The Leaning edge: strange meat allergy

Despite decades of extensive study at the molecular level, many fundamental issues remain unexplained about the adaptive immune system.  We have two types of immunity, adaptive immunity whose genetic basis originated in jawed fish 500 million years ago, and is now shared by all jawed vertebrates. This system uses scrambled coding sections that generate randomly configured proteins to produce an open-ended repertoire of antibody and related molecules that quickly 'learns' to recognize and how to fight unknown pathogens as we meet them.

In addition we have an 'innate' immune system that generates predetermined responses, for example to general inflammation and some basic structures of bacteria.  We share this system with all other organisms.  Even plants can mount immune responses to pathogens and other kinds of assaults, including repertoires that are largely open-ended -- that is, that did not evolve in a Darwinian way one-by-one to respond to specific pathogens.  Adaptive systems of these sorts are terrific because they can evolve within organisms as fast as bacteria or viruses and so on can mutate.

However, one major unknown is why we can develop allergic responses to what, for most people, are entirely benign molecules.  It's one thing to be able to attack and destroy viruses or bacteria that would kill us if we didn't, but why some of us become hypersensitive to substances like bee venom or cow milk or dust mites -- or sometimes even our own tissues and organs, in autoimmune responses -- is not understood.  Thus there's a lot that can still surprise researchers in allergy and immunology.

Last week's story about a recent upsurge in red meat allergies was interesting.  In case you missed it -- though with those glaring photos of the culprit, it was hard to miss -- first in the southwestern US and now up the US Eastern seaboard, people have been developing a severe allergic reaction to red meat in droves, induced by the bite of a lone star tick.  The same syndrome is occurring in Europe and Australia as well.

Lone star tick; CDC Public Image Library

In general, the reaction is developing in people who have been eating red meat all their lives, but the bite of one of these ticks can change that fast.  The thinking is that the tick's saliva contains a carbohydrate, called galactose-α-1,3-galactose (α-gal), which is also found in red meats like beef, lamb, pork, venison, and so on.  When the tick bites, it injects enough α-gal into its blood source to cause the victim to create antibodies to this carbohydrate.  Then, upon next consuming meat, the immune system is primed to overreact to the α-gal in the meat.  Essentially, and ironically, while we may think we are preying on the cow or pig, they are treated as if they're preying on us!

The reaction usually occurs 3-6 hours after the meal, so the connection between the meat and the reaction isn't always immediately made when someone is trying to understand what they could possibly be allergic to.  And this kind of a delay is unusual for an allergic response.

The story is just hitting the news but in fact it's not a new story.  The first paper to describe delayed anaphylaxis after red meat consumption appeared in 2009 ("Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-a-1,3-galactose," Commins et al., Allergy Clin Immunol. 2009;123:426–33.).  The association between α-gal and allergic response was first noticed, and explored by Commins et al., because of a geographically localized cluster of anaphylactic reactions to the monoclonal antibody cetuximab, a cancer drug. People who reacted to the drug were found to have antibodies to α-gal, and maps of the prevalence of allergic response to the drug were a close match to prevalence of Rocky Mountain Spotted Fever. This suggested a strong likelihood that one of the two ticks that cause RMSF, D. variabilis or A. americium, also were causing the allergic response.

The authors documented allergic reaction to red meat with skin prick tests in 24 people, and found raised IgE (immunoglobulin E, which indicates an immediate allergic response) antibodies to α-gal.  The association with tick or mite bites was proposed in that paper, and Commins et al. confirmed in a paper published in 2011 that the cause of the raised IgE antibodies in the USA at least is bites from the lone star tick Amblyomma americium.  In the 2011 paper, they wrote:

The evidence comes from i) prospective studies of the response to tick bites in three subjects, ii) epidemiological evidence that these IgE antibodies are present in areas where tick bites are common, iii) correlation between IgE antibodies to tick proteins and IgE antibodies to alpha-gal, and iv) evidence for an expanding range of the lone star tick, Amblyomma americanum.

Documented occurrences of this reaction now number in the thousands, and Commins et al. suggest they may be seeing the beginnings of an epidemic.  They relate this to an increased number of ticks and thus tick bites with the increasing population of deer around urban areas, although the tick host includes small mammals as well, and the increasing range of the A. americanum.

Hamburgers on the grill; Wikipedia

This is a nice piece of medical detective work, but not all has been explained.  It seems that the reaction is worse after consumption of fatty meat, and there may be no reaction at all if the meat is lean.  The reaction isn't always severe, even in the same person, ranging from a few hives to severe anaphylaxis.  Why ticks induce this response isn't yet entirely clear.  And, most food allergy reactions are immediate, or within minutes of consumption of the allergen, but this one is delayed by hours.  That may be because the offending allergen is a sugar, while most food allergens are proteins.  Or, it may be the lipid connection, as Commins and Platts-Mills wrote in 2013:

The reason(s) for the 3–6-h delay in this IgE-mediated food allergy has not yet been elucidated. Given the apparent role for lipids in producing the clinical reaction, it may well be that absorption of lipid is the rate-limiting step in the delay. Biochemically, fats are absorbed and processed much differently than are carbohydrates and proteins. Fats ultimately enter the bloodstream via the thoracic duct 3–4 h after a meal. The conversion and processing of fats to chylomicrons and then further in LDL particles of various sizes may also explain a portion of the delay. Alternatively, chylomicrons themselves may transport alpha-gal antigens from the gut and intestinal epithelium via mesenteric lymph nodes to the circulation. Intestinal epithelial cells have been postulated to secrete antigen on newly formed chylomicrons, a process that could also help to explain the delayed response to mammalian meat in patients with IgE Ab to alpha-gal.

Unexplained, or idiopathic hives are a common reason for people to see an allergist.  And most commonly, people leave the allergist without an answer.  Commins and Platts-Mills are hoping that explaining the reason for the delay in the response to red meat may help elucidate aspects of allergic reactions that aren't yet understood.  And one can ask if something like this is also the story that may explain the apparent recent high rise of allergies to peanuts, gluten, and others.

Allergists and immunologists are responding to this increasing outbreak with surprise.  As food allergies go, meat allergies have been fairly uncommon, so the rapid increase in allergy to red meat is interesting enough.  But the delayed response is also unusual.  Or so they have thought -- when so many cases of chronic or recurrent hives are unexplained, it's hard to know whether they represent delayed or immediate responses.  If this is indeed an epidemic, it may teach immunologists a lot about a system about which much remains a mystery.