Symptoms, mediators and mechanisms: A general review (Part 2 of 2)

 

Gynecologic symptoms    
Symptom Mediators Mechanism
Irregular and painful menstruation Histamine (H1), bradykinin Smooth muscle constriction
Uterine contractions Histamine (H1), serotonin, bradykinin Smooth muscle constriction

Increased estrogen

 

 

Neurologic symptoms    
Symptom Mediators Mechanism
Appetite dysregulation Histamine (H1), histamine (H3), leptin Dysfunctional release of neurotransmitters, suppression of ghrelin
Disorder of movements Histamine (H2), histamine (H3) Dysfunctional release of neurotransmitters, increases excitability of cholinergic neurons
Memory loss Histamine (H1), histamine (H3) Dysfunctional release of neurotransmitters
Headache Histamine (H1), histamine (H3), serotonin (low) Dysfunctional release of neurotransmitters

 

Low serotonin

 

Decreased blood flow to brain

Depression Serotonin (low), TNF, histamine (H1) Low serotonin

Disordered release of dopamine

Irregular sleep/wake cycle Histamine (H1), histamine (H3), PGD2 Dysfunctional release of neurotransmitters
Brain fog Histamine (H3), inflammatory cytokines Dysfunctional release of neurotransmitters, neuroinflammation
Temperature dysregulation Histamine (H3) Dysfunctional release of neurotransmitters, dysfunctional release of catecholamines

 

 

Miscellaneous symptoms    
Symptom Mediators Mechanism
Bleeding diathesis (tendency to bleed easily) Tryptase, heparin Participation in anticoagulation pathways

In which I am so hopelessly behind

Hi, everyone –

I am weeks behind in responding to some emails and comments.  I don’t want anyone to think I’m ignoring them.

I am strongly considering stripping some questions of identifying information and posting the responses on a weekly basis because I am often asked similar nuanced questions that aren’t really completely addressed in any one post I have already written.  What do you guys think?  Does anyone strongly object to this?  I would ensure that the question would not be identifying.

Thanks for your patience!

Lisa

Symptoms, mediators and mechanisms: A general review (Part 1 of 2)

Skin symptoms    
Symptom Mediators Mechanism
Flushing Histamine (H1), PGD2 Increased vasodilation and permeability of blood vessels

Blood is closer to the skin and redness is seen

Itching Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Possibly stimulation of itch receptors or interaction with local neurotransmitters
Urticaria Histamine (H1), PAF, heparin, bradykinin Increased vasodilation and permeability of blood vessels and lymphatic vessels

Fluid is trapped inappropriately between layers of skin

Angioedema Histamine (H1), heparin, bradykinin, PAF Increased vasodilation and permeability of blood vessels and lymphatic vessels

Fluid is trapped inappropriately between layers of tissue

 

Respiratory symptoms    
Symptom Mediators Mechanism
Nasal congestion Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production

Smooth muscle constriction

Sneezing Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production

Smooth muscle constriction

Airway constriction/ difficulty breathing Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Increased mucus production

Smooth muscle constriction

 

Cardiovascular symptoms    
Symptom Mediators Mechanism
Low blood pressure Histamine (H1), PAF,  PGD2, bradykinin Decreased force of heart contraction

Increased vasodilation and permeability of blood vessels

Impact on norepinephrine signaling

Change in heart rate

Presyncope/syncope (fainting) Histamine (H1), histamine (H3), PAF, bradykinin Increased vasodilation and permeability of blood vessels

Decrease in blood pressure

Dysfunctional release of neurotransmitters

High blood pressure Chymase,  9a,11b-PGF2, renin, thromboxane A, carboxypeptidase A Impact on renin-angiotensin pathway

Impact on norepinephrine signaling

Tightening and decreased permeability of blood vessels

Tachycardia Histamine (H2), PGD2 Increasing heart rate

Increasing force of heart contraction

Impact on norepinephrine signaling

Arrhythmias Chymase, PAF, renin Impact on renin-angiotensin pathway

Impact on norepinephrine signaling

 

Gastrointestinal symptoms    
Symptom Mediators Mechanism
Diarrhea Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction

Increased gastric acid secretion

Dysfunctional release of neurotransmitters

Gas Histamine (H1), histamine (H2), bradykinin Smooth muscle constriction

Increased gastric acid secretion

Abdominal pain Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction

Increased gastric acid secretion

Dysfunctional release of neurotransmitters

Nausea/vomiting Histamine (H3), serotonin Dysfunctional release of neurotransmitters
Constipation Histamine (H2), histamine (H3), serotonin (low) Dysfunctional release of neurotransmitters

 

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.

 

Cardiovascular manifestations of mast cell disease: Part 5 of 5

Low blood pressure causing lightheadedness or fainting is a classic manifestation of mast cell disease with as many as 22-55% of patients having experienced it at least one. For comparison, the control group demonstrated a frequency of 5%.  Some patients experience this symptom often while others only rarely experience it or never do.

A staggering amount of mast cell mediators can induce low blood pressure; indeed, this is the reason why low blood pressure is the hallmark sign of severe allergic reaction and anaphylaxis.  Histamine can induce hypotension through the H1 receptor.  Heparin makes histamine and tryptase less susceptible to degradation, allowing longer action.

Many mediators are vasodilating, widening the blood vessels. Vasoactive intestinal peptide (VIP) is a vasodilator.  PGD2 is also a very potent in this capacity. PGE2 is not released in large amounts by mast cells, but has the same effect. Platelet activating factor decreases blood pressure in multiple ways: by decreasing the force of heart muscle contraction, by slowing heart rate and by widening blood vessels. IL-6 and nitric oxide are also vasodilating.

Some mediators lower blood pressure by their participation in the bradykinin pathway.  Bradykinin is a potent stimulator of fluid loss from the blood to the tissues, causing low blood pressure and angioedema. Heparin can serve as an initiator for the production of bradykinin. Tryptase and chymase both participate in bradykinin formation.

Mast cell medications can be very effective in increasing blood pressure by decreasing fluid loss from the blood to the tissues.  As PGD2 can be a strong vasodilator, COX inhibitors like NSAIDs that interfere with prostaglandin production can help to increase blood pressure.  Aspirin, 81-325mg once or twice daily, is sometimes recommended for adults that are not sensitive to the medication.  Early data on the use of omalizumab (Xolair) in SM patients indicates that it may prevent episodes of sudden onset low blood pressure.

References:

Kolck UW, et al. Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research 2016; x:1-10.

Gonzalez-de-Olano D, et al. Mast cell-related disorders presenting with Kounis Syndrome. International Journal of Cardiology 2012: 161(1): 56-58.

Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 2013; 138: 53-65.