What causes allergies and autoimmune disease? /  Getting Stronger

What causes allergies and autoimmune disease? /  Getting Stronger

Tags: , , , , , , , , , , , , , , , , , , , , , ,

Posted 26 Mar 2013 in Health, Hormesis


Allergies and autoimmune disease are reaching epidemic proportions — not just in the U.S. and Europe, but in the rest of the industrially developing world.  Asthma, celiac disease, Type 1 diabetes, arthritis, multiple sclerosis, lupus — all are on the rise. Even certain conditions not previously considered immune disorders, such as autism, metabolic syndrome and obesity, are now seen as manifestations of immune dysfunction.

What caused all this?  Can the epidemic be reversed?  And what can you do if you suffer from asthma, allergies and autoimmune disease?

Many who follow this site are generally sympathetic to the “paleo” hypothesis: namely, that allergies, autoimmune disease , and other degenerative diseases are the spawn of neolithic agents — such as wheat and other grains, and legumes, introduced during the transition to an agrarian society  about 10,000 years ago.  These neolithic foodstuffs expose us to higher levels of carbohydrates and novel proteins and anti-nutrients — such as gluten, phytic acid and lectins — that our evolutionary history as primates did not adapt us (or at least many of us)  to tolerate.   There is a lot of evidence to support this idea — from archeology and comparative anthropology, to studies in genetics and immunology.

But is it true?

There is an alternative explanation that has now been put forward, based upon a revolution in immunology during the past decade.  Like the paleo hypothesis, this new theory is grounded in evolutionary biology, and it likewise sees our modern lifestyle as an evolutionary anomaly.  But this new perspective places the advent of the twin epidemics of allergy and autoimmunity — and more generally inflammatory disorders — not at the introduction of agriculture, but much more recently:  at the upswing and aftermath of the Industrial Revolution. And it identifies the causal agent not as the addition of neolithic foods, but rather the subtraction of a key protective factor that we’ve lived with since the beginning of human evolution, or even mammalian evolution.

The agent of our immunological misery is the disappearance of something we co-evolved with in a mutually beneficial relationships:  microbes and parasites that have lived inside our bodies for millennia.

This new hypothesis is brilliantly summarized in a recent book by Moises Velasquez-Manoff:  An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Disease.  In 307 pages the author, a science writer, synthesizes a diverse range of research, interviews and adventures into a detective novel that ends with a quest to treat his own rare autoimmune disorder.  The book is both compelling and honest in probing both the promise and the limits of the arguments and evidence for this new perspective on practical immunology.

This new view leads to some unorthodox ideas about how to combat allergies and autoimmune diseases.  Some of the ideas being tested may seem wild to you.  But I’ll end with one very safe recommendation that makes good sense to me now, despite earlier doubts, and which I’ve already implemented with great gusto.

Too clean?  The message of this book may sound familiar to you:  It has the ring of the  ”hygiene hypothesis”: the thesis that our twin epidemics of allegy and autoimmunity arise from an environment that is in some sense “too clean”.  I discussed the hygiene hypothesis two years ago in my post “Allergies and hormesis“.  There, I summarized research indicating that the allergic response represents an over-reaction by an immune system that was not adequately “educated” by exposure to foreign environmental substances like bacteria, parasites, dander and proteins — particularly during early childhood.  As I wrote,
The adaptive immune cells (B and T) cells develop normal responses only if they are stimulated by exposure to foreign substances…Children get primed with IgG antibodies from their mother and IgA antibodies from breast milk which provide “passive” immunity for the first two years of life.  After that, children need to begin activating their own adaptive immunity – their own IgMs and IgGs….If this process of educating the adaptive immune system is not sufficiently activated in early childhood, the immune system of the adolescent or adult remains underdeveloped.  Then the response to foreign bodies relies more on the “emergency” system, using IgE antibodies instead of IgG, IgA, or IgM antibodies. It is these IgE antibodies that tend to overreact, causing allergies. Essentially, an “under-trained” adaptive immune system, such as that of someone raised in a sterile environment, is more prone to confuse harmless foreign bodies like pollen, dog hair, peanuts, eggs, or insect venom, for parasites. Their IgEs become sensitized towards these allergens, attach themselves to the mast cells on mucous membranes or beneath the skin.  Once the allergen reappears, a full-blown chemical attack, including histamine release, is initiated.
Stated this way, the hygiene hypothesis has a certain plausibility to it.  As a broad explanation, it makes sense.  But it doesn’t explain certain things:
  • images-1
    Children who grow up in cities have triple the rate of allergies as those who grow up on farms. Allergies are rising in urban environments where children are exposed to dust mites and dander even at an early age.  Why doesn’t that early exposure to allergens suffice to “prime” their adaptive immune systems ?
  • Even if one grants the role of a cleaner environment, people respond in different ways.  Why do some people get specific allergies, and others develop certain autoimmune diseases?  What explains the differential response that leads to asthma, celiac disease, or multiple sclerosis?
  • The rise of obesity, cardiovascular disease and metabolic syndrome parallels the rise of immune disorders.  Can these be linked to a common cause?
Co-evolution. Velasquez-Manoff rescues, refines and elevates the hygiene hypothesis, putting it on firmer ground by framing it in the context of a key insight about our evolution.  Our long evolutionary history inextricably entwines us with a diverse set of microscopic companions who have been along for a long ride.  These companions are a collection of microbes, parasites and viruses who have been fellow travelers travelers from our earliest origins.  These infection agents have at times caused illness and death, and our immune systems defend us against them with varying effectiveness.
But here’s the new insight:  they’ve been with us so long, that we now depend upon them.  And removing them from the scene has harmed us. That sounds strange.  How can removing an “enemy” be a bad thing?  It could be, if the enemy is a recent invader.  But what if you have lived with the “enemy” for a very long time?

One of the protagonists of “An Epidemic of Absence” is University College London immunologist Graham Rook.  In the book, Rook is described as the “godfather” of the hygiene hypothesis, recasting it in a new, more accurate and more interesting light:
In the late 1990s, he insisted that the then-dominant model of immune function–two immune response types, the pursuit of microbes and the repulsion of parasites, cross-regulating each other–was incorrect. A third peacekeeping arm, which prevented both autoimmiune and allergic disorders from arising, was key–a view that has since achieved orthodoxy. (Epidemic, p. 110).
This third “peacekeeping arm” — a kind of police to oversee the police — is made up of regulatory T cells, called “T-regs” for short.  The first line of B and T cell immune cells work by activating an inflammatory response that goes after invading bodies.  While effective, this inflammatory can get out of hand and inflect collateral or “friendly” fire.  T-regs provide an anti-inflammatory response that keeps the first responders in check.

Finding the emphasis on “hygiene” misleading, Rook rechristened the hygiene hypothesis the “old friends” hypothesis.  Major infections don’t help the immune system, he argues.  If anything, acute inflammation makes things worse. A very specific group of organisms meets the “old friends” criteria–organisms that have accompanied us since the Paleolithic.  That includes worms, cowshed-type microbes, lactobacilli, and our own fecal bacteria. It doesn’t include, however, measles and your everyday cold virus.  Evolutionarily speaking, these are latecomers. They arrived after the domesication of animals, and after humans had aggregated in crowds sufficient to sustain them. (Epidemic, p. 110-111).
The list of “old friend” organisms–”house guests” with whom we’ve coevolved long enough to develop a mutually beneficial relationship–includes parasites like hookworms, parasitic bacteria like mycobacteria (including M. tuberculosis), Helicobacter pylori, and saprophytes — nonparasitic “pseudocommensals” that are ever-present in  dirt and (unfiltered) water.

Outsourcing immune regulation. But how did these foreign organism come to be welcome residents, rather than invaders to be repelled in defense of the homeland?  Graham Rook responds to this question with two pithy phrases:
  • “Coevolution leads to codependence”
  • “Evolution turns the inevitable into a necessity”
The principle here is well known in other contexts of evolutionary biology.  As Rook explains, if some helpful or harmful element in the environment is always there, a species will evolve a way adapt to it. He uses the example of Vitamin C, which many species synthesize for themselves because it is essential.  At some point in our pre-evolution, our primate ancestors had round-the-year access to vitamin C rich fruits, and hence lost the ability to manufacturer it for themselves.  It saves energy to stop making something you can get without effort, so we lost the genes to make our own vitamin C.
Now what happens when we are exposed to a constant stressor — be it UV rays, toxins in plants, or microscopic invading organisms?  As Velasquez-Manoff explains:
Contact with another organism–saprophytes say–develops your immune regulatory circuits. Over evolutionary time, the ability to regulate immune function yourself dulls or disappears. Losing this capacity incurs no immediate cost, however. Saprophytes are ubiquitous, and contact with them is unavoidable.  Nonetheless, you’ve outsourced your immunoregulation to microbes. Now you’re dependent on them. (Epidemic, p. 113)
To avoid dependence on any single organism, we prudently outsource the “job” of teaching immune tolerance to a diverse set of organisms in our environment.  So if any single organism disappears, our immune system continues to function in a balanced way.
The “old friends” help us out by activating our regulatory T-cells to dampen or blunt the primary inflammatory response .  In that way, these organisms have taken on the job of “policing the police” within our immune systems.  They have literally become an part of our immune systems, just as our digestive bacteria are essential to our gaining nutrition from our diet.
But this evolutionary strategy didn’t anticipate what would happen if we suddenly lost all or most of these old friends that help keep our immune function balanced!

The Industrial Revolution.
 Until the last few centuries–when most humans lived as hunters,  as farmers, or in small settlements–our immunological reliance on cohabiting microbes and parasites involved  redundancy. We weren’t dependent on any single organism.  But then two dislocations took place.  First, industrialization brought with it an intense urbanization and crowding that resulted in the spread of infectious disease.  We are all familiar with the epidemics of tuberculosis, pneumonia, influenza, polio and other diseases that felled millions, often in early childhood.
The scourge of these infectious pandemics led to advances in sanitation and medicine which significantly tamed infectious diseases.  Without question, society has benefited from greatly reduced child mortality, and significant increases in average longevity.   Not all is rosy, of course.  The widespread use of antibiotics has to some extent tempered this success by giving rise to antibiotic resistant organisms.  But there is widespread acknowledgement of the resistance problem, and efforts are made to be more selective in prescribing antibiotics.
Yet if Rook and his fellow immunologists are right, there is a much more serious consequence to the widespread eradication of microbes and parasites during the last two centuries.  Connecting the dots, this eradication of microbiotic diversity is at the root of the meteoric rise in asthma, allergies and autoimmune disease.
Puzzle pieces.  In this blog post, I can’t adequately summarize the masterful job that Moises Velasquez-Manoff did in piecing together the evidence that supports the “old friends” version of the hygiene hypothesis.  For that, you’ll have to read the book. But I will tease you here with some particularly compelling pieces of the puzzle:
  • The Finns.  Karelia is an ethnically Finnish region of Russia, separated from Finland after the World War II.  Finland has one of the highest rates of asthma and autoimmune disease in the word, while Karelians have one-seventh that rate  – similar to that of pre-war Finland.  Finns and Karelians have similar consumption of wheat, sun exposure, vitamin D blood levels, and pollution.  Urbanization is actually slightly higher on the Russian side of the border.  So you can’t blame those factors! The biggest difference is much higher infection by organisms like H. pylori, T. gondii, hepatitis A, and far higher exposure to saprophytic microbes found in unfiltered drinking water. ( p. 114)
  • Farm mothers.  Studies of pregnant women in cultures as diverse as Sweden and Uganda show that the amount of time spent farming while pregnant strongly correlates with increased regulatory T-cells and reduced allergies in their children. While maternal exposure to most infections increased inflammation and allergies, the presence of lactobacilli or parasitic worms decreased allergy in their offspring. Deworming Ugandan mothers resulted in more allergic offspring.
  • Urban allergies.  If the hygiene hypothesis is right that “dirty” environments reduce allergies, why are allergies on the rise among the urban poor? The answer is that urban homes have plenty of allergens, but a relative lack of protective microbes that moderate the immune system.  Dust mites, fleas and cockroaches found in urban slums are “external” invertebrates  that don’t invade us and live inside us, and thus cannot “engage” our immune regulation circuits.  They prompt the IgE response meant to repel invading species, without the temperance induced by microbes, parasites and viruses that have co-evolved with us. (p. 96).
  • Celiac disease.  Studies of children with celiac disease find that their gut microbiota are higher in gram negative bacteria and deficient in bifidobacteria and beneficial clostridia that boost T-regs.  Elimination of wheat from the diet doesn’t appear  to alter the balance of gut microbes.  Transplantation of microbiota from humans into rats induced leaky gut.  Adding bifidobacteria from a healthy nursing infant blunted the toxic symptoms gliadin in celiac sufferers. (pp. 173-174)
  • images-2
    Peanuts and other food allergies.
    Whether a food is tolerated or becomes an allergen depends upon whether it is first encountered by oral ingestion or by external skin contact.  When oral ingestion comes first, tolerance is induced. But skin contact prior to ingestion induces allergies.  The rise in peanut allergies in Britain has been traced to the use of skin creams for diaper rash that contained peanut oil.  Mice lathered with egg protein became asthmatic; but not if they ate the egg first.  Some proteins cross-sensitize, so soy based creams can also sensitize to peanuts.  The basis of immunotherapy is to build up tolerance gradually through sublingual exposure; it doesn’t work to build up by exposure on the skin.
  • Autism and Schizophrenia.  Evidence in humans and monkeys points to inflammation of the brain during pregnancy as a primary cause: “chronic, low-grade inflammation predisposes to autism; sharper acute inflammation like that accompanying an infection predisposes to schizophrenia. When the inflammation occurs during gestation influences the outcome.”  The decline of infectious disease has tracked the decline of schizophrenia and the rise of autism.  The inflammation can have many causes.  But all autistic children have low T-regs and abnormal gut microflora, particularly desulfovibrio, bacteriodetes and propionibacteria. Helminthic therapy — infection with hookworm — has shown dramatic benefits in improving autistic symptoms of many autistic children. (pp. 214-238).
  • Multiple sclerosis.  The etiology of MS is uncertain, and likely involves a complex interaction of infection, environment and genetics.   Velasquez-Manoff focuses on evidence for the role played specifically by the Eppstein-Barr virus (EPV).  While almost all adults have the EPV as a silent infection, the vast majority of us get exposed as children and are asymptomatic.  EPV appears to cause MS specifically in individuals not exposed until their teens or twenties.
    Deliberate infection with helminths has been shown to modulate EPV and put MS into remission
  • Metabolic syndrome and obesity.  Many foods are blamed for obesity, diabetes and other symptoms of metabolic syndrome. A “junk food” diet has been shown to flush out bifidobacteria and othe probiotics, and foster the growth of inflammatory gram negatives like E. coli and C. difficult.  Conversely,  studies show that the presence of  ”good” gut bacteria or parasites appears to protect against from obesity and insulin resistance, even when eating poorly.  In mice studies, protective parasites didn’t “steal” calories from the host, but interfered with the inflammatory response by prompting macrophages in the intra-abdominal fat to switch from being “pro” to “anti” inflammatory.   “Fecotherapy” –fecal transplants of gut microbes from lean humans to obese ones–caused them to lose weight and reverse insulin resistance, at least temporarily, without switching diets. (pp. 246-248)
To summarize:  The rise of allergy and autoimmune disease is not an evolutionary accident or  malfunction.  These disorders aren’t the consequence of novel substances in our environment.  Rather, they are the result of an unprecedented disappearance of an important part of our immune system — the friendly organisms with which we’ve co-evolved, and to which we had outsourced the regulation or our inflammatory immune response.  While we might not depend on any single organism, never before in our evolutionary history have our bodies and our daily environment become so devoid of these helpers.  The result is that we are increasingly victims of an overactive and unmodulated inflammatory response that often shows up as friendly fire against our own tissues.
Hopes and treatments.  Understanding causality doesn’t automatically lead us to effective treatments.  It may well be true that removing parasites and diverse intestinal microbes from our midst has provoked the current epidemic in autoimmune disease, allergy and other manifestations of an under-regulated immune system.


But that doesn’t mean that re-introducing these “old friends” will always reverse these conditions, or that it is yet possible to use deliberate infection as a therapy.  All these infective agents can be double-edge swords. Moises-Velasquez notes the importance of timing in the nature and effectiveness of how bacteria, viruses and parasites “educate” and moderate the inflammatory tendencies of our immune systems.  Timing is key!  Early exposure to Eppstein-Barr virus, Helicobacter pylori, and M. tuberculosis can be protective, whereas too late exposure can cause autoimmune disease, cancer, and respiratory disease.

There is an emerging field of “helminthic therapy” much of it underground.  People are deliberately infecting themselves with hookworms and other parasites,  encouraged by the developing science, but equally out of desparation.  The successes are many and are impressively documented in his book. But Velasquez-Manoff honestly reports on those who fail to respond or suffer setbacks — including his own experiences using the worm Necator americanus to largely banish his hayfever, yet produce only minor improvement in his alopecia universalis, a rare autommune disease that attacks body hair.

What would I do?
 I’m fortunate not to suffer from asthma, allergies or autoimmune disease.  Yet these conditions are prevalent among friends and those close to me — my wife has multiple sclerosis.  So it’s not just an academic question. The science is exciting, and I intend to follow it.  But it’s still early days. I’m not so adventurous yet as to advocate or try helminthic therapy, fecal transplants — and certainly not deliberate infection by viral agents.  I’m not that much of an early adopter.
But there is one practical insight I take from Graham Rook’s “old friends” hypothesis:  the idea that in our long evolution, we outsourced our immune regulation not to any single organism, but to a diverse network of microbes, parasites, and viruses that live within us.  Which means that there are probably many different organisms and combinations of organisms that we turn to in achieve immune moderation.

For that reason, I think the safest and robust set of microbial helpers may be those in our  gut — our microbiome. We frequently hear that the bacteria in our intestines outnumber all the other cells in our body by a factor of ten.  More importantly, the genetic diversity and metabolic pathways provided by gut bacteria outstrips that of our human cells.  So why not take this seriously and pay more attention to the microflora that live in our intestines?

Gut health.  It is increasingly apparent that the composition of bacteria in out gut has major effects on our health.  Shifting the gut population away from pro-inflammatory species like bacteriodetes and towards anti-inflammatory species like bifidobacteria and lactobacilli has systemic benefits that appear to tip that balance away from metabolic and immune disorders and towards health. These beneficial microflora have been shown not only to help police the immune system, but to keep the intestinal barrier intact and reduce the risk of diabetes. In addition, these good bacteria convert this indigestible fiber into short chain fatty acids like butyrate that not only provide a sustained sourced of energy, but support the health of the intestinal lumen.  Ironically, you could say that a high fiber vegetarian diet is a “high fat” diet!

While “transplants” may be a dramatic way to colonize the gut with the good bugs, I’m most impressed by a simpler route:

We should be sure to include ample amounts of prebiotic fiber in our diet

A year ago, I never thought I would advocate a high fiber diet.  I thought of fiber as inert “roughage” , or a means of  reducing the glycemic index of fruits and other carbohydrate rich foods, by slowing the release of sugars during digestion.   But now I see fiber through entirely different eyes:  as “food” required by the microbes we co-evolved with and rely upon intensely for our health.  The most important type of fiber is soluble fiber, particularly fructooligosaccharides and other non-starch polysaccharides that we can’t digest without the aid of bifidobacteria, lactobacilli and other beneficial bacteria.  To ensure a robust colonization of our gut by these microbes, we don’t need to “eat” them as probiotics and yogurts or transplant them through the rear end.  The most natural way to colonize your gut is to feed them by eating a high fiber diet, and to minimize the sugars that lead to intestinal “blooms” of deleterious bacteria like E. coli and C. difficult — which you might think of as “intestinal weeds”


In recent months, I’ve significantly increased the volume of green, leafy cruciferous vegetables in my diet — such as kale, broccoli, brussel sprouts;  colored and bitter fruiting bodies like red and green peppers, herbs and spices like curcumin.  The original impetus was a natural way to add polyphenolic phytonutrients that activate the endogenous antioxidant enzyme systems — as I discussed in my post, The case against antioxidants.  But my newer reason for doing this is to keep the “old friends” in my gut happy and working on my behalf.  Other than basing this decision on the science, I can’t yet point to personal benefits of this regimen, other than limitless energy, no cravings, and a virtual absence of post-workout soreness or pain.

So we come back to a “paleo” diet,  replete with healthful meats, fish, and nuts —  and abundant with green and colored fibrous plants.  But the justification for such a diet is not the traditional paleo line of avoiding ”novel” toxins and antinutrients in grains, starches, and processed foods, so much as it is one of fortifying our defenses by feeding the peacekeeping armies of microflora that live inside us, balance our immune systems, and provide us with a sustained source of short-chain “fat” energy.  We should think of our gut microflora not as invaders or visitors, but literally as integral parts of our body — what Velasquez-Manoff calls our “superorganism”.

During our evolution, we outsourced these important protective functions to the gut microbes — so we need to keep them happy by feeding them well.  Maybe it took the epidemics of autoimmune disease to teach us to appreciate the essential role that microflora play in our health.