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Stimulated Human Mast Cells Secrete Mitochondrial Components That Have Inflammatory Actions

Discussion in 'Mast Cell Disorders/Mastocytosis' started by camas, Jan 12, 2013.

  1. camas

    camas Senior Member

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    The latest from Dr. Theo. Comments welcome as this is over my head...

    PLoS One. 2012;7(12):e49767. doi: 10.1371/journal.pone.0049767. Epub 2012 Dec 17. Full Article Here.

    Stimulated Human Mast Cells Secrete Mitochondrial Components That Have Autocrine and Paracrine Inflammatory Actions

    Bodi Zhang, Shahrzad Asadi, Zuyi Weng, Nikolaos Sismanopoulos, Theoharis C. Theoharides

    Mast cells are hematopoietically-derived tissue immune cells that participate in acquired and innate immunity, as well as in inflammation through release of many chemokines and cytokines, especially in response to the pro-inflammatory peptide substance P (SP). Inflammation is critical in the pathogenesis of many diseases, but the trigger(s) is often unknown. We investigated if mast cell stimulation leads to secretion of mitochondrial components and whether these could elicit autocrine and/or paracrine inflammatory effects. Here we show that human LAD2 mast cells stimulated by IgE/anti-IgE or by the SP led to secretion of mitochondrial particles, mitochondrial (mt) mtDNA and ATP without cell death. Mitochondria purified fromLAD2 cells and, when mitochondria added to mast cells trigger degranulation and release of histamine, PGD2, IL-8, TNF, and IL-1β. This stimulatory effect is partially inhibited by an ATP receptor antagonist and by DNAse. These results suggest that the mitochondrial protein fraction may also contribute. Purified mitochondria also stimulate IL-8 and vascular endothelial growth factor (VEGF) release from cultured human keratinocytes, and VEGF release from primary human microvascular endothelial cells. In order to investigate if mitochondrial components could be secreted in vivo, we injected rats intraperiotoneally (ip) with compound 48/80, which mimicks the action of SP. Peritoneal mast cells degranulated and mitochondrial particles were documented by transimission electron microscopy outside the cells. We also wished to investigate if mitochondrial components secreted locally could reach the systemic circulation. Administration ip of mtDNA isolated from LAD2 cells in rats was detected in their serum within 4 hr, indicating that extravascular mtDNA could enter the systemic circulation. Secretion of mitochondrial components from stimulated live mast cells may act as “autopathogens” contributing to the pathogenesis of inflammatory diseases and may be used as targets for novel treatments.
     
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  2. SGR

    SGR

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    I'm thinking this explains my profound level of exhaustion - a level new to me since the beginning of this year since joining the MCAS club.
     
  3. anciendaze

    anciendaze Senior Member

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    We seem to be entering a new phase of research concerning the role of mast cells. There have long been anecdotal reports of allergies preceding onset of ME/CFS. We also have some overlap with patients diagnosed with MCAS. Just today we added a possible link with fibromyalgia. Mast cells are responsible for a great deal more than allergies. They have been called the border guards of the immune system, and they do a lot of signalling.

    The pro-inflammatory cytokines described in this paper would be natural in the acute onset of an illness like ME/CFS. If components of mitochondria are being released at the same time, there is the possibility of an immune response against mitochondria. Since all cells need mitochondria this is such a potential hazard that a long-term response reducing metabolism begins to make sense.

    The Naviaux paper on metabolic abnormalities gave us evidence of pervasive metabolic anomalies in long-term patients without telling us how they reached this state. With current definitions it is practically impossible to study the acute onset, and various studies of inflammation produce contradictory results likely because there is a change after onset and/or during flares.

    This paper offers one possible acute response causing pervasive changes, but tells us nothing about long-term effects. Studying mast cells or mitochondria in isolation is unlikely to complete the picture if we miss communication between different cells. We need to study systems.
     
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  4. lansbergen

    lansbergen Senior Member

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    Yep
     
  5. Strawberry

    Strawberry Senior Member

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    @SGR Thank you for bumping this thread! Although I am in the same boat as the original poster. Wayyyy over my head.

    So to anyone that understands this stuff, if it explains our muscles that fatigue abnormally, does it point a finger towards a "fix?" I think my ketotifen is a mast cell stabilizer, as is possibly the neuroprotek. But would these alone eventually reverse this problem? Or should I have something else added to block those chemicals from degranulating and allow my muscles to heal? Or something completely different?

    Or maybe even moringa (or anything on this web page)? Someone at one of my facebook groups just posted this yesterday. http://alisonvickery.com.au/anti-histamine-foods/ Note is says moringa is almost as effective as ketotifen.:thumbsup:
     
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  6. actup

    actup Senior Member

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    @Strawberry, I puzzle over the same questions. I use anti histamines and track food histamine intake. I haven't used a mast cell stabilizer yet. So does a high histamine level set off the human herpes virus flu syndromes I suffer with or do the chronic HHV infections cause large amounts of histamine release. I suspect the latter.Then there's the Von Willebrand's bleeding disorder. Feels like a very difficult puzzle ;-?
     
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  7. SGR

    SGR

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  8. SGR

    SGR

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    Absolutely fascinating, @anciendaze. Very interesting about the signaling and somewhat horrifying about mitochondria being targeted by the immune system. Yes, there is so much more that needs to be done - space is not the final frontier.
     
    Last edited: Sep 19, 2016
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  9. SGR

    SGR

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    That food list gives me hope. I can't afford to buy as much DAO as I need so these things are definitely going on my grocery list. Surely pea sprouts cost less than DAO. Thanks, @Strawberry.
     
  10. Strawberry

    Strawberry Senior Member

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    You are most certainly welcome! If you can't find pea sprouts, you can do it yourself. Find an organic source of pea seed, and wet them. The "stuff" is higher if you sprout them in the dark, and you can take clippings off the growth for up to 10 days. After that, it runs out and should be tossed. I haven't tried it yet myself, as I have not had the energy to go scrounging for peas. But I will.

    Here is a link that talks about sprouts, and about 2/3 of the way down, how to sprout your own.

    http://www.low-histamine.com/tag/pea-sprouts/
     
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  11. Strawberry

    Strawberry Senior Member

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    I can't see why not, as both herpes and histamine release can be triggered with stress. But I don't have a clue. Yes, we are a puzzle. I used to like puzzles, but I hate this one!
     
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  12. anciendaze

    anciendaze Senior Member

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    Please note this is no more than an hypothesis at this time. Though it does help explain the contradictory results from earlier research.

    We have a number of indications that the disease begins with an acute phase showing evidence of inflammatory cytokines. Generally, this is assumed to take place in the first six months, when the disease cannot be diagnosed, but we simply don't know. There is research from Lipkin et al. showing a shift in inflammatory markers between those sick less than three years and those sick longer. I'm assuming the long-term outcome is the hypometabolic state described by Naviaux et al. since all patients in that study had been sick for quite a while.

    I will make one other observation based on different patients who have described their symptoms on this forum: PEM appears to be a feature of the hypometabolic state, not the acute onset. Doctors have mostly assumed the onset is over when the fever associated with original flu-like symptoms disappears, but that may be only part of it. I'm now wondering if conditions like mast-cell activation syndrome (MCAS) are prolonged versions of the acute phase. I seriously doubt that the problems are isolated to those with a current diagnosis of ME/CFS.
     
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  13. anciendaze

    anciendaze Senior Member

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    Histamines are released by mast cells in significant quantities. Part of your description sounds like mast cell activation. That bleeding disorder is generally blamed on genetics, though it is not always easy to find the genes responsible.

    Now I'm going to go beyond what I know, and pose a question: are autoimmune diseases and reactions to otherwise harmless bacteria or viruses the result of sterile cell death due to episodic ischemia or bleeding not caused by pathogens? When immune systems recognize evidence of damage to healthy tissues they go on high alert looking for a culprit. If there is no such culprit, they will pounce on whatever they find at the scene of the crime.
     
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  14. flybro

    flybro Senior Member

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    pluto
    Is there any info on yhe 'bleeding disorder?
     
  15. lansbergen

    lansbergen Senior Member

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    But with injury they stop when it is healed.
     
  16. anciendaze

    anciendaze Senior Member

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    We are probably talking about repeated localized episodic bleeding or ischemia. After a long series of incidents which fall "below the radar" for medical doctors the immune system becomes "convinced" it has found a culprit in something beneficial or harmless. Even so, interventions which target immune cells infected with a normally-harmless virus could relieve symptoms, if that virus is responsible for continuing immune activation.

    We need ways to ask immune systems, "what do you think you are doing?"
     
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  17. anciendaze

    anciendaze Senior Member

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    Try this for a start. It is not extremely rare, and most people with the problem are never diagnosed.

    In cases without a clear genetic marker, the disease appears to result from an autoimmune response to von Willebrand's factor. This is strongly suspected in a case I know, where the bleeding only appeared during the second pregnancy.

    This is only one specific example of an autoimmune response to one kind of molecule. There are a lot of different molecules in a healthy human body which might be similarly targeted. We are really only at the beginning of this subject.
     
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  18. SGR

    SGR

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    Okay, duly noted, but what an intriguing concept.

    Now I'm wondering if there is any other disease that requires a six month duration of symptoms before a diagnosis can be made. Perhaps this will change with more science. Imagine if there were a vaccine against this disease. I can't think of another way to get in front of it; although for those who get this as a result of brain trauma, I guess that wouldn't work. My onset was viral and other people I was working with came down with it so that is my bias.

    I don't know what I think of MCAS being a prolonged version of the acute phase; I do feel as ill as the first few years, but the symptoms are different.

    Thank you for all your insightful ideas and information.
     
  19. SGR

    SGR

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    Excellent information, @Strawberry. I have a brown thumb, but maybe even I could grow something in the dark . Ten days would be a great supply. Love the scrounging reference....
     
    Last edited: Sep 21, 2016
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