Allergies and Asthma

As we learned in our last lecture, our immune system can be both friend and foe

Sometimes the immune system can turn on us, causing an autoimmune disease

In this lecture, well consider what happens when the immune system over-reacts, leading
to allergies and asthma

The word allergy comes from the Greek allos, meaning other, and ergon, meaning work or
action

Allergy means hypersensitivity to a foreign substance to which most people do not react

An allergen is any substance that causes an allergic reaction

You would think that Clemens von Pirquet, who coined the word allergy in 1906, would
have received some credit for his efforts
Instead he was widely criticized for proposing it, and rather harshly at that

The physiologist Charles Richet, winner of the 1913 Nobel Prize, reminded him in no
uncertain terms that there was already a perfectly good term to describe the condition
anaphylaxis
And you can probably guess who coined that term

von Pirquets new term was called superfluous, useless - allergies werent clinically
important

Allergies werent nearly as big a problem as they are today

In fact, they were almost fashionable - they were widely viewed as a rich mans disease

Having allergies or asthma, like having gout, implied that you were a member of the upper
crust
And it didnt help von Pirquets cause that his work was based purely on traditional clinical
observation, rather than on the new techniques of experimental medicine

von Pirquet is also notable, incidentally, for devising the tuberculin test used to diagnose
TB
He had a long and distinguished career, but unfortunately, his personal life wasnt quite so
successful

The son of minor nobility, von Pirquet was the Austrian equivalent of a baron

In a family at war with itself over their inheritance, he found solace in his loving wife
Maria

His family, however, scorned her as beneath their social station - most of them refused to
even attend the wedding!

Bad enough that he had become a doctor, a profession any true aristocrat should scorn

But true love turned out to be a rocky road for von Pirquet

Maria suffered from several physical and psychological problems, including an increasing
fondness for barbiturates
But despite their many problems, they remained constant and loving, and in 1929 they
committed suicide together, after 25 years of marriage

von Pirquet saw the allergic reaction as part of a bigger picture of the role of antibodies in
fighting disease
He claimed that the eruptive symptoms of diseases like measles were not cured by the
immune system, as Ehrlich had suggested, but were actually caused by it

The skin eruptions resulted from the interaction between antibody and microbe

Unfortunately for von Pirquet, he was only partially correct

In the case of measles, we now know that the attack of killer T cells is responsible for the
rash and fever
But in the case of smallpox and other eruptive diseases, despite his vigorous defense, he
was wrong

He gradually turned away from immunology, rejecting a research position at the Pasteur
Institute to take a position at Johns Hopkins, where he became the schools first professor
of pediatrics
He was a well-loved and highly respected teacher, who soon moved on to the University of
Vienna, where he spent his remaining years as Chair of Pediatrics

von Pirquet later turned to nutrition, and developed what became known as the Pirquet
System of Nutrition, which saved the lives of many young Austrian children in the wake of
the First World War

Food of any kind was scarce in Austria in 1919, and author Stephan Zweig tells us that:
Every trip to town was a shocking experience, for the first time I looked into the yellow,
dangerous eyes of famine. The black bread crumbled and tasted like pitch and glue, the
coffee was an extraction of burnt barley, the beer was yellow water, the chocolate colored
sand. Most people bred rabbits in order to have some taste of meat . . . and well fed dogs
and cats rarely returned home from a stroll.

Under Herbert Hoover, von Pirquet organized the American Children's Relief, and 400,000
undernourished Austrian children were fed using the Pirquet system

von Pirquet was a true pioneer

Immunology was a brand-new field, born in the last decades of the 19th Century

von Pirquet worked in the shadow of giants like Paul Ehrlich, and Emil von Behring, who
won the first Nobel Prize in Medicine, in 1901, for curing diphtheria with blood serum

Blood serum is blood from which the blood cells and clotting factors have been removed

von Behring knew that diphtheria carried an extremely potent toxin

Remember that the toxin is only produced when the bacterium is attacked by a
bacteriophage virus

Roux and the intrepid Yersin had isolated the diphtheria toxin, a poison so potent that one
ounce would be enough to kill 600,000 guinea pigs

But they couldnt figure out how to neutralize it

That job fell to Emil von Behring, a young army doctor working with Robert Koch

Known as the strangling angel, diphtheria was a major killer of children - Paul de Kruif
tells us:
The wards of the hospitals for sick children were melancholy with a forlorn wailing; there
were gurgling coughs foretelling suffocation; on the sad rows of narrow beds were white
pillows framing small faces blue with the strangling grip of an unknown hand.

Fresh from his co-discovery with Kitasato of the tetanus toxin, von Behring was
determined to find a cure for diphtheria
He felled a small army of guinea pigs with treatment after treatment, but couldnt solve the
mystery

He finally hit upon a solution of iodine tri-chloride, but the cure was nearly as fatal as the
disease

A few guinea pigs, however, somehow managed to survive this brutal treatment, and the
serum he made from their blood now carried the antibodies that had neutralized the toxin

The story goes that on Christmas Eve, 1891, an eight-year old child lay dying of diphtheria
in a Berlin clinic, while von Behring prepared his one and only dose of the precious
antitoxin

The child was injected, and made a dramatic recovery

The ancient killer of children had finally been brought to its knees

The famous dogsled race the Iditarod, incidentally, commemorates a 1925 emergency run
of diphtheria antitoxin through a bitter Alaskan winter, to fight an epidemic in Nome,
Alaska

But, as von Behring quickly learned, for some patients, the cure was almost as bad as the
disease
They reacted strongly to some element in the blood, leading to serum sickness

von Pirquet and his colleague Bela Schick, observed that some people reacted extremely
strongly to a second injection of blood serum
Somehow, their immune systems had become hypersensitive to the serum, a condition he
and Bela called allergy

Its an age-old problem

The Hippocratic Corpus comments that many people can eat cheese without the slightest
hurtothers come off badly
The Roman philosopher Lucretius tells us that What is food to one, is to another biting
poison

People who suffer from allergies are called atopic

Atopy is hereditary

> If either parent is atopic you have a 25% greater risk of being atopic
> If both parents are atopic your risk is 50%

50-60 million Americans suffer from allergies, about 1 in 5 in the developed world!

For some, like myself, its just a seasonal nuisance, a source of profit for the Kleenex
industry

Ill never forget my first trip to Florida

I slept next to a window near a bottlebrush shrub in full bloom, and spent the next six days
blowing my nose

But for many people, allergies are a serious medical problem, requiring regular injections,
and avoidance of certain foods or objects or environments

My niece and nephew had such bad allergies they had to give up their pets and stuffed
animals

Life is tough enough, without having to lose your teddy bear

Allergies affect different people to different degrees

Why are some people extremely sensitive to things like cat hair, while other people are not?

Food allergies are especially common, affecting about 2% of the population

Food allergies are caused by small bits of undigested proteins that slip out of the digestive
tract and into the blood, where they are seen by the immune system as invaders

The most common causes of food allergies are milk, egg whites, peanuts, fish, wheat and
soy
Peanut allergies are especially deadly, and extremely hard to avoid

One victim nearly died from eating a tuna fish sandwich cut by a knife that had also been
used to cut a peanut butter sandwich!
Food allergies hit 3 million children in 2007, up 18% over the previous ten years!

Allergens that have a mild effect on one person, could be fatal to another - like a simple bee
sting

Anaphylaxis is the most severe form of allergic reaction, involving the entire body

Symptoms can include respiratory problems, vomiting, diarrhea, hives, and loss of bladder
control

Blood pressure drops so quickly that the victim sometimes slips into shock and dies

The first victim of anaphylactic shock from bee stings was recorded 4,500 years ago in
Egypt

There are many similar reports in antiquity of death from minor insect stings

Bee stings cause about 40 deaths every year in the US

In anaphylaxis, first contact with an allergen causes a reaction

This sensitizing dose causes the immune system to over react if it encounters that same
allergen again, the shocking dose

Between 1% and 5% of American citizens are at risk for anaphylaxis

And 1% of those who have a reaction will die from it, about 1,500 deaths a year

The incidence of anaphylaxis, like that of allergies in general, is rapidly increasing, and has
more than doubled since the 1980s

We still dont fully understand what causes this deadly reaction to bee venom

But fortunately for those sensitive to bees, researchers at John Hopkins have taken a page
from Rappaccinis daughter

In Nathaniel Hawthornes classic yarn, Dr. Rappaccini exposes his daughter to toxins from
poisonous plants until she not only becomes immune to them, but becomes poisonous
herself

Researchers at John Hopkins gave increasingly large amounts of bee venom to their beesensitive subjects, and reduced the chance of shock to 2% after 3 to 5 years of regular
treatment

This type of therapy is called desensitization

Remember that when a macrophage finds a foreign antigen, it takes it to a helper T cell

Helper T cells stimulate the B cells called plasma cells to divide rapidly, and start making
lots of antibodies

Desensitization depends on two antibodies that lie at the heart of the allergic reaction,
Immunoglobulin G (IgG) and Immunoglobulin E (IgE)
There are five different classes of antibodies in the immune system - IgA, IgD, IgE, IgG,
and IgM

IgG is the most common antibody, making up about 75-80% of the antibodies in circulation

Theyre critical in fighting viruses and bacteria, and are the only antibody that can cross the
placental barrier from mother to fetus

IgE antibodies are found in skin, in mucous membranes, and in the lungs

Theyre best at handling allergens like pollen or fungal spores, and parasitic worms

Small doses of IgG provoke a low level immune response, and continued doses can often
gradually override the more hypersensitive IgE response, desensitizing the patient against
an extreme reaction

There is relatively little IgE in the body compared to IgG (1 to 100,00)

But this tiny amount of IgE can do an incredible amount of damage

IgE stimulates mast cells and basophils, which are involved in the inflammatory response

Mast cells are especially dense in lung tissue (20,000 / mm2) and nasal mucosa (5,000 /
mm2)
When they all kick in at once, the effects on the body can be overwhelming - itching in the
mucus membranes, runny nose, tears etc.

Mast cells were named by Paul Ehrlich, who called them Mastzellen, meaning well-fed
cells

They certainly look well fed, but the granules they contain are not filled with food

Theyre stuffed with a powerful cocktail of chemicals

Mast cell granules contain 10 or more potent chemicals, like histamine

Remember that histamine makes tiny capillaries leaky, so immune system cells can slip
through to get to the trouble spot

When we get stung by a bee, histamine makes the area red, and warm, itchy and swollen

Annoying and inconvenient perhaps, but hardly life threatening

But for the unfortunate few who are hypersensitive to bees, anaphylaxis can occur

The reaction is not localized it flashes throughout the body

And when too many blood vessels start to leak at the same time, blood pressure can drop
rapidly, and the victim slips into shock
If that werent bad enough, histamine binds to smooth muscles that lead into the air sacs in
the lungs, causing them to contract, and close down the airways

The fluids that accumulate in the lungs from the histamine reaction also restrict the uptake
of oxygen, as does the copious mucous blocking the airways, adding to the respiratory
distress

Its like signaling a four alarm fire for a lit cigarette

Now you know why the walls of drugstores around the world are lined with anti-histamines

A similar over reaction to common allergens lies at the heart of hay fever

Hay fever is a modern problem, theres very little mention of it before the mid-19th Century

The Japanese had no problem before 1950, now 13% of the population have hay fever

Hay fever is actually a misnomer its not a fever, and its not usually caused by hay

The preferred name is allergic rhinitis

Its a reaction to plant antigens, like pollen

This is a subject where Im particularly well versed

Noses run in my family

Noses are lined with B cells, basophils, mast cells - the whole fire brigade!

This dense concentration of histamine releasing cells can lead to an immediate and intense
reaction to anything we inhale
Most of the time, however, this is not the case the reaction to foreign antigens entering
our nose is local and low key

But for those who suffer from perennial allergic rhinitis, there is no relief, and misery is
year round
For some unknown reason, women are three times more likely to suffer from perennial
allergic rhinitis

One theory for the recent increase in allergies is that modern homes are airtight, and full of
objects that retain large amounts of allergens - upholstered furniture, carpets, drapes,
bedding, mattresses etc
This allows huge populations of tiny little arthropods called dust mites to build up

A study by Arshad in 1992 took 120 babies with high IgE levels at birth, and therefore at
high risk for allergies, and separated them into two groups
The control group was raised normally

In the experimental group, however, the parents got instructions on keeping the house free
of dust mites

By 10 months of age, 40% of the babies in the control group had developed allergies

But only 13% of the babies in the clean environment experimental group had allergies

Dust mites, cat hair, mold, and cockroaches are among the most common indoor allergens

The basic problem is that urbanization has created new and highly artificial environments
for microscopic critters
Many organisms like dust mites are taking advantage of those new urban environments

The hygiene hypothesis is still a bit controversial, but the modern surge in allergies might
be due to raising our children indoors, in tightly sealed homes
Farm children have fewer allergies than non-farm children living in the same rural area

Incidentally, if youre allergic to cats, you arent allergic to cat hair itself, but to an antigen
called Fel d 1, one of five allergens produced by the cats sebaceous and salivary glands
Cat hair and skin is covered with spit from grooming, so cat hairs and skin flakes are
coated with Fel d 1

In my house, we call the balls of cat hair that accumulate in the corners kitty cotton

Were hoping to develop a market for it

The distinction between hay fever and asthma is as fuzzy as kitty cotton

In fact, asthma used to be called hay asthma!

Pollen grains are too large to get through the tiny airways leading into the lungs, so hay
fever is an upper respiratory problem
Asthma is a chronic allergic condition which primarily affects the lower respiratory system

The CDC reports that 18 million adults, 8.2% of the population, and 7.1 million children,
nearly 10%, suffered from hay fever in 2009

Famous victims of asthma include Presidents John Kennedy, Calvin Coolidge, Woodrow
Wilson, and Teddy Roosevelt, along with Beethoven, Vivaldi, Charles Dickens and Marcel
Proust

Asthmatics have unusually high levels of IgE in their blood, and are hypersensitive to
common allergens
Asthma can also be triggered by stress and exercise, whats called non-atopic or intrinsic
asthma

The airways become tightly constricted during an asthmatic attack, giving asthmatics a
characteristic wheeze

Many may need to be hospitalized to reopen the airways, and a severe attack can be fatal

Asthma kills 4,000 to 5,000 Americans every year, roughly 11 people per day

Fortunately, the death rate for asthma, after climbing sharply for decades, has started to
drop in the last ten years

Between 1980 and 1994, the number of asthma cases in the US increased 75%

Asthma in infants under 5 shot up 160% during that same period

Since the 1990s, this trend has leveled off, but the incidence remains at historically high
levels

9.6% of US children under18 now suffer from asthma, thats just over 7 million children!

It ranks third in causes of hospital admittance for children under 15

In the US, asthma cases cost $19.7 billion in 2007

Adults miss over 10 million days of work every year due to asthma, and children miss 13
million days of school
European nations report similar increases in both the frequency and severity of asthma

Unfortunately, the incidence of asthma and allergies may continue to increase in the near
future due to changes in the atmosphere

Carbon dioxide is a trace gas, it only makes up 0.03% of the atmosphere

But plants need all the CO2 they can get, in order to make sugar through photosynthesis

Thats one of the reasons most leaves are flat, thin blades, it maximizes the surface area for
absorbing sunlight and taking in carbon dioxide

So the small supply of CO2 makes it an important limiting factor in the growth of plants

CO2 is an extrinsic, density-independent limiting factor

Industry and transportation release large amounts of CO2 into the atmosphere from the
combustion of fossil fuels, which will help plants to grow faster, and produce more pollen
its called CO2 fertilization

Experiments in greenhouses have shown that doubling the CO2 in the air makes ragweed
produce 61% more pollen than normal
Pollen grains, incidentally, are actually microscopic little male plants

Their unique shapes and chemical signatures allow plants to distinguish pollen of the right
species from all those pretenders that land on the same flower
Unfortunately, they also offer a diverse set of antigens that can trigger an IgE reaction

Why such a huge IgE over reaction to microscopic grains of pollen?

Given that 25% of humanity suffer from allergies, youd think we would have figured it out
by now

Asthma has a strong genetic component, but the heredity of asthma is poorly understood

Its rarely seen in wild animals, and rarely reported in zoo animals, though other mammals
have the same basic IgE system that we do

And we can induce asthma in lab animals

It remains a mystery

Our approach to allergy and asthma is almost entirely pharmaceutical, prescribing steroids,
antihistamines, and bronchodilators to treat symptoms
Monoclonal antibodies, which have also been used to treat rheumatoid arthritis, are now
being used to treat asthma with some success

Theres little emphasis on environmental intervention and control, though that approach
may offer more hope for asthma victims

Isolated tribes of native Americans, for example, have virtually no cases of asthma

Asthma may be a disease of civilization

Maybe asthma is the price we pay for reducing our exposure to parasitic worms

Individuals with heavy loads of parasitic worms rarely get asthma

Remote South American tribes, with 60-98% levels of worm infection, have unusually high
IgE levels but no asthma

The IgE system probably evolved as a defense against parasitic worms

Hookworms, pinworms, Ascaris (intestinal roundworms), Schistosoma worms, flukes, and

other parasitic worms have attacked us for millennia

Schistosoma infections are widespread in tropical Asia, with 200 million infections a year

From 8 to 20% of the victims IgE will rally to attack these parasites

Those who cant make a lot of IgE, suffer more severe Schistosoma infections

When a worm invades the body, some of its antigens diffuse through the intestinal wall,
and are carried to the lymph nodes
IgE antibodies are released and cause mast cells to discharge, attacking the worms - B and
T cells also join the attack

The parasitic worm theory of allergic reaction is supported by experiments with lab rats,
who show a very strong IgE reaction to parasitic worms
If their IgE production is blocked, the rats become more vulnerable to the parasites

And if IgE from infected rats is injected into other rats, it helps protect against new worm
infections

Parasitic worm infections occur in over 1/3d of the population in less-developed countries

But in urbanized areas, worm infections are relatively rare

So maybe IgE now over reacts to different allergens, like dust mites and pet hairs

The timing of exposure may also be critical

Both lab rat and epidemiological studies show that if youre exposed to parasites before
youre exposed to inhaled allergens, the rate of asthma is low - and vice versa if you
encounter inhaled allergens first, the rate of asthma is higher

Marc Lapp, one of the chief proponents of evolutionary medicine, says that asthma is an
evolutionary gatekeeper
Asthma keeps us from inhaling dangerous mold spores associated with grain

The domestication of grain about 14,000 years ago created new environments for many
organisms, including many species of fungi
The increased risk of inhaling mold spores from grain storage areas may have led to the
evolution of asthma

Fungal spores from Aspergillus, and other common fungi associated with grain or grain
storage areas, can cause severe infections
Aspergillosis occurs when spores of Aspergillus begin to grow in the lungs its very bad
news

A severe allergic reaction expels mold spores from the body and constricts the respiratory
passages so we cant accidentally ingest more of them
But the actual allergic reaction may not be to the fungal spores themselves, but to another
organism that hangs out in the same habitat - grain mites

Grain mites dont cause a big problem by themselves

But maybe the body learned to attack them because theyre often associated with moldy
grain and mold spores

Guilt by association

The first cousins of grain mites are still with us today - dust mites!

Modern airtight homes expose us to large numbers of dust mites

Maybe our bodies still remember the ancient grain mite / fungi connection, and react
strongly to dust mites

The IgE system appears to have evolved as a defense against infestations of parasitic
worms
But in our modern sanitized environments, this adaptation is no longer necessary for
survival, and the system now over reacts to common allergens

As Marc Lapp concludes, Old adaptations often provide the scaffolding on which new
diseases are built

Over the course of our last six lectures, weve learned that the immune system is our best
weapon against microbial invasion

Weve also learned that this particular sword cuts in both direction

Thats the problem with weapons

Once forged, they can be used by anybody, and the evolutionary arms race has produced
some formidable microbial weaponry

In our next two lectures, well learn how weve seized those microbial weapons, sharpened
their edges, and used them on one another, as we explore the deadly history of germ
warfare, and discover why microbes have become a favorite tool of modern terrorists