Why is there a distinction between an *allergic* and an *immune* response?

Why is there a distinction between an *allergic* and an *immune* response?

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Our immune system has evolved to protect us against potentially dangerous non-self particles. I have difficulty in understanding why there is a distinction called an allergic response: what's wrong with using the term immune response full stop? Surely a person's immune system should react to a particle of grass pollen in EXACTLY the same way as it does to a non-self protein expressed on cells of some transfused blood. The mystery that I absolutely don't understand is why our body can then differentiate the scale of the response.

The trouble is, you can't live without being exposed to all sorts of non-self particles. Some of those particles signal an actual threat to your health (proteins associated with a disease causing virus), some are nearly harmless (bee stings), some are completely harmless (grass pollen or cat dander), and some are potentially valuable as part of a food substance (seafood or peanuts). Ideally you'd like your immune system to respond to the harmful ones, and ignore the harmless or useful ones. An allergy is defined as an unneccesary immune response to a harmless (or nearly harmless) substance.

You do want your immune system to deactivate venom from a bee sting, but you don't want it to react so strongly that as a side effect your throat swells up and you can't breathe. Most people breath in grass pollen every day of their live with no ill effects, so those folks who have an allergy to grass pollen are being made miserable by their immune system to no good purpose.

Ideally the immune system mounts a full response only when the presence of particular non-self particles is associated with other signals indicating that something "bad" is happening which merits an immune response. However, the process by which the immune system is regulated is incredibly complex, involving feedback loops from hundreds of different chemical pathways and dozens of different cell types. The process is imperfect. Sometimes it goes wrong, and the immune system mounts an aggressive response to a harmless foreign substance or even worse part of your own body.

Allergy is an exacerbated inflammatory reaction of the immune system in reaction to small quantities of foreign inert substances called allergens. It is a clinical condition characterized by its symptoms: redness of the eyes, ocular and nasal discharge, itching, eczema, asthma, headache, digestive disorders and swelling. The most critical clinical manifestation is the anaphylactic shock that may lead to death.

The immune reaction is triggered by pathogens (viruses, bacteria, parasites) that have the ability to replicate within the body.

Both the allergy and the normal immune reaction share the same principle: a primary immune response where the immune system learn about the antigen/allergen, and a secondary immune response where it can unleash its full potential (too much in the case of allergy).

Why children are more likely to develop food allergies

An estimated 15 million Americans suffer from food allergies, many of them children. These are non-trivial concerns, as food allergy or intolerance can cause symptoms ranging from a harmless skin rash to a potentially lethal anaphylactic shock. The good news is that many affected children outgrow their allergy, presumably as the immune system learns to tolerate food initially mistaken as "foreign."

A new study published in the January 28, 2016, online issue of Science by La Jolla Institute for Allergy and Immunology (LJI) researcher Charles Surh, Ph.D., may explain how food tolerance emerges over time in normal individuals.

Coupling molecular approaches with a long-forgotten model of "antigen-free" mice, the study is the first to demonstrate that consumption of a normal diet stimulates cells in the gut that suppress rejection of food by the immune system. Knowing this could explain why children, who have more limited exposure to novel foods than adults, are more susceptible to food allergies.

"The immune system evolved to protect us from things that are not ourselves, like viruses or pathogens, yet we consume nutrients, which are themselves foreign," says Surh, an adjunct professor in LJI's Division of Developmental Immunology. "Our work shows food tolerance is acquired and involves specific populations of T cells that develop following its consumption. Without them, we would mount a strong immune response to macromolecules contained in food."

Like pathogens, food displays macromolecular markers known as antigens that announce to the immune system that food is "foreign." Previous analysis of how the body distinguishes antigenic friend from foe revealed that feeding lab mice a novel test protein--for example, the egg protein ovalbumin--induced development of immunosuppressive T-regulatory, or "Treg" cells, in the gut, which then acted to block the immune response to that particular protein. What researchers didn't know was whether this happened in "real life" as young mammals--be they mouse pups or human toddlers--encountered new foods.

To address that question, Surh re-established "antigen-free" mouse models designed to represent an immunological blank slate. These animals were not only raised in a germ-free environment but were also fed an "elemental" diet of amino acids, the building blocks of proteins, rather than foods that contain intact proteins themselves. The mice were, in essence, immunologically naïve, because the amino acid building blocks are too small to be recognized by the immune system. These mice therefore have little or no prior contact with antigenic proteins and other macromolecules.

Using molecular marker analysis, Surh and colleagues found that antigen-free mice were depleted of Tregs in the small intestine whereas a large number of these Tregs were present in germ-free counterparts fed a "normal" protein diet. That difference alone suggested that proteins contained in food stimulate Treg development. It also hinted that Tregs present in the gut of normal mice might suppress a potentially disastrous immune response to those proteins.

Surh says antigen-free mice are not new, just forgotten, as their prototypes were developed over 30 years ago to study nutrition. "We brought them back because we're no longer in the dark ages: We know a lot more about immunology!" he says. "Decades ago, researchers could monitor changes in lymphocyte numbers but couldn't distinguish between cell types like we can now."

The researchers took full advantage of these technical advances to also demonstrate that food and the beneficial bacteria in the intestine generate molecularly distinct populations of Tregs. Hence, germ-free mice only possess the food-dependent Treg, but not the Tregs that are induced by the healthy microbes. Intriguingly, germ-free mice are known to be highly susceptible to allergies. Hence, Surh hypothesizes that the presence of both food- and microbe-induced populations of Tregs is required to prevent allergic symptoms.

Finally, the team revealed what happens when immune cells fail to ignore harmless antigens. To do so, they transferred "reporter" T cells designed to serve as a read-out for an immune reaction into antigen-free mice and then fed mice a test protein they had never encountered (the lab stand-by, ovalbumin). Those mice mounted a massive immune reaction--what Surh calls the default response-- to ovalbumin relative to germ-free mice fed a normal diet.

This dramatically inappropriate reaction to a nutrient resembled the immunological storm aroused by harmful microbes. Surh's group concludes that it occurred because the antigen-free mice had not readied a population of immunosuppressive Tregs that would normally be primed to dampen an inflammatory response to food.

By extension, the new work could explain why children, who have more limited exposure to different types of novel nutritious macromolecules (that is, food) than adults, are more susceptible to food allergies. It also suggests what happens on a cellular basis as some outgrow it: namely, they may be expanding their repertoire of Tregs that recognize new foods as "safe."

Those issues continue to interest Surh, who in addition to his position at LJI is a director and professor in the Academy of Immunology and Microbiology (AIM) at the Institute for Basic Science (IBS) in Pohang, in Korea. "We are now examining the cellular and molecular details of how the 'default' strong T cell response to food is regulated," he says. "In this context, we plan to pay particular attention to certain foods, such as peanut, egg and other foods that cause food allergy."

What's the Difference Between a Food Allergy and a Food Intolerance?

Food allergies and food intolerances (or sensitivities) can have similar symptoms, but are very different conditions:

  • Intolerances, such as lactose intolerance and celiac disease, can cause someone to feel ill.
  • Food allergies not only can make someone feel ill, but also can cause a life-threatening reaction (called anaphylaxis).

A food intolerance means either the body cannot properly digest the food that is eaten, or that a particular food might irritate the digestive system. Symptoms of food intolerance can include nausea, gas, cramps, abdominal pain, diarrhea, irritability, nervousness, or headaches.

A food allergy happens when the body's immune system, which normally fights infections, sees the food as an invader. This leads to an allergic reaction &mdash a response from the immune system in which chemicals like histamine are released in the body. The reaction can cause symptoms like breathing problems, throat tightness, hoarseness, coughing, vomiting, abdominal pain, hives, swelling, or a drop in blood pressure.

Even if previous reactions have been mild, someone with a food allergy is always at risk of the next reaction being life-threatening. Eating a microscopic amount of the food, or sometimes even touching or inhaling it, could lead to anaphylaxis. So anyone with a food allergy must avoid the problem food(s) entirely and always carry emergency injectable epinephrine.

Many people with food sensitivities, on the other hand, can ingest a small amount of the bothersome food without a problem.

While food sensitivities vary from person to person, there are some common culprits often associated with food intolerance. These include:

Food additives and processed foods like sulfites or artificial color

Beef, pork and lamb (a lot of livestock is raised on corn and soy)

High FODMAPs foods, or fermentable oligosaccharides, disaccharides, monosaccharide and polyols, are certain carbohydrates found in common, often healthy foods and drinks that are fermentable, osmotic, and poorly absorbed, resulting in digestive distress and intestinal gas buildup.

Here are a few examples: dried fruit, stone fruit, cherries, apples, mango, papaya, sour cream, cottage cheese, yogurt, milk from cows, sheep or goats, beans, lentils, squash, garlic, mushrooms, cabbage, broccoli, onions, coffee, high-fructose corn syrup, agave and artificial sweeteners. Sorry, chocoholics, chocolate unfortunately falls into this category as well.

The No. 1 Reason Why Vaccine Reactions Vary, Doctors Say

This is why COVID vaccine side effects range so widely from one person to another.


As the COVID vaccine rollout continues across the country, you've likely noticed how differently people have reacted to their shots—whether they're made by Johnson & Johnson, Pfizer-BioNTech, or Moderna. Some individuals experience side effects that have them stuck in bed for a day or two and others seem to experience nothing at all. So, what does it mean if you're on one end of the spectrum or somewhere in the middle? Keep reading to find out the key reason behind recipients' varying vaccine reactions, and for more vaccine news, This Vaccine Side Effect Could Mean You Already Had COVID, New Study Says.


In an article for The Conversation, Robert Finberg, MD, a professor of medicine at the University of Massachusetts Medical School, explains that your body develops two responses to a vaccine: the initial response is called the innate immune response, but it's the later response, called the adaptive immune response, that helps protect you should you come into contact with the virus later. "The long-lasting adaptive immune response … relies on your immune system's T and B cells that learn to recognize particular invaders, such as a protein from the coronavirus. If the invader is encountered again, months or even years in the future, it's these immune cells that will recognize the old enemy and start generating the antibodies that will take it down," he explains.

As far as how well your body develops these T and B cells, Mark Loafman, MD, told NBC 5 Chicago recently that vaccine reactions are "really just kind of a reflection of how unique each of our systems are." "Each of our immune systems is a mosaic composite of all that we've been through and all that we have and all we've recently been dealing with," he explained. "Our individual response varies. Everybody gets the appropriate immune response."


Chris Thompson, MD, an immunologist and associate professor of biology at Loyola University Maryland, told Healthline people react differently to vaccines for a variety of reasons. He said factors such as health, genetics, nutrition, age, gender, preexisting immunity, environment, and use of anti-inflammatory medicines can all be connected to vaccine reactions. "Even if you don't feel crummy after your vaccines, chances are your body still had a good, protective immune response," Thompson explained.

A 2013 study published in the scientific journal Cell found evidence that suggests genetics play a role in our body's immune response. The researchers looked at approximately 8.2 million gene variants in blood samples taken from 1,629 people in Sardinia, Italy. The SardiNIA researchers found 89 independent gene variants and 53 sites linked to regulating immune system cell production. " From this study, we wanted to know the extent to which relative immune resistance or susceptibility to disease is inherited in families," said, David Schlessinger, PhD, a study author and chief of the Laboratory of Genetics at the National Institute of Aging (NIA). "If your mother is rarely sick, for example, does that mean you don't have to worry about the bug that's going around? Is immunity in the genes? According to our findings, the answer is yes, at least in part."

And for more COVID news delivered right to your inbox, sign up for our daily newsletter.


The most common side effects of the COVID vaccine range from pain, redness, and swelling in the injection site, to tiredness, headache, muscle pain throughout the body, chills, fever, and nausea, according to the Centers for Disease Control and Prevention (CDC). But whether you experience one of these side effects mildly or all of them severely, that doesn't mean the vaccine worked worse or better. Anna Wald, MD, an infectious diseases physician, recently told HuffPost that the vaccine's effectiveness is "unlikely to be determined by how severe your side effects are," the news outlet reported.

In his article for The Conversation, Finberg wrote: "Scientists haven't identified any relationship between the initial inflammatory reaction and the long-term response that leads to protection. There's no scientific proof that someone with more obvious side effects from the vaccine is then better protected from COVID-19. And there's no reason that having an exaggerated innate response would make your adaptive response any better."

And for a more on why certain people are hit harder by the vaccine's side effects, check out This Is Why Half of People Have Stronger Vaccine Side Effects, CDC Says.


In answering a Q&A with, Amy Ray, MD, a director at MetroHealth, said people should not "use the presence or absence of side effects as 'proof' of immunity." "If you don't have side effects, it doesn't mean your immune system isn't working," James Fernandez, MD, an allergy and immunology expert, told the news outlet. "I wouldn't focus on those early side effects related to the vaccine to judge whether you had an [effective] response or not."

Kelly Elterman, MD, a board-certified anesthesiologist in San Antonio, Texas, also explained in a recent article for GoodRx that a lack of side effects doesn't correlate with decreased immunity. "Only about 50 percent of people vaccinated with either the Pfizer or Moderna vaccines experienced side effects other than arm pain, while 95 percent were protected from COVID-19 infection," Elterman wrote. Additionally, less than half of Johnson & Johnson recipients developed side effects other than pain at the injection site, "while up to 74 percent were protected from COVID-19 infection."

And if you're curious as to how long your vaccine works for, Dr. Fauci Says Your COVID Vaccine Protects You For This Long.

Is it a food allergy or an intolerance?

A food allergy is different from food intolerance, although some people may not always know how these vary. A food allergy involves an immune system response by the body, while a food intolerance does not.

A person with a food intolerance cannot digest a substance in certain foods properly, often because they have an enzyme deficiency. A food allergy does not relate to an enzyme deficiency.

The table below shows features associated with either a food allergy or an intolerance.

  • Beans
  • Cabbage
  • Citrus fruit
  • Grains that contain gluten
  • Milk, or lactose
  • Processed meats
  • Eggs
  • Fish
  • Groundnuts, or peanuts
  • Milk
  • Tree nuts (Brazil nuts, walnuts, almonds, and hazelnuts)
  • Soybeans
  • Shellfish
  • Wheat

An immune response or an enzyme deficiency?

Food allergies and intolerances are unwanted reactions to food that some people experience, but they are not the same and happen for different reasons.

Share on Pinterest Nuts are a common trigger food for people with allergies.

Immune response: When a person has a food allergy, their body’s immune system responds incorrectly to a substance known as an allergen.

An allergen is not necessarily a harmful substance. Doctors call them allergens because they trigger an immune system response in certain people. However, allergens do not cause an adverse effect in most people.

According to the United States Food and Drug Administration (FDA) , the following foods are most likely to cause a reaction:

  • milk
  • eggs
  • peanuts (groundnuts)
  • Brazil nuts, walnuts, and hazelnuts (tree nuts)
  • fish
  • shellfish
  • wheat
  • soybeans

Enzyme deficiency: A food intolerance usually means that a person has an enzyme deficiency.

Enzymes are substances in the body that enable people to digest food. If a person has an enzyme deficiency, their body cannot digest certain foods properly. The problematic food depends on the enzyme that is lacking.

Food intolerance may also result from:

  • certain chemicals in foods due to the presence of toxins
  • the natural occurrence of histamine in some foods
  • the presence of salicylates that occurs in many foods
  • specific food additives

Food allergies and food intolerance have different symptoms.

Allergy symptoms

According to the FDA , an allergic reaction to food can cause:

If swelling occurs in the airways, this can make it difficult for a person to breathe. If the airway closes, this can become fatal.

An allergic reaction can happen suddenly. If a person shows symptoms of an allergic reaction, they need medical help immediately.

Intolerance symptoms

The main symptoms of a food intolerance are:

Other symptoms may occur, but the core symptoms relate to a person’s gut.

Some symptoms of food allergy and food intolerance can be similar. This makes an accurate diagnosis more difficult.

If a person reacts to a food, the treatment will depend on whether they have an allergy or an intolerance.


A person with an allergy may have a mild reaction on one occasion and a severe reaction on another occasion. About 20 percent of people with an allergy have a severe reaction.

Anaphylaxis can range in severity from mild to life-threatening. It can happen quickly and is a medical emergency.

The symptoms of anaphylaxis include:

  • skin reactions
  • swelling
  • difficulty breathing
  • a sudden drop in blood pressure

Anyone who knows they have an allergy and may have a severe reaction should carry an injector, such as an EpiPen, that delivers epinephrine, or adrenaline. The should carry two doses in case one is not sufficient.


A food intolerance will not usually need urgent treatment. The best treatment is a long-term plan to manage the problem.

Managing an intolerance usually starts with an exclusion diet. This is when a person avoids a food that may be causing the problem for some time, usually 2 to 6 weeks.

The individual may benefit from keeping a food diary to record whether their symptoms improve. After this, they reintroduce the food and note any new reactions.

People may need to repeat this monitoring with different food items to pinpoint which food is causing the problem.

Sometimes, people can reintroduce a food without any reaction occurring. It may be that they develop a tolerance, or that a small amount of the food does not cause a problem any longer.

Food intolerance varies widely between individuals, and so each case is likely to have its own characteristics. Sometimes, an underlying problem makes the intolerance worse and needs appropriate treatment.


As a service to our readers, Harvard Health Publishing provides access to our library of archived content. Please note the date of last review or update on all articles. No content on this site, regardless of date, should ever be used as a substitute for direct medical advice from your doctor or other qualified clinician.


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Meet MCAS, An Allergic Immune System Disorder Linked To Lyme Disease

Any series of essays written for Lyme Disease Awareness Month would be incomplete without addressing Lyme disease co-infections. Those who live with Lyme disease understand the role of coinfections those who don’t know anything about Lyme other than what the news and federal public health agencies advise (”Check for ticks, and have a nice summer!”) without a doubt need their awareness raised. But before I get into coinfections, I want to talk about a coinciding disorder, mast cell activation syndrome, that is not infectious, but which is a nefarious gift of the Lyme-causing Borrelia burgdorferi bacteria that could last a lifetime. Some of what appears below is a bit technical, but if you know anyone who has been infected with Lyme disease, it could explain many otherwise inexplicable and life-affecting symptoms.

As discussed last week, the nature and even the existence of chronic Lyme disease are hotly debated because (in my opinion) not enough research is being done and despite what parties on either side of the debate say, not enough is known about how and why so many Lyme disease patients end up so ill for so long despite short-term antibiotic treatment.

However, all the way back in 1999, a study published in Infection and Immunity, the journal of the American Society for Microbiology, discussed how Borrelia burgdorferi spirochetes induce mast cell and cytokine release. An even earlier 1990 study from the journal Infection also observed this phenomenon in gerbils that were infected with human isolates of Borrelia burgdorferi. That study concluded:

In short, the bacteria that cause Lyme disease also have been shown to trigger dysfunctional mast cell activation, and mast cell activation causes inflammation that can then bring about a great number of characteristic mild to life-threatening symptoms.

These symptoms are discussed below. but before we get there, it may help to understand exactly what mast cells are and how and why these cells function as they do, and how that may affect Lyme disease patients.

About Mast Cells

Eons ago—well, 20 years or so—in high-school biology classes, I learned about white blood cells. These are the guardians of our bodies. Comprised of a number of different types, including neutrophils, eosinophils, basophils, lymphocites and monocites, which are collectively known as leukocites (”leuko” meaning “white”), these white blood cells search out and destroy invaders. They are the Hungry Hungry Hippos of the immune system, and most infectious agents are nothing but pellets to be gobbled up. Yay, white blood cells!

Let’s watch human white blood cells search out and destroy invading bacteria and viruses.

Having come of age at the height of the HIV/AIDS crisis in the 80s and 90s, there was also a lot of talk on TV about T cells because a primary means by which to gauge the wellness of a person who carries the HIV virus is to count the T cells in his or her blood. If the T cell count is very low, the person’s shields are down and even bacteria, viruses and fungi that are always present in our bodies can become potentially deadly. T cells are manufactured in bone marrow.

But despite what I remember learning, and despite common understanding, the immune system is incredibly complex, as illustrated by this video.

Also manufactured in the bone marrow are a kind of cell I don’t recall ever having learned about in biology class—and it turns out that mine are all out of sorts. At 0:28 in the video above, fifth row, top column, you can see mast cells, whose jobs in the video are listed as “communicate, fight worms, cause inflammation, activate other cells.” The inflammation part becomes highly significant when mast cells release too many histamine and cytokines particles.

Mast cells—”multi-functional master cells” or mastocytes (scientists give us lots of formal and informal labels for everything)—are a primary aspect of our immune systems. They’re a bit complicated to understand, but this is how I picture them in my mind:

When we take capsule pills, we usually only notice the little oblong plastic-y encasement. But have you ever broken one open? (Of course you have!) Once broken, depending on the medication, hundreds of tiny little balls of different colors explode from inside, bouncing and skittering across every surface they hit, some of them rolling away never to be seen again. Mast cells are a lot like that.

Here’s a short video that shows how bee or snake venom would activate a mast cell. The little red balls inside of the cell membrane are histamine granules.

Mast cells contain a number of different tiny granulated chemicals, including histamine, heparin, cytokines, and others. When released, these are the agents of inflammation.

Most of us are familiar with the term antihistamine—Benadryl, Claritin, Allegra fall into this category of medication. Antihistamines help to inhibit mast cell degranulation, the process by which mast cells explode or dissolve and set their little chemical babies free. When we have seasonal or food allergies, what’s really happening is that some kind of substance that our bodies are exposed to holds the key that unlocks mast cells and causes them to degranulate.

Mast cell degranulation serves important roles in our well being. When histamines are released, for example, they cause inflammation, signaling the immune system to go into attack mode. That’s great when the body has to attack a foreign invader. It’s not so great when immune cells get their own “brain fog” (It’s an analogy please don’t write to point out that cells don’t have brains.) and start attacking the body’s own native cells. And inflammation is meant to be a short-term battle mode, not a constant, chronic state of being. When there’s too much inflammation for too long, our bodies can’t operate as they are supposed to operate. Often, this type of dysfunction is due to a mast cell disorder.

Mast Cell Disorder Symptoms

When mast cells don’t function as they should, a wide range of allergic symptoms may occur, including flushing (skin that turns red or purple and becomes hot to the touch), itching, gastrointestinal problems including pain and acid reflux, and most dangerously anaphylaxis.

As you can see above, mast cell activation disorder symptoms are almost as broad, multi-systemic and variable as Lyme disease symptoms. Some of the symptoms, particularly the neurologic, cardiovascular and systemic ones, can be indistinguishable from Lyme disease symptoms. Some are specific.

A lot of people who have Lyme disease complain that the internal nature of their symptoms makes it difficult for anyone to believe that they actually have an ailment. Lyme is known as an “invisible disease,” as many other chronic illnesses are. People who have co-occurring mast cell disorders have visible signs.

This is what happens to my arm when I wear a ribbed sweater:

Don’t think people don’t notice when your skin does that freaky texture-changing thing that octopuses do.

Not only that, but this is what happens if I very lightly scratch letters on my arm with a dull pencil:

Within five to 10 minutes, mast cells break apart where I scratched my skin, causing inflammation. The letters aren’t only red, but puffed up. This allergic phenomenon is known as dermatographic (”skin writing”) urticaria (hives). If I went to parties, it would be a neat party trick. It has been a neat (albeit disgusting to most people) office trick. But it’s not all fun and games. Shortly after the dermatographia appears, hives are triggered generally throughout the body, and I break out in red welts on my legs, my arms, etc.

These are symptoms fairly specific to mast cell disorders. Other unusual symptoms include flushing—skin turning red and hot in response to stimuli—and anaphylactic reactions to heat and exercise.

I am allergic to exercise now. If I break a sweat, I almost always break out in hives. That’s annoying. Much more troublingly, I also become dizzy and lightheaded and sometimes have difficulty breathing. That last one can be deadly—although I’ve lived with this for years and never knew it. I thought I was just out of shape and couldn’t catch my breath after 15 minutes of cardio.

But then beyond just mast cell symptoms, when I overheat in the summer, or from exercise, or even from a hot bath, I also sometimes get Parkinson’s-type tremors—sometimes extreme ones (Imagine Katharine Hepburn in a helicopter.)—double vision and other disturbing symptoms that go away when I cool down. If living with one chronic illness is a challenge, having more than one at once is, well, a greater challenge.

In any case, if you have dermatographia or break out in hives while you’re exercising, you should probably look into mast cell problems.

Same Symptoms, Different Disorders

There are two different types of mast cell disorder: mastocytosis and MCAS.

Mastocytosis is a disease in which for largely unknown reasons a patient has more mast cells than usual gathered in one or more organ systems. As a result, when mast cells are activated, the presence of a greater number of mast cells causes a greater release of histamines, cytokines, etc., and that causes greater inflammation than an average patient would experience. Mastocytosis is further broken down into three different types, cutaneous mastocytosis (primarily affecting skin), systemic mastocytosis (present in bone marrow), and mast cell sarcoma, which is very rare and as described in the medical journal Modern Pathology “bizarre.” More about mastocytosis.

Mast cell activation syndrome/disorders, or MCAS/MCAD, are very similar to mastocytosis but patients diagnosed with MCAS don’t fulfill all the criteria for a mastocytosis diagnosis. According to the Mastocytosis Society, three criteria must be met for an MCAS diagnosis:

  1. Specific symptoms, including flushing, itching, hives, low blood pressure and others
  2. Increased serum tryptase (a simply blood test) levels or urine prostoglandin levels and
  3. Improvement of symptoms when treated with antihistamine-based protocols.

A bone marrow biopsy is required to differentiate between mastocytosis and MCAS.

What About Lyme?

As discussed at the beginning of this article, decades-old research observes that mast cells can be triggered by Borrelia burgdorferi infections to flood the body with histamine, which then causes inflammation and MCAS symptoms. Since the criteria for diagnosing MCAS are relatively simple—unusual and easily identifiable symptoms, a blood or urine test, and response to antihistamine treatments—Lyme disease patients who have any characteristic symptoms may be able to find relief for many of them with proper diagnosis and over-the-counter antihistamine treatment that, to the relief of many Lyme patients, should not be controversial in any way.

I’ve simplified (and hopefully not too egregiously misstated) these complex and still little-understood conditions. Patients who believe they may have a mast cell disorder might want to print out this article, including this table of diagnostic criteria, and bring them to their doctors for consultation.

If you think you may have a mast cell activation disorder, invest the time in watching this video and the video below.

Find me (and say hi!) on Twitter @Artistlike.

If you’d like to see more in-depth research about Lyme and associated tickborne diseases, please consider supporting my work via Patreon.

Why is there a distinction between an *allergic* and an *immune* response? - Biology

A food allergy can be a terrifying thing. When someone eats even a small amount of a food to which they are allergic, a minor reaction can involve itching, swelling, and stomach ache. But one in four people unlucky enough to have a food allergy, even a mild one, will at some point experience a severe reaction: anaphylaxis, a state of shock defined as a reaction involving two of the body's organs, is characterised by symptoms like wheezing, dizziness and vomiting. The pulse can slow, blood pressure can drop, and the airways can close. In an alarming number of people in the last few years, it has been fatal.

More of the population has food allergies than ever before – and around the world, they are sending more and more people to hospital. One large-scale review of hospital admissions data found anaphylaxis cases on the rise in the US, Australia and Europe, among other regions. In the US, hospital visits for food allergy increased threefold from 1993 to 2006. Between 2013 and 2019, England saw a 72% rise in the number of hospital admissions for children caused by anaphylaxis, from 1,015 admissions to 1,746.

“That food allergies have risen is unquestionably the case, to an absolutely crazy extent,” says Graham Rook, emeritus professor of medical microbiology at University College London.

One theory behind the rise has been that we’re simply more aware of food allergies. But Kari Nadeau, a Stanford University allergy specialist who calls the rise an “epidemic” in her new book The End of Food Allergy, says this isn’t the case. “It's not just because we're getting better at diagnostics, because we're actually not,” she says. “We are becoming more aware of it, but that's not increasing the diagnosis.”

It’s difficult, however, to pinpoint just how much food allergies have risen. Three to four times as many people think they have a food allergy as actually do, making self-reported data difficult to trust. Much of this is because food intolerance and food allergy can be confused. Meanwhile, many countries have no data on food allergy prevalence. Furthermore, the “gold-standard” test for a food allergy – which involves feeding a small amount of the food to the person in question in a clinical setting – is time-consuming, costly, and comes with risks.

Three to four times as many people think they have an allergy as actually do (Credit: Getty Images)

Nevertheless, looking at data from multiple peer-reviewed sources, Nadeau says that the rate of food allergies worldwide has increased from around 3% of the population in 1960 to around 7% in 2018.

And it isn't just the rate that has increased. The range of foods to which people are allergic has also widened. Peter Ben Embarek works for International Food Safety Authorities Network, a World Health Organisation body that responds to food safety emergencies. “Initially, decades ago, it was only the classical ones: seafood, milk and nuts,” he says. “That has expanded dramatically to a whole range of products now.”

Experts agree that food allergies are on the rise. The question is, what explains it?

One explanation goes by the name the “hygiene hypothesis”, although the phrase itself is now given a wide berth by allergy experts. “The 'hygiene hypothesis' is an appalling name because it gives everyone the wrong idea about what's going on,” says Rook. It would imply that the cleaner we are, the more likely we are to contract allergies. But that’s not quite right.

The theory was postulated by epidemiologist David Strachan, who observed in 1989 that children with older siblings are less likely to get hay fever and eczema. “Over the past century,” he wrote, “declining family size, improvements in household amenities, and higher standards of personal cleanliness have reduced the opportunity for cross-infection in young families.”

Children who have older siblings are less likely to get hay fever and eczema (Credit: Getty Images)

But many scientists now disagree with the theory – and recent research contradicts it. Rook points out that getting the common infections of childhood makes you more likely to have asthma. And experts agree that it is vital to maintain good hygiene to guard against disease.

A more modern interpretation of the hypothesis is that it doesn’t have to do with whether you keep your home clean or not, but rather with whether your gut is encountering different types of microorganisms. (Read more about what we do and don’t know about gut health.) “The reason that having older siblings was actually a good thing was because that increases your likelihood of meeting the microbiota of the family and in particular the microbiota of the mother,” Rook says. In doing so, you populate your gut with microorganisms that “educate” the immune system.

This is one of the reasons that there could be a link between food allergy and babies born by caesarean section: not emerging through the birth canal means that the baby does not ingest the useful bacteria there. In Denmark, it was even proved that the more cats and dogs you have, the less likely you are to have an allergic disorder.

Owning a cat or dog may lower your risk of developing an allergy (Credit: Getty Images)

Rook coined the phrase “old friends” to describe his theory. Humans' microbiota – the microorganisms of a particular habitat – are slowly changing, he says. Our modern homes, with their biocide-treated timber and plasterboard, have microbiota that bear no relation to that of the outside world in which we evolved. We are therefore meeting fewer of the friends – the microbes of old – that helped our immune system respond to foreign substances. This may also be why, for example, there is good evidence that the more antibiotics someone is given as a child, the more likely they are to have a food allergy the antibiotics kill the healthy bacteria that colonise our gut.

“The rise of allergies we see is a part of a more generalised phenomenon of a failure of the control mechanisms of the immune system,” says Rook.

Aside from our “old friends”, another fascinating theory is dual-allergen exposure.

To explain dual-allergen exposure theory, it is worth exploring a detour into the way that food allergy advice has changed over the years. “When these food allergies started appearing [in the 1990s], people got very worried about people introducing peanut into babies' diets,” says Clare Mills, a professor of molecular allergology at England’s University of Manchester. “And we actually ended up with guidance that said, 'Don't give these foods to your baby until they're three years old'.”

This advice, she says, wasn't really based on any evidence. In fact, parents should have done the very opposite: introduced allergenic foods as early as possible.

Rather than not giving peanuts to children, parents should have introduced allergenic foods as early as possible (Credit: Getty Images)

The reason is that just because an infant does not eat peanuts does not mean that they won't encounter people who have. The child can be exposed to peanuts through dust, contact with furniture, and even creams containing peanut oil. If the child has not eaten peanuts, this contact with the skin can trigger a response from their immune system.

“If you've got a little infant with early-onset eczema and the parents are eating peanuts without washing their hands and then handling the baby, the baby can get sensitised through the broken skin,” says Amena Warner, head of clinical services at Allergy UK. When the child then eats the food, the immune system perceives it as a threat and attacks. Nadeau has turned this wisdom into a memorable rhyme: “Through the skin allergies begin through the diet allergies can stay quiet.”

This is why, especially for children with eczema, experts are unanimous: a diverse range of foods should be introduced through weaning from around three or four months of age. “There is this window of opportunity in the early years to establish tolerance,” says Alexandra Santos, an associate professor in paediatric allergy at King's College London. She helped demonstrate through a Learning Early About Peanut Allergy study that introducing peanuts between four and 11 months gave five-year-old children an 80% lower chance of having peanut allergy.

Children like 17-year-old Trece Hopp, who has a severe tree nut and peanut allergy, often keep an EpiPen on them at all times (Credit: Calla Kessler/Getty Images)

It might seem to follow that eating peanuts in pregnancy could protect children even further. But how much the prenatal environment affects allergy development remains unknown. In 2000, the American Academy of Pediatrics cautioned women against eating peanuts in pregnancy. In 2008, however, after a wide range of studies failed to find a conclusive link between prenatal diet and food allergies, the Academy changed tack and said that there was no persuasive evidence that pregnant women should either avoid or favour potential allergens.

That food allergies vary according to environment is proven by the absence of peanut allergies in countries where the population barely eats peanuts: the huge EuroPrevall study, which investigated the environmental, dietary and genetic influences on food allergy across Europe, found that peanut allergy in Greece, where they eat very little peanut, was 0%. Santos says that when people emigrate, they are more vulnerable than natives to food allergies probably because of the difference in their genes. The earlier they emigrate, the more vulnerable they will be.

Another factor could be vitamin D. Are we suffering higher food allergy rates because we are spending more and more time indoors, depriving ourselves of vitamin D, which plays an important role in the development of the immunoregulatory mechanisms? Here the evidence is ambiguous. Some studies have demonstrated a link between vitamin D and modified food allergy risk (here, here, and here) but researchers in Germany found a positive association between maternal vitamin D levels and the risk of food allergy before the age of two another German study found that infants with higher vitamin D rates at birth were more likely to have developed a food allergy by the age of three. “It may be a Goldilocks scenario,” Nadeau writes in her book. “Both too little vitamin D and too much vitamin D are problematic.” (Read more about whether everyone should be taking vitamin D.)

Both too little, and too much, vitamin D may contribute to allergy risk (Credit: Getty Images)

Trials and questions

The many unknowns leave a quandary for researchers hoping to develop better treatments for food allergies: Is it better to supply a full, healthy microbiome, or to replenish just a few helpful microbes? &ldquoI scratch my head every day thinking about this,&rdquo Rachid says.

She&rsquos leading a clinical study to test the first possibility. In this small trial, adults with peanut allergies will swallow pills containing a full slate of gut bacteria from healthy donors pre-screened for safety by the nonprofit stool bank OpenBiome. The approach, known as fecal transplantation, is not FDA-approved but is increasingly used to treat severe intestinal disorders with the aim of fixing diseased microbiomes by infusing healthy, balanced ones.

Other trials are also underway. Using the protective strains identified by the Boston team, Pareto Bio of La Jolla, California, is developing a live microbial product to treat food allergies. Another company, Vedanta Biosciences of Cambridge, Massachusetts, is developing a probiotic capsule that contains a mix of Clostridia strains selected for their ability to induce regulatory T cells. Vedanta is testing the capsules as an add-on to oral immunotherapy in adults with peanut allergies.

A third company, Prota Therapeutics of Melbourne, Australia, is commercializing a similar strategy combining peanut oral immunotherapy with a probiotic&mdashin their case, a Lactobacillus strain commonly prescribed for gastrointestinal problems.

Administering whole microbiomes from donors is not without risk: Four patients have been hospitalized, and one died, from serious infections linked to stool transplants. So some researchers think it may be better to use precisely defined species. Though this risks weakening the benefit, &ldquoyou&rsquore less likely to induce unanticipated problems,&rdquo says Wayne Shreffler, who directs the food allergy center at Massachusetts General Hospital in Boston and is leading the Vedanta study.

But there&rsquos one challenge shared by all microbiome-modulating approaches: getting new microbes established when someone already has a microbiome in place, even an unhealthy one. Traditionally, patients receive antibiotics to help new bacteria gain a foothold. But maybe there&rsquos another way. A start-up that Nagler cofounded with University of Chicago biomolecular engineer Jeff Hubbell&mdashClostraBio&mdashis developing a therapy that combines live bacteria with a key microbial metabolite, butyrate.

The chemical is known to enhance gut barrier function and may also have antimicrobial effects, which could help create a niche for the added microbes. ClostraBio plans to launch its first human trial by 2021, Nagler says.

Over the next few years, researchers will learn more about harnessing the microbiome to fight food allergies. It won&rsquot be easy. Genetics, diet, environmental exposures: All influence allergy risk. &ldquoIt&rsquos a big puzzle,&rdquo says Bunyavanich. The microbiome is only one piece of it&mdashbut she, Nagler and others are betting it will turn out to be a big one.

This article originally appeared in Knowable Magazine, an independent journalistic endeavor from Annual Reviews. Sign up for the newsletter.


Esther Landhuis is a freelance science journalist in the San Francisco Bay Area.


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