Mechanism for delayed food allergies

[luark]

I've been reading a lot of research articles, trying to get an idea of what's going on with my delayed food allergies. 
By "delayed food allergy", I mean an allergy that doesn't show up in blood tests for IgE food allergy, and is similar to the food reactions I have. 
My food reactions start about 1/2 hr after eating the food and last about 4 days.  Mostly, it's a groggy sick feeling, but I've also had belly pain, back pain, frequent urination, joint pain, mild itchiness all over my body, and psychological symptoms like anxiety, tension, being more emotionally reactive.   This kind of food reaction seems to be rather common, except that I've had pain in my kidney area and I haven't heard of anyone else having this symptom.  I can have a reaction from a fraction of a milligram of food protein.
These reactions are acquired.  I have gotten many new such allergies when I ate foods often.  So they involve the immune system and are legitimately called allergies. 
Here's the picture I've come up with: 
The mucous membrane lining the gut has mast cells in it.  The mast cells aren't right on the surface and normally various mechanisms suppress IgE food allergy. 
When the gut barrier is somehow disrupted, or the regulatory T-cell aren't working right, or whatever - one can develop specific IgE antibodies to foods.   See "Food Allergy" by Wang and Sampson http://www.ncbi.nlm.nih.gov/pubmed/21364287 for more on how the body maintains tolerance to foods. 
People who are allergic tend to have higher gut permeability, and are more likely to have IBS.  Many people with food hypersensitivities have allergy problems such as allergic rhinitis, eczema and asthma.  People with IBS and allergies tend to have higher numbers of IgE-armed mast cells in their gut, than people with IBS but no allergies.   See "Indications of 'atopic bowel' in patients with self-reported food hypersensitivity" http://www.ncbi.nlm.nih.gov/pubmed/20163379  Also see "Perceived food hypersensitivity: A review of 10 years of interdisciplinary research at a reference center" http://www.ncbi.nlm.nih.gov/pubmed/21679125. 
Celiac disease also causes higher gut permeability, I think much more so than being an allergic person. 
So, people who are allergic, especially if they have a tendency to autoimmunity and develop celiac disease, are liable to develop IgE-mediated allergic reactions in their gut. 
It's possible to have allergic reactions that are localized in a specific organ, so that skin and blood tests are negative - but one still has an allergy.  See "'Entopy': local allergy paradigm" http://www.ncbi.nlm.nih.gov/pubmed/20642577  "Local allergic rhinitis" is IgE-mediated nasal allergy that doesn't show up on skin or blood tests.  See http://www.jiaci.org/issues/vol20issue5/cme.pdf  Local allergies are best understood for the nose, but there's also evidence that one can have local allergies in the gut.  See for example "Local allergic reaction in food hypersensitive adults despite a lack of systemic food-specific IgE" http://www.ncbi.nlm.nih.gov/pubmed/11994715 
I don't know why some people would have local food allergies in their gut, and others systemic food allergies.  The symptoms of systemic food allergies can be immediately life-threatening, so the body has evolved to try and prevent this.  The immediate part of local food allergies may be less intense than in systemic food allergies.  See "Response to intestinal provocation monitored by transabdominal ultrasound in patients with food hypersensitivity" http://www.ncbi.nlm.nih.gov/pubmed/16028432. 
The symptoms of delayed food allergies are different from systemic food allergies.  I've experienced this myself.  I had an "equivocal" result for corn allergy in a blood test for IgE antibodies, and when I ate some corn after doing an elimination diet, I got nasal congestion.  Other foods didn't do this to me.  Also, I was eating date sugar at one time (ground up dates).  Dates have a lot of yeast, and I have a yeast allergy in skin tests.  The date sugar caused awful hives on my legs, I was sick in bed for days, rubbing calamine lotion on the hives.  The hives went away when I stopped eating date sugar.  Other foods didn't cause hives, except that for awhile I had some minor itchy patches on my legs that came and went, likely caused by foods since I don't have skin allergies. 
When someone has a systemic food allergy, there's some kind of control mechanism that has failed.  In the case of delayed food allergies, it hasn't failed. 
One of the ways that the body suppresses IgE-mediated allergic reactions is to generate IgG antibodies.  IgG4 antibodies can influence allergic responses, presumably by acting as "blocking antibodies", i.e. they bind to food antigens before they can reach mast cells.   An antibody bound to an antigen is called an "immune complex".  See http://medical-dictionary.thefreedictionary.com/blocking+antibody and Food Allergy: Adverse Reaction to Foods and Food Additives by Metcalfe, Sampson, Simon and Lack, p. 550 and  "IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and FcγRIIb cross-linking" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1378186/
When lots of immune complexes get into the bloodstream, they can cause symptoms elsewhere in the body, such as swollen, painful joints, a raised skin rash, nephritis (kidney damage, causing blood proteins and even red blood cells to leak into the urine), diminished blood flow to the brain, or gut spasms.  See http://www.britannica.com/EBchecked/topic/720823/immune-system-disorder/215507/Type-III-hypersensitivity  Does some of the mental fog that people have from delayed food allergies, result from diminished blood flow to the brain? 
Many people with celiac disease say they have inflammatory reactions to other foods besides gluten.  It looks like what is going on is that celiac disease involves an autoimmune attack which damages the gut lining, causing increased intestinal permeability and other changes in the gut lining.  This results in IgE-mediated reactions to food - but since most celiacs don't have the particular defect that results in systemic food allergies, they develop delayed food allergies instead.  The body tries to prevent these symptoms, resulting in large numbers of IgG immune complexes, which get into the bloodstream and cause problems like joint pain and perhaps mental fog. 
Celiac disease, like being an allergic person, may result in  increased mast cells in the gut.  Dr. Scot Lewey, a gastroenterologist who's a celiac disease specialist in Colorado (see http://thefooddoc.blogspot.com/ tests for "mastocytic enterocolitis" in some of his patients with celiac disease.  The testing involves a biopsy of the small intestine with a special stain for mast cells, and the pathologist looks for excessive mast cells.  See "Mastocytic enterocolitis: increased mucosal mast cells in chronic intractable diarrhea" http://www.ncbi.nlm.nih.gov/pubmed/16519565 and "Allergic Mastocytic Gastroenteritis and Colitis: An Unexplained Etiology in Chronic Abdominal Pain and Gastrointestinal Dysmotility" http://www.hindawi.com/journals/grp/2012/950582/  I don't know that mastocytic enterocolitis has been definitely associated with the "other food intolerances" in celiac disease.  Dr. Lewey treats it with oral cromolyn, H1 and H2 antihistamines, Singulair and probiotics. 
I've found that taking oral cromolyn, Singulair and loratadine at least an hour before tiny amounts of foods I'm allergic to, reduces my food reactions greatly.  I'm taking 20 mg loratadine (Claritin), which seems to be more effective than the usual 10 mg dose.  From what I've seen online, one can take 20 mg loratadine if the side effects aren't too unpleasant.  The brand name for oral cromolyn is Gastrocrom, but Gastrocrom is horribly expensive.  I get it much more cheaply in powder form from a compounding pharmacy, and I dissolve the powder in hot water and drink. 
That cromolyn and antihistamines help, suggests that my food reactions do start with mast cells.  In the first couple years after I went gluten-free, my food reactions were much worse, and they might have also involved immune complexes. 
A non-IgE mechanism for antigen-specific triggering of mast cells has been found - immunoglobulin free light chains (FLC's).  An immunoglobulin molecule (such as IgE) is composed of two light chains and two heavy chains, but immunoglobulin light chains also wander around by themselves.  See http://dspace.library.uu.nl/handle/1874/221010  FLC's are produced in some autoimmune diseases, and they may cause as much sensitivity to antigen as in IgE-mediated allergic reactions. 
So perhaps delayed food allergies are mediated by FLC's rather than by IgE.  FLC's may also be involved in inhalant allergies, see "Evidence for the involvement of free light chain immunoglobulins in allergic and nonallergic rhinitis" http://www.ncbi.nlm.nih.gov/pubmed/19818484
Both "non-IgE" (unknown mechanism actually) and IgE-mediated food allergies involve Th2 skewing of the immune system.  See "Food Allergy" by Wang and Sampson http://www.ncbi.nlm.nih.gov/pubmed/21364287 and "Antigen-specific T-cell responses in patients with non–IgE-mediated gastrointestinal food allergy are predominantly skewed to TH2" http://www.ncbi.nlm.nih.gov/pubmed/23083674  Th2 is antibody-mediated immunity.  So it seems like these allergies aren't cell-mediated.  Also, cell-mediated allergic reactions are known to require a time period longer than 24 hours - see "Usefulness of Lymphocyte Stimulation Test for the Diagnosis of Intestinal Cow's Milk Allergy in Infants" http://www.ncbi.nlm.nih.gov/pubmed/21912174, and delayed food allergies often start making people feel sick within a few hours of eating the food. 
It's common for people with delayed food allergies, including celiacs with "other food intolerances", to become hypersensitive once they start avoiding the food.  The felt reaction that celiacs have when they accidentally get "glutened" is similar to the symptoms from "other food intolerances" - so it seems likely that celiacs develop a delayed food allergy to gluten grains, which is separate from the autoimmune process triggered by the gliadin protein in gluten.  Wheat is a major allergen, after all. 
For me, delayed food allergies, both to gluten and non-gluten foods, had HUGE psychological effects.  With any of the foods I have these delayed allergies to, I tend to get irritable and more emotionally reactive.  Little things loom large.  Taking allergy medications beforehand helps prevent this. 
Histamine is a neurotransmitter, see http://www.ncbi.nlm.nih.gov/pubmed/21713693.  Perhaps histamine acting as a neurotransmitter in the gut, explains the psychological aspects of delayed food allergies. 

[CMdeux]

I typed out a VERY long and detailed post in the other thread.

I'm going to leave this one with this one comment, and an encouragement to read that other post.

This is HIGHLY speculative, and a real mash-up of preliminary research articles and the occasional non-peer-reviewed source.  I can't say for sure that any of the links above are CLEARLY into pseudoscience territory, but I urge a LOT of caution with anything that isn't peer-reviewed and associated with a reputable institution.

Mostly, it's a groggy sick feeling, but I've also had belly pain, back pain, frequent urination, joint pain, mild itchiness all over my body, and psychological symptoms like anxiety, tension, being more emotionally reactive.

Many of those symptoms are NOT at all typical of a systemic food allergy.  They may be indicative of any number of other conditions, and may even be associated with more typical symptoms of food anaphylaxis.

I've found that taking oral cromolyn, Singulair and loratadine at least an hour before tiny amounts of foods I'm allergic to, reduces my food reactions greatly.

This is BAD advice.  BAD.  It's dangerous, and I sincerely hope that NOBODY reading this will attempt this without discussing it with a board-certified allergy specialist FIRST.


I'll add that the majority of parents/patients who are reading here are probably carrying epinephrine.

So I'll add this here--

http://www.the-clarkes.org/stuff/ana.html

and this

Why antihistamines won't stop anaphylaxis

and  this

How epinephrine works to stop Anaphylaxis

PLEASE DO NOT TRY DESENSITIZATION WITHOUT CONSULTING YOUR OWN ALLERGIST FOR ADVICE.

[luark]

This is HIGHLY speculative, and a real mash-up of preliminary research articles and the occasional non-peer-reviewed source.  I can't say for sure that any of the links above are CLEARLY into pseudoscience territory, but I urge a LOT of caution with anything that isn't peer-reviewed and associated with a reputable institution.

The links are to peer-reviewed articles, mostly on Medline.  There's nothing wrong with the research, and it's not in the slightest pseudoscience. 
Yes, it's a subject about which little is known.  I've tried to piece together what is probably going on as well as I can.

"Mostly, it's a groggy sick feeling, but I've also had belly pain, back pain, frequent urination, joint pain, mild itchiness all over my body, and psychological symptoms like anxiety, tension, being more emotionally reactive."

Many of those symptoms are NOT at all typical of a systemic food allergy.

I didn't say they were.  These allergies don't show up in blood tests for IgE-mediated allergy. 

"I've found that taking oral cromolyn, Singulair and loratadine at least an hour before tiny amounts of foods I'm allergic to, reduces my food reactions greatly."

This is BAD advice.  BAD.  It's dangerous, and I sincerely hope that NOBODY reading this will attempt this without discussing it with a board-certified allergy specialist FIRST.

I wasn't giving advice - and certainly it's not intended as advice for people with systemic food allergies.  The delayed food allergies aren't immediately dangerous.  I've done food challenges with normal portion sized amounts of the foods I'm allergic to, and I get quite sick.  It's very unpleasant but it's never seemed at all dangerous. 

Actually, I did tell someone with systemic food allergies about cromolyn.  She was grateful (go figure!)  Her food allergies aren't severe enough to be dangerous - so she would go ahead and eat the food anyway, and she told me afterwards she felt like she had wool in her head. She said she loved the idea of something that would allow her to eat the foods she wanted to, without bad consequences later.   
Oral cromolyn is a prescription drug, so you have to ask a doctor's advice about it anyway.  So is Singulair. 
Also, many people with delayed food allergies don't know these drugs help!  Many allergists don't know this, or at least never tell you.  Many of them don't know that Singulair can help, or antihistamines. 
With delayed food allergies, one is in different territory than with systemic food allergies.  Little is known.  There isn't good diagnostic testing.  This kind of allergy is very unlikely to kill anyone.  Allergists can't help much, and mostly ignore the subject.  I've been to allergists for my inhalant allergies and mentioned my delayed food allergies.  Almost always, the delayed food allergies are ignored in their treatment.  Yet I think what I've been through with the delayed food allergies may be central to messing up my immune system. 
People are on their own with delayed food allergies, for the most part. 
I'm doing the best I can in that difficult situation. 
I can't have it figured out, that would be a miracle. 
Just trying to figure it out and figure out what to do as well as I can.
I hardly have anything left to eat that I'm not allergic to.  It's a very different situation from someone who has a systemic food allergy to one or two foods, that might send them to the ER. 
In my situation it's probably a very bad idea to NOT eat at least a little of the foods I'm allergic to!
Also, I don't "know the territory" with systemic food allergies.  I've never used an epi-pen and don't go through that kind of thing. 
And I sure hope that researchers don't have the attitude that they "won't touch this subject with a ten-foot pole", because research is desperately needed.  If they actually are that prejudiced - then it's a self-confirming prejudice. 

[CMdeux]

I'm glad that you didn't take that the wrong way--

I really, REALLY urge you to hook up with a physician that can offer you more help than you seem to have gotten from your own thus far.

Have you looked at what it would take to get a referral to somewhere like National Jewish which has a lot of experience with GI-based phenomena?  I have a very strong feeling that you have not seen the right physician or group of them.

Actually, I did tell someone with systemic food allergies about cromolyn.  She was grateful (go figure!)  Her food allergies aren't severe enough to be dangerous - so she would go ahead and eat the food anyway, and she told me afterwards she felt like she had wool in her head. She said she loved the idea of something that would allow her to eat the foods she wanted to, without bad consequences later.

That's so dangerous.  I'm sorry-- but it REALLY is.  Yes, I'm well aware of what cromolyn sodium is and what it can do-- but I'm also well aware of its bioavailability and off-rate, which make this SO frightening to me as a recommendation for anyone.

Anyone that tries that with IgE-mediated food allergies is really playing with fire.  It's a nitpicky-seeming thing to you, I am sure...

but the bottom line is that doing that could kill someone with the kind of food allergies that this community lives with.  Period.  One of two things is true there-- either this person has (currently) got a high threshold dose, and probably has NO idea how dangerous a game s/he is playing (which I profoundly hope is NOT the case), or those "systemic" food allergies aren't IgE-mediated-- in which case, I truly wish that others would NOT call them allergy, because coopting this term makes my life much, much, MUCH harder.   The level of cooperation that I need for basic safety is so much higher... Please, "intolerance" is a MUCH better, and more accurate term.    I cannot pick out an allergen from something I plan to eat.  I have to know about shared surfaces, and sometimes I have to be able to control what others are eating around me in order to just be SAFE.    This is the world that I live in.   Not everyone has to live in it, I realize-- but I do need that level of understanding and cooperation.  I need it.  Or I could die.  I cannot just "take" anything ahead of time that will mitigate my risk of death from eating scampi, or anything that has shared a pan with it.  Can't happen. 

"Allergy" is immune-mediated, and in fact, almost synonymous with IgE-mediated.  So calling, say, celiac disease or lactose intolerance "allergy" to milk or wheat is rather like equating a panic attack with cardiac arrest.  Yes, there are some similarities, and nobody is suggesting that just living with it is a good idea... but the one thing is immediately life-threatening, and they definitely don't respond to the same treatment. 

The problem with cherry picking from research studies is that so much of what applies to IgE-mediated phenomena won't apply at all to, say... celiac.  Or MS.  Or CF.  Rather like panic attacks and cardiac arrest, if you see what I mean there.  Yes, shortness of breath might be a feature of both, but a rescue inhaler isn't a good solution either way.  If you happen to have ASTHMA and a panic attack/cardiac arrest on TOP of that, then that picture just became a lot more complicated.

Now, if you have an IgE-mediated process happening, that's applicable.  But you've said that you don't.  Yet-- at the same time, you also say that you have not:  a) had skin testing conducted at all-- though apparently you were tested for.... yeast?  via a spt, b) had any kind of scope/biopsy work done to rule out some fairly obvious causes for your symptoms. I'm not sure why you are SO sure that you do NOT have IgE-mediated food allergy.  Some of your reported reactions sound really implausible barring an IgE-mediated mechanism, and some of your symptoms are classically IgE-mediated (hives, itchiness). 

How have you worked to rule out celiac?  HAVE you ruled it in or out?  Many of your symptoms don't sound at all like food allergy symptoms, but they sound like rather TEXTBOOK symptoms for celiac.  If you are gluten-free, just how confident are you in your management?  Because if you're getting glutened by something, that's probably the simplest explanation of all.  Also worthy of note-- celiac is NOT going to respond well to "desensitization."  Yes, you may become "hypersensitive" through avoidance and notice major symptoms when you err, but avoidance is really the only way to deal with celiac.  Long-term consequences of NOT practicing avoidance are pretty awful. 

What kind of physician are you working with?  Someone is prescribing you xolair-- is this a board-certified allergist?  What kind of specialty?  Some of them are great with asthma, but awful with food allergy...   

General practitioners usually lack the expertise to adequately address individuals with complex or multiple allergic/autoimmune issues.  But there is SO much misinformation out there.  SO much.  And-- please forgive me-- but inaccurately terming all food intolerance as "allergy" is a huge step down that alt-med, woo-infested path.    Board certified allergists most certainly DO know about mast-cell stabilizers, antihistamines, proton-pump inhibition, etc. etc.  They do know.  What they also know is that it is NOT enough to prevent some degree of degranulation in someone with the potential for anaphylaxis.    If you're seeing an allergist that has never heard of these therapuetic agents, RUN like the wind.  Actually, if you're seeing any M.D. who hasn't you should run.   

Cromolyn sodium is frequently a front-line therapeutic for eosinophilic disorders.  Are you seeing a specialist?  If not-- PLEASE do, because treating them is very much a delicate balancing act, and one that DOES have precedent and well-established protocols.  Expert physicians exist for these conditions, though they are far from garden-variety.

Really-- I'm posting about this not to challenge you about your personal decisions, but out of concern for your well-being.  It really sounds as though you aren't getting great support from a physician, and are feeling (understandably) that you HAVE to solve this all on your own. I'm worried for you.

I'm worried that either you DO have food allergies and you're placing yourself at severe risk without knowing it (particularly if you do not have epinephrine on hand, and I'm guessing you do not), or that you don't, and you're not figuring out what IS actually the underlying cause of your symptoms (all or part of them), which might be just as bad.

[Macabre]

If I read your post correctly, then you are considering it non-IgE mediated in part because you don't have it immediately.

FWIW I don't consider 30 minutes delayed, but then my IgE-mediated crustacean allergy has a reaction start time of 2 hours. And that is very atypical.

I would be concerned that you might have a life threatening allergy.

[CMdeux]

I'm worried about that as well.  VERY.  Four days is well in line with "protracted anaphylaxis."

And I sure hope that researchers don't have the attitude that they "won't touch this subject with a ten-foot pole", because research is desperately needed.  If they actually are that prejudiced - then it's a self-confirming prejudice.

How do you think that researchers DO what they do in the first place?  Right-- they have to get MONEY to do it.  From somewhere that thinks what they want to look into is a good idea. 

How good do you suppose the money is, in something associated primarily with some of the best known quacks in America?  Yeah, not good.

So sure-- judge them if you will, but know that they'd be committing professional suicide to touch those things-- and therefore they wouldn't be able to do ANY research once they became known as "that person that looks at {funky woo topic}." 

Don't blame scientists and research physicians.  Blame the unscrupulous quacks who are out to blur the lines sufficiently around complete bull-puckey so that it's less obviously a cowpie, and looks like it might be this sort of scientific-sounding (but unrelated, mostly) thing instead, mostly in order to make a few more bucks.   For exhibit A, there, look at homeopathy, which is self-evidently ludicrous.  Good luck studying anything that has ever come along hand-in-hand with it, no matter how possible/interesting scientifically.

Guilt by association.  Human beings are pretty bad about this kind of thing and sadly that is who awards grant monies and publishes manuscripts.