you accept with blind faith?”

          No, it’s arrogant to assume we know all there is to know.

          I’ve no interest in religion.

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