IgE-independent anaphylaxis; or, I haven’t been this excited on a Tuesday night in a long time

Mast cell patients are intimately familiar with the phenomenon of testing positive for allergies to things you know aren’t problems and negative for things that almost killed you.  If you ask any health care provider what the allergy antibody is, they will say it is IgE.  And for the most part, that is true.  But mast cell patients suffer reactions that do not demonstrate an IgE pathway to their allergies and anaphylaxis, and it is reason most of us suffer for years before being diagnosed correctly.

The idea that anaphylaxis is a function directly executed by IgE is a deeply ingrained part of western medicine.  In this model, IgE specific for an allergen binds to the allergen, and binds to the IgE receptor on mast cells and basophils, resulting in massive degranulation.

This is the classic model of anaphylaxis, with some creative license:

  1. You come into contact with something. Let’s say it’s Peanut, an anthropomorphic peanut.
  2. Immune cells called B cells think they once saw Peanut in a dark alley behind a bar. Peanut could have been waiting for a ride like any responsible peanut who has been drinking, but dark alley = shady = Peanut is trouble.
  3. The B cells make “Wanted!” posters with a picture of the peanut on it. Many, many posters.
  4. The B cells make lots of IgE to make sure every cell in the body sees the Wanted! posters. There will be nowhere for peanuts to hide. (I swear that as I was typing, I just heard the theme to the Good, the Bad and the Ugly.  I SWEAR.)
  5. Everyone knows that Peanut is a bad guy. They have seen the poster many times.  They do not need to see it again.  Do not show the poster again.  WE KNOW PEANUT IS BAD, IGE.  GO HOME, IGE, YOU’RE DRUNK.
  6. You guys know what happens next.  Peanut shows up.
  7. Someone remembers that IgE has been coming around the bar with the poster of Peanut. Peanut = bad guy.
  8. Everyone is hoping that if they tell IgE where Peanut is that IgE will leave them alone. No one really likes IgE but he is making such a big deal about Peanut and maybe Peanut is bad.  A little bad.  No one really knows but they know they do NOT want to deal with IgE if Peanut gets away.
  9. IgE and Peanut have a Western style gun duel at high noon. IgE captures Peanut by binding to him.
  10. While IgE is bound to Peanut, he also binds to a mast cell, which is like home base. IgE knows that Peanut is trouble and he is part of a Peanut gang and they are all bad, too.
  11. Mast cells deploy the tanks, duckboats, submarines, helicopters and fighter planes in the early allergy response to fight the Peanut gang. This causes massive inflammation with effects throughout the whole body.  Mediators released in the early response include histamine and tryptase.
  12. Mast cells start building more defenses and release them a little at a time later on in the late allergy response. Mediators released in the late response include prostaglandins and leukotrienes.

But we all know that it doesn’t always happen like this, because mast cell patients often have normal tryptase and IgE despite having a massive anaphylactic event, or even normal histamine or prostaglandins.

Last month, a comprehensive paper described alternative anaphylaxis pathways in mice that may be analogous to what is happening to mast cell patients having anaphylaxis that is not mediated by IgE.  That is to say, this pathway needs more research to know for sure if it is what is happening to us, but I have been watching the literature on this closely for a while and I100% think this is real.

There have now been multiple reports of the ability to induce anaphylaxis in mice while interfering with the IgE allergy pathway (either by not making IgE or the IgE receptor, or by treating the mice with anti-IgE, which blocks the IgE from binding to the receptor). Scientists found that by anaphylaxis could be mediated by IgG if the trigger was given intravenously. In particular, they were able to identify the murine IgG2b as the antibody subclass responsible.  In mice, IgG2b can cause anaphylaxis when IgE is not able to participate, at all.

The most important mediator in IgE anaphylaxis is histamine.  But the most important mediator in IgG anaphylaxis is platelet activating factor (PAF).  PAF levels have been linked with severity of anaphylaxis previously (I wrote a post about this around this time last year).  This could explain why many patients have normal tryptase, n-methylhistamine or histamine levels despite a very short amount of time elapsed from anaphylaxis. This is not a histamine show.  And maybe the reason so many mast cell patients cannot get complete relief despite taking huge doses of antihistamines is because histamine isn’t the PRIMARY issue.  (Author’s note: Please do not stop taking your antihistamines.  I love my antihistamines.  Just saying I think maybe there is something happening above histamine in these reactions.)

It’s also not just a mast cell show.  IgG can activate basophils, monocytes and macrophages, and neutrophils to release PAF.  Human neutrophils can mediate IgG dependent anaphylaxis when infused into mice.  So now we have a mechanism for anaphylaxis that is not IgE independent – it can also be mast cell independent.  Mind blowing. (Worth mentioning here that the phenomenon of mast cell independent anaphylaxis is not new or specific to IgG anaphylaxis – groups have found instances of mast cell independent anaphylaxis for almost thirty years.)

PAF levels are much higher in anaphylaxis patients than in control patients, and the enzyme that degrades PAF, called PAF acetylhydrolase, is much lower. It is important to note that binding at the IgE receptor can also produce PAF, but that also causes degranulation and release of histamine and tryptase, which seems to be absent in some patients.

To induce IgG mediated anaphylaxis, you need more allergen than for IgE anaphylaxis.  A lot more. 100-1000x more.  So in mice that have both IgE and IgG for peanut (not really peanut), doesn’t it seem like the IgE would react first to the peanut, and you would have IgE anaphylaxis?  But that’s not what happens.  What happens is that the IgG scoops up the peanut faster than the IgE can.  The IgG can block IgE anaphylaxis.  (WHAT UP MAST CELL PATIENTS DOING WAY BETTER ON IVIG?!?!)

IgG anaphylaxis in mice has been exclusively isolated to triggers administered intravenously.  The reason this fact matters is because of the frequency with which people (who don’t always have mast cell disease) have anaphylaxis to intravenous antibody treats, like IVIG, monoclonal antibodies for treating various diseases, or transfusions (which contain IgG antibodies). Treatments of this kind provide a huge influx of allergen. This pathway favors IgG anaphylaxis over IgE anaphylaxis because of how the IgG will scoop the allergen up (see previous paragraph).

As a final aside, there is also the curious fact that a group of patients with CVID (common variable immunodeficiency, a primary immunodeficiency disease) have a mutation that makes one of the IgG receptors found on cells like mast cells WAY more active.  The CVID patients with this mutation also have antibodies to IgA and experience anaphylaxis after IVIG.

I know I have gone on and on but this is the most exciting thing to happen to tryptase and histamine normal anaphylaxis patients in the last decade, at least.  There is SO much work that needs to be done.  Mouse and human mast cells are different.  Mouse and human IgG antibodies are different.  They could not induce food allergy in mice with an IgG dependent mechanism.  We need to pursue research on the role of PAF specifically in anaphylaxis patients with normal tryptase and histamine.

But now, when you tell your doctor that anaphylaxis is not always IgE dependent, you can give them a reference to a solid paper that fairly describes the findings, the caveats and the strengths of the current research on IgE independent anaphylaxis.  And it’s not just speculation. PEOPLE OUTSIDE OF MAST CELL DISEASE RESEARCH GROUPS ACKNOWLEDGE THAT THIS IS REAL.  IGE INDEPENDENT ANAPHYLAXIS IS REAL.

Boom.

Someone hold my Epipens while I make my dog dance with me.

Reference:

Finkelman FD, Khodoun MV, Strait R. Human IgE-independent systemic anaphylaxis. J Allergy Clin Immunol 2016.

 

14 Responses

  1. Cindy Maak May 3, 2016 / 9:56 pm

    One of your best. Thanks

  2. Janmarie May 3, 2016 / 9:57 pm

    Thank you thank you..

  3. Karen May 3, 2016 / 10:29 pm

    Dear Lisa,
    Thanks for another excellent post. Perhaps you should consider adding a warning as this information may cause extreme excitement and subsequent loss of sleep and should not be read during the late evening hours. After reading your post, how can I possibly consider sleep tonight as I must now read all about platelet aggregating factor and learn ways to modulate its production or degradation through diet, lifestyle modifications, and medication. Of course, the resulting lack of sleep will most likely trigger a flare tomorrow, but sometimes we have to walk on the wild side at stay up late partying through the pubmed database. In all seriousness, thanks for livening up our evening and as always, thanks for continuing to give us hope.

    • Susan May 16, 2016 / 10:32 pm

      Grin!
      This med looks interesting: https://en.m.wikipedia.org/wiki/Rupatadine
      A second-generation antihistamine that also affects mast cells … but I suspect it won’t work for me, as I have a CYP-450 issue that precludes my body being able to activate most of the non-sedating antihistamines. (So far, the only one of the bunch that does anything for me is Allegra; it was neat, when I had the pharmacogenomic testing, to find out why!)
      Good luck to you, and to all of us.

  4. Barbara May 3, 2016 / 10:43 pm

    OMG! This is exactly what happened to me! Dr told me he didn’t know what made me so sick but it wasn’t the mastocytosis because my tryptase level was normal immediately following my anaphylaxis!

    • Tammy May 16, 2016 / 6:19 pm

      I just saw the ‘top’ Dr. for Alberta and traveled 8 hours to hear her tell me I’m the mildest case of Masto she has ever seen because my Tryptase was 3, it was taken 3 1/2 hours after my attack and my questionable Bone Marrow was negative. I turned red as a lobster head to toe… eyes swelling, allover itching, gastro, tremors, tachycardia, nausea, headache etc. twice in one week in ER. I have never had this happen in my life…I flush a lot but this was nothing like that. I was flabbergasted and she sent me, the ‘mildest case’ ever, home with a Cromolyn prescription for 800 (mg?) Until we have a Tryptase over 20 she can do nothing. Despite the fact I have enlarged liver, GI issues for over 20 years, bladder issues, brain lesions and brain fog, Hashimoto’s, nodule on my neck lymph gland, degenerative discs and extreme weakness, exhaustion, tachycardia and flushing all backed with labs, MRI’s and CT’s. I was having tremors, shaking. flushing and extreme brain fog right in her office and she told me she can’t support the fact I am no longer able to work! So frustrating 🙁 I hope You can get the proper help You need…this should not be so hard for so many people!

  5. Tara May 4, 2016 / 12:58 am

    Absolutely amazing! This is unbelievable news! Thank you so much, Lisa!!!!!!! ***Happy dance***

  6. Linda May 4, 2016 / 7:13 am

    Very interesting! Thank you!

  7. louise May 4, 2016 / 7:33 am

    I am new to all this my son in ICU having anaphylaxis everyday for about the last week. It started a year ago for no apparent reason long and short how do we stop this . they are saying Mastocytosis but still happing everyday

  8. Sheryl May 4, 2016 / 9:16 am

    Thank you, Lisa, for your dedication to those of us trying to understand and get proper medical treatment for this baffling condition. You are greatly appreciated.

  9. David Harrison May 4, 2016 / 10:31 am

    Does tgis mean that a test for PAF could be done to diagnose those with normal mediators?

    • Susan May 16, 2016 / 10:21 pm

      Maybe, eventually. Fingers crossed!

  10. Lucy May 4, 2016 / 7:12 pm

    Wow… Here I am with a normal IgA, high IgE’s, low IgG’s and on IVIG and do better. And one of my doc’s thinks my “flares” are partly bacterial and/or viral AND episodes of mast cell degranulation. This is like puzzle pieces slowly…ever to slowly… falling into place. Thank you for sharing this.

  11. Ann May 13, 2016 / 8:28 pm

    Just subscribed to your website today after being diagnosed with mastocytosis. Already your info is invaluable. Thank you from the bottom of my heart…and all my mast cells!

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