Autoimmunity: The immune system is a double-edged sword. Its main role
Autoimmunity: The immune system is a double-edged sword. Its main role is to protect us against foreign invaders,
but in certain cases, it can see “self” (i.e. it determines that self-antigens are foreign and launch an immune response
against our own tissues).
What is autoimmunity?
The National Institute for Health (NIH) probably defines it best:
“Our bodies have an immune system, which is a complex network of special cells and organs that defends the body
from germs and other foreign invaders. At the core of the immune system is the ability to tell the difference between
self and nonself: what’s you and what’s foreign. A flaw can make the body unable to tell the difference between self
and nonself. When this happens, the body makes autoantibodies (AW-toh-AN-teye-bah-deez) that attack normal
cells by mistake. At the same time special cells called regulatory T cells fail to do their job of keeping the immune
system in line. The result is a misguided attack on your own body. This causes the damage we know as autoimmune
disease. The body parts that are affected depend on the type of autoimmune disease. There are more than 80 known
So, what does the hygiene hypothesis have to do with this?
The hygiene hypothesis simply states that individuals who grew up in a clean and healthy environment are more
prone to autoimmune disorders and overactive immune systems. IgE is the main antibody that mediates allergic
reactions and releases histamine in response to certain allergens. Individuals in a dirty environment are more
exposed to helminth and other parasitic infections that are also the target of IgE infections. Because these
individuals are generally more susceptible to infections, their immune system is more active, and IgE is usually kept
busy. For individuals in developed countries, hygiene is an expected, daily principle, which leads to the inevitable
downside of excessive free-floating IgE that is free to bind to multiple substances (including allergens like pollen,
grass, etc.) and leads to allergies and other autoimmune disorders. Many studies have already correlated higher
incidences of autoimmune diseases in developed countries compared to developing (and more likely, dirtier)
countries. So, the take home message? Be dirty, be happy and healthy.
More information? Check out this article by Alina Bradford (
“The hygiene hypothesis was first introduced in the late 1980s by David P. Strachan, a professor of epidemiology, in
the British Medical Journal. Strachan found that children in larger households had fewer instances of hay fever
because they are exposed to germs by older siblings. This finding led to further research that suggests a lack of early
childhood exposure to less than pristine conditions can increase the individual’s susceptibility to disease. For
example, in the late 1990s, Dr. Erika von Mutius, a health researcher, compared the rates of allergies and asthma in
East Germany and West Germany, which unified in 1999. Her initial hypothesis was that East German children,
who grew up in dirtier and generally less healthful conditions, would have more allergies and suffer more from
asthma than their Western counterparts. However, her research found the opposite: children in the polluted areas of
East Germany had lower allergic reactions and fewer cases of asthma than children in West Germany. Further
research has found that children in developing areas of the world are less likely to develop allergies and asthma
compared with children in the developed world.
The idea is simple. When babies are inside the womb they have a very weak immune system because they are given
protection by their mother’s antibodies. When they exit the womb, though, the immune system must start working
for itself. For the immune system to work properly, it is thought that the child must be exposed to germs so that it
has a chance to strengthen, according to the U.S. Food and Drug Administration (FDA). The idea is similar to the
training of a body builder. For a body builder to be able to lift heavy objects, the muscles must be trained by lifting
heavier and heavier objects. If the body builder never trains, then he will be unable to lift a heavy object when
asked. The same is thought to be true for the immune system. In able to fight off infection, the immune system must
train by fighting off contaminants found in everyday life. Systems that aren’t exposed to contaminants have trouble
with the heavy lifting of fighting off infections. Mutius hypothesized that the reason children who are not exposed to
germs and bacteria are sicklier is due to how the human immune system evolved. She thinks there are two types of
biological defenses. If one of the defense systems isn’t trained or practiced enough to fight off illness, the other
system overcompensates and creates an allergic reaction to harmless substances like pollen. Research by other
scientists has found similar results. Exposure to germs triggered an internal inflammatory response in children who
were raised in cleaner environments, leading to ailments such as asthma, according to a 2002 article in Science
What are some of the underlying causes of autoimmune diseases? (Check out an excerpt from the article below!)
Autoimmune Disorders: When Your Body Turns On You
There’s been a stark rise in autoimmune disorders over the past 50 years, from type 1 diabetes and multiple
sclerosis to celiac disease and asthma. The first step toward a cure is understanding and controlling the
More than 23 million Americans suffer from autoimmunity, which makes it the third most common category of
illness in the United States after cancer and heart disease. Yet, 90 percent of Americans cannot name a single
autoimmune disease, writes Donna Jackson Nakazawa in her book The Autoimmune Epidemic (Simon & Schuster,
2008). “It boggles the mind,” she says. The name deserves some of the blame. “Autoimmune disease” is an umbrella
term for dozens of conditions, most of which do not actually use the word “autoimmune” in their titles.
Some of the most common autoimmune diseases include rheumatoid arthritis, type 1 diabetes, lupus, Hashimoto’s
thyroid disease, multiple sclerosis (MS), inflammatory bowel disease (IBD, which includes Crohn’s disease and
ulcerative colitis), celiac disease, and asthma. The National Institutes of Health (NIH) currently labels more than 90
diseases as autoimmune disorders, and that number is certain to rise as scientists continue to identify and further
understand the origin of other diseases. Type 1 diabetes, for example, was only recently found to be autoimmune
driven. (For a list of more autoimmune diseases, see “Autoimmune Diseases…So Far” below.
At first, the medical establishment more or less missed this epidemic because specialists who rarely talked to one
another treated individual diseases in a vacuum, says Nakazawa. Patients suffering from joint problems, like
rheumatoid arthritis and lupus, typically saw rheumatologists; those with skin issues, like psoriasis, went to
dermatologists; gut disorders, like Crohn’s disease, ulcerative colitis, and irritable bowel syndrome, fell under the
jurisdiction of gastroenterologists; and so on. “There was no one standing on the mountaintop saying, ‘Wow, look
what’s happening in all these valleys,’” Nakazawa says.
The system is catching up to the problem and adapting its protocols, though. One catalyst for the change is the ever-
widening scope of the problem. Since the 1950s, celiac disease alone is up fourfold, lupus rates have tripled, and
type 1 diabetes has soared — up 23 percent in the past decade alone.
Today’s doctors and scientists also have a more sophisticated understanding of how the immune system can go
awry. One of the top experts in the field is Alessio Fasano, MD, the director of the Center for Celiac Research &
Treatment at Massachusetts General Hospital for Children in Boston. Decades of research led him to deduce that
every autoimmune disease has three basic ingredients: a genetic predisposition, an environmental trigger, and a
leaky gut.
Identifying the first two components was easy. Scientists have long known that autoimmunity runs in families and
that onset of some disease can be triggered, for example, by an environmental factor such as an infection. But it
wasn’t until 2000 that Fasano and his team discovered the third and final ingredient — a leaky gut. Specifically,
Fasano discovered zonulin, a protein that regulates gut permeability.
“Zonulin works like the traffic cop of our bodies’ tissues,” he says. “It opens the spaces between cells, allowing
some substances to pass through while keeping harmful substances out.” Some people produce excess amounts of
zonulin, which pries apart the cells of the intestinal lining and allows toxins, bacteria, and undigested bits of food
into the bloodstream — hence the term “leaky gut.”
While functional- and integrative-health practitioners have long said gut permeability is the crux of chronic ills,
including autoimmune disorders, many conventional physicians distanced themselves from the idea. The science
behind gut permeability, however, is now too convincing to ignore.
The leaky gut is especially important in any conversation about autoimmune disorders because it’s the thing that
allows environmental factors to trigger predisposed genes.
Family history accounts for roughly one-third of the risk of developing an autoimmune disease. Certain clusters of
genes can directly affect the immune system, making it hyperreactive. Other genes play an indirect role by exposing
an organ to attack.
Although the science of genetics and autoimmunity is in its infancy, researchers have discovered a combination of
genes called human leukocyte antigens (HLA for short), which may determine who develops an autoimmune disease
and who does not. In short, it is most important to understand that genes determine how sensitive your immune
system is to environmental triggers.
Some toxins alter the structure of our DNA, which can prompt the immune system to see the mutated tissue as a
foreign substance and attack.The surge of autoimmunity paralleled the growth of consumer products made from
plastics, artificial fibers, and synthetic dyes. There are now more than 80,000 chemicals used in commercial
products, and less than 15,000 of those have been safety tested (much less tested in frequently used combinations).
According to consumer advocates at the Environmental Working Group, the average person is exposed to more than
126 chemicals before even leaving the bathroom in the morning (shampoo, conditioner, toothpaste, soap, deodorant,
sunscreen, etc.). Chemicals in personal-care products might be one reason that the majority of autoimmune sufferers
— 78 percent — are women. Nakazawa thinks it is only a matter of time before scientists connect the dots between
the gender difference in autoimmune diseases and endocrine disrupters in women’s personal-care products, such as
phthalate esters and parabens in things like lotion, perfume, and sunscreen. Studies are under way to pinpoint which
chemicals are most egregious. One that comes up again and again is mercury, which can trigger autoimmunity by
ramping up the production of lymphocytes, a type of white blood cell in the immune system.
Additionally, the NIH is researching whether a protein in cow’s milk may help trigger type 1 diabetes in genetically
susceptible children.
Infections can also cause autoimmunity. Certain infections, such as group A beta-hemolytic streptococcus, spark the
onset of rheumatic heart disease, an autoimmune disease that attacks the heart. Infections may also kick off type 1
diabetes, MS, lupus, and rheumatoid arthritis.
What does gut microbiota have to do with this?
You might be genetically susceptible and be exposed to a host of environmental triggers, but in most cases you
won’t develop autoimmunity unless you also have a leaky gut. The gut’s slick, slimy insides, if spliced and laid flat,
would carpet a tennis court. The uppermost lining is a mere one cell thick and is home to trillions of bacteria. In a
healthy gut the good bacteria outnumber the bad. But keeping a healthy ratio is tough. Years of eating junk food,
popping pain relievers, and experiencing stress inflames the gut’s lining.
Everyone’s gut can spring a leak from time to time. A leak can form after an infection, a virus, or gastric upset.
Some people have symptoms, like bloating, gas, or indigestion. If the gut is healthy, the lining will heal. But if the
gut is in bad shape, it may not be able to close the fissures. Inside a leaky gut, zonulin opens the door for bacteria,
viruses, fungi, parasites, chemicals, and pollutants to enter the bloodstream. Confronted with a steady stream of
invaders, the immune system makes T helper cells, which speed up its response.
“Humans evolved over 2.5 million years, during which time our immune system was designed to attack one enemy:
infection,” says Fasano. “Now the same machinery is forced to fight thousands of enemies it has never seen before.”
Not every leaky gut will lead to an autoimmune disease, but if you are genetically predisposed, the fight can be very
dangerous. Substances produced by T cells can irritate and inflame the body and indirectly activate genes capable of
triggering autoimmunity.
Why are women more affected in autoimmune diseases? (This is still uncertain, but the article below has some
valuable insight!)
Why are Women More Susceptible than Men to Autoimmune Disease?
By Rory Linehan
Key Messages:
 More than three out of every four people with autoimmune disease are women
 The reasons for the ‘gender bias’ in autoimmune disease are still not well understood but can be
grouped broadly into three categories; Immune Response, Hormones and Genetics
 Women are able to mount a stronger immune response than men which may make them more likely
to develop autoimmune disease
 Some male predominant hormones reduce autoimmune disease while some female predominant
hormones increase autoantibody production
 Women carry two X Chromosomes, while men only carry one. X Chromosomes carry a number of
genes which may relate to immunity.
You may have heard that autoimmune disease is now the third most prevalent type of disease in the US and affects
up to 8% of the population[1]. But this is not unique to the US. Right across the world the prevalence of
autoimmune disease is increasing, including in my neck of the woods, Australia and New Zealand, where
approximately 5% of the population is affected by the condition[2].
What you might not know is that autoimmune disease disproportionately affects women. In fact, conservative
estimates indicate that 78% of the population affected by autoimmune disease are women. Or put another way, more
than three out of every four people with an autoimmune disease are women!
Graphic from the American Autoimmune Disease Related Disease Association Inc.
*Graphic from Gender differences in autoimmune disease by S.T. Ngo, F.J. Steyn and P.A. McCombe
1. Immune Response:
According to several studies[3][4], the gender difference in autoimmunity may be driven by differences between the
male and female immune systems. Women’s immune systems have heightened immune reactivity when compared
to men’s immune systems, meaning that women can mount more powerful immune responses than men[5].
This means that women was have greater resilience to infections and diseases (maybe man-flu is real?!) but on the
flip side, it is possible that this greater immune reactivity makes women more prone to developing autoimmune
2. Hormones:
Sex hormones, such as estrogen, testosterone, and progesterone account for much of the difference in the prevalence
of autoimmune disease between men and women.
The precise interaction between hormones and the immune system is just beginning to be understood. Several
studies show that male-predominate hormones, such as androgens, reduce autoimmune disease while some
female-predominate hormones, such as estrogen, stimulate antibody (autoantibody) production[6], which can lead
to autoimmune disease.
What the literature shows is that the science on the role of sex hormones in autoimmune disease is still very nascent
and more research needs to be done before firm conclusions can be made.
3. Genetics:
Men carry an X and Y chromosome while women carry two X chromosomes. Although most of the second X
chromosome in women is deactivated during fetal development, some of its genes remain. As a result, women may
express more genes from the X chromosome than men do, and a number of these play a major role in
immunity[7]. Some researchers believe this difference might explain at least some of the sex-bias in autoimmune
Major Autoimmune Disorders:
 Type I Diabetes: Only recently was Type I diabetes characterized as an autoimmune disorder. Many children
experience juvenile diabetes after an infection in which a virus altered pancreatic beta cells’ antigens, causing
the immune system to launch a response to it. Some cases may have a hereditary link. However, most cases are
spontaneous. Because pancreatic beta cells are responsible for insulin production, the destruction of beta cells
means Type I diabetes patients can’t produce insulin and must receive synthetic insulin injections to counteract
high glucose concentrations (especially after eating) in the blood. There is currently no cure for type I diabetes
since beta cells are continuously destroyed even if pancreatic transplants are performed.
 Fatal Hemolytic Disease of the Newborn:
The Rh factor is another antigen that occurs on the surfaces of red blood cells. Humans can either be Rh+ or Rh-
. On blood types, this is noted as “-“ or “+” after the blood type antigen (i.e. O-, A+, AB-, etc.). Just like blood
types, if an individual is Rh- and gets exposed to Rh+ blood, it can develop antibodies against the Rh factor.
This is problematic for mothers who are Rh- and carry a Rh+ baby. Since having the Rh factor is a dominant
allele, that means if either of the parents have the Rh factor (in most cases, this is the father), the baby is most
likely to be Rh+. Because the placenta is involved in nutrient exchange through blood, the mother will be
exposed to the baby’s Rh+ red blood cells. The first baby is no problem, if the mother has never been exposed
to Rh+ blood (like through a blood donation of Rh+ blood). The first time the mother is exposed to the Rh
factor, it will produce antibodies against it. Therefore, if the second baby is Rh+ as well, the mother’s antibodies
will target the baby and cause the baby to have anemia due to red blood cell damage. This is often fatal and
causes fatal hemolytic disease of the newborn. To prevent this from occurring, doctors must be made aware of
the mother’s Rh- status and prescribe RhoGAM during the second pregnancy. RhoGAM blocks the mother’s
antibodies against the Rh factor, preventing the baby from harm.
 Rheumatoid Arthritis: Rheumatoid arthritis develops from the accumulation of antibody-antigen complexes
in small joints around the body. Although the exact cause is unknown (i.e. possible viral infection,
environmental exposure, or genetic risk), women are more likely to get this disease than men. Debilitating
pain around joints and deformed joints are common symptoms.
 Systematic lupus erythematosus: The key diagnostic tool for lupus is the butterfly
Why are autoimmune diseases more prevalent in developed countries compared to developing countries? Hint: consider the concept behind the hygiene hypothesis (2 pts)
Explain one underlying cause towards the development of autoimmune diseases, and describe what occurs on the cellular level (immune cells and mediators involved in autoimmune development). (2 pts)
Name two reasons why women are more susceptible to autoimmune diseases compared to men. (2 pts)
What cells are destroyed in Type I diabetes, and why does this cause the need for synthetic insulin injections for Type I diabetes patients?  (2 pts)
What happens during the first Rh+ pregnancy of a Rh- mother, and what is so special about the second Rh+ baby of a Rh- mother? What disease can result if this condition is not caught early? (2 pts)
EXTRA CREDIT (optional – 2 pts) – Research any specific autoimmune disease on your own, and discuss two interesting or special findings you discovered about this autoimmune disease.