Autoimmunity - Self Versus Self

Christopher Columbus was a pioneer in more ways than one

Upon his return from the New World, his eyes were so badly inflamed, they actually bled

His joints were stiff, and sore

This is one of the first records of an autoimmune disease

Columbus suffered from a rare disease known as Reiters disease, or Reactive arthritis

It has such diverse symptoms, that doctors recognize it by remembering cant see, cant
pee, cant bend the knee

He probably picked up a microbe in the New World that triggered an autoimmune response

Columbus may have brought several microbial souvenirs back with him

And as Columbus learned the hard way, the immune system can turn out to be a fair
weather friend

When things are going well, we arent even aware of the microbial bullets were dodging

But every so often, the immune system fails to keep pace and we get sick

Ironically, I got sick while writing these immunity lectures - a classic case of life imitating
art

And sometimes, the immune system turns on us, attacking our cells and tissues as if we
were the enemy
We get an autoimmune disease

Autoimmune diseases include rheumatoid arthritis, multiple sclerosis, lupus, myasthenia

gravis, Type 1 diabetes, and a score of others

About 5-7% of the population suffer from autoimmune diseases

The distinction between self and non-self turns out to be a tricky thing to learn

The acceptance of self, the bodys own tissues, is called immunological tolerance

And usually, our bodies do a good job of learning friend and foe

But sometimes this self-learning mechanism breaks down

Then our friendly guard dog suddenly changes into a rabid beast!

And sometimes, like a compulsive over-achiever, it does its job too well

It overreacts to certain antigens, and causes allergies and asthma

In this lecture, well examine the nature of autoimmunity, and try to determine what causes
diseases like multiple sclerosis, rheumatoid arthritis, and lupus

In the lecture that follows, well consider the role of the immune system in allergic
reactions, and asthma

The more you think about it, doesnt the whole idea of autoimmune disease seem a little
strange - how could the body not recognize parts of itself?
And why hasnt natural selection weeded out those individuals whose immune systems
cant make that critical distinction?

The great immunologist Paul Ehrlich was the first person to realize the dreadful
consequences if our immune system turned on us

He called it horror autotoxicus

Ehrlich was a real medical pioneer - he shared the 1908 Nobel Prize with Elie Metchnikoff

Among his many accomplishments, he discovered the first cure for syphilis, a compound of
arsenic called Salvarsan

Most contemporary methods of treating syphilis involved compounds of metals, like

arsenic, bismuth, or mercury
Such drugs were so widely used that the common saying was One night with Venus, a
lifetime with Mercury

Arsenic was a favorite tool of murderers, and a dangerous substance to use for medicine

Early trials were not promising, but Ehrlich persisted long past the point where most men
would have thrown in the towel, and finally discovered a safe but effective drug on his
606th attempt
Salvarsan became the most highly prescribed drug on Earth, until it was replaced by
penicillin

Ehrlich also coined the term magic bullet, to describe drugs that would target a specific
microbe
He was a master at developing dyes called stains, that would highlight different tissues, or
different species of bacteria under the microscope

One of his stains was the precursor for the gram stain, still a common diagnostic tool

Ehrlich reasoned that if a stain could home in on a particular type of tissue or microbe, then
it should be possible to develop a toxin, a magic chemical bullet, that would know right
where to go

His vision was finally realized in the 1970s, with the invention of monoclonal antibodies,
antibodies for a specific antigen, that can be made by cloning the particular B cell that
produces them

Ehrlich was relentless in his pursuit of the secrets of immunity, a commanding presence with his
perpetual cigar

He smoked up to 25 cigars a day, and often carried a small box of them under his arm

He was a driven man, leaving tottering piles of books and journals in his wake, always
looking for a blank canvas to jot down his latest ideas

Paul De Kruif tells us:

He would draw pictures of his theories anywhere, with no more sense of propriety than
an annoying little boy, on his cuffs and the bottoms of shoes, on his own shirt front to the
distress of his wife, and on the shirt fronts of his colleagues if they did not dodge fast
enough.

Success in research, he tells us needs four Gs: Glck, Geduld, Geschick und Geld.
Luck, patience, skill and money
Unfortunately, Ehrlich may have done his job a bit too well

Ehrlich became intrigued by Jules Bordets discovery of immune hemolysis in 1898, the
destruction of red blood cells by the immune system
So he set about mixing the blood of different species together

Although he often found antibodies in these mixtures, he was never able to get blood to
react with blood from the same animal

So Ehrlich concluded that the body would never endanger itself by forming antibodies
against its own tissues, horror autotoxicus

While he had to admit that auto-antibodies could form, as had been demonstrated with
animal sperm, he firmly denied the possibility of autoimmune diseases
And his influence was so pervasive, that autoimmune diseases were not generally
recognized until the 1960s

Now, autoimmunity isnt entirely a bad thing - the body can handle a certain number of
self-reactive cells
Although self-reactive T cells and B cells are weeded out early on, self-reactive B cells
often survive, and you can usually find them in the blood in small numbers - they dont
seem to cause a big problem

And it reminds us that autoimmunity is a normal, natural process

Its as if the immune system needs to constantly challenge itself to stay sharp

A lot like the Kenyan prostitutes who are immune to AIDS, as we learned in our last lecture

When they cut back on their frequency of sexual contacts, many of them developed AIDS

Their immune systems needed to be constantly challenged to stay one step ahead of the
rapidly mutating HIV virus

But a little challenge can go a long way

Self-reactive cells are like ticking time bombs in the immune system

Very early in development, there must be a critical learning period for self versus non-self

And any B cells or T cells that bind to normal cell antigens must be ruthlessly exterminated

The body probably learns this while we are still embryos - but the situation is more
complicated than you might think
Every fetus is the product of two parents, which means it will have both moms and dads
antigens on every cell

Mothers must acquire maternal-fetal tolerance, or the half-foreign baby would be attacked
in the womb as an invader
The physical barriers between the two arent sufficient to keep all of the fetal antigens out
of the mothers body

But if any fetal cell does activates an antigen presenting cell, special cells called Tr1 and
Th3 cells are ready to snuff out the APC and save the fetus from attack

These same cells have been shown to have a role in miscarriages in lab animals

Fetal cells also lack most MHC I and II sites

Without an MHC docking port to present an antigen, the cells cant activate a T cell

Self-reactive B cells, and maternal-fetal tolerance, remind us once again that autoimmunity
is a fundamentally natural process

But its not enough to nip self-reactive cells in the bud, while were still babies

Adaptive immunity is a life-long learning process

The immune system must continue to police every new generation of T cells as we grow

T cells originate in the bone marrow, but have to migrate to the thymus to complete their
development, which is why we call them T cells
Most people have heard of the thymus, although Im willing to bet you dont know where it
is, or what it does

Well, dont feel bad I had to look it up myself!

Its part of your immune system, and a very important part, at that(its also a great
Scrabble word!)
The thymus gland is located above the heart, at the base of the neck

And while were on the subject of obscure bodily organs, the spleen is another important
organ in the immune system

Among its many functions, it filters out antibody-coated microbes and blood cells, and
generates cells called monocytes, that create lots of dendritic cells and macrophages

Because its an important filtration point, the spleen is a handy place to station B cells and T cells
to patrol the passing traffic

The thymus has an equally challenging job its the college from which T cells have to
graduate before going out into the body

So its the logical place to give T cells their final exam, to detect and destroy any selfreactive T cells that arise during our lifetime
This winnowing is savage

Roughly 99% of the T cell candidates that are tested in the thymus will flunk out, and be
destroyed, either because they are self-reactive or because they are non-reactive

Only 1% will leave the thymus as mature, functioning T cells

In a similar fashion, 50% of all new B cells are destroyed in the bone marrow as self
reactive

Autoimmune diseases represent a failure of self-tolerance, with respect to a specific set of

our own antigens

Those antigens are no longer seen as self, and any cell bearing them will be attacked

Are these diseases simply an accident of nature, or are they a clever microbial plot?

What we may be witnessing is the strategy of the agent provocateurIve seen James
Bond do it many times

By provoking the immune system into triggering an autoimmune response, the microbe
incites a rebellion, and deflects attention from itself

Autoimmune attacks are often triggered by completely unrelated infections

Common microbes that can cause an autoimmune response include Syphilis, Chlamydia,
Salmonella, Shigella, Staphylococcus, and Borrelia, the cause of Lyme disease

This bacterial connection seems solid, but evidence has been hard to come by

How can you ever know for certain if that Salmonella food poisoning you got from your
ninth-grade cafeteria, was the cause of the autoimmune disease you acquired in middle
age?

Molecular mimicry may be the missing link between microbial infection and autoimmune
diseases

We share many similar epitopes, small bits of proteins, with microbes like bacteria

And its no accident ultimately, all life is related, we all stem from the same primal cells

So a bacterial antigen could be similar to one of ours, but just different enough to trigger an
immune response
The body now associates that antigen with the microbe, even though something much like
it appears on the bodys own cells

Both microbes and body cells are now attacked by the immune system, guilt by association

And even though the original microbial stimulus is gone, and we recover from the
infection, the damage has already been done

The newly awakened self-reactive cells may continue to attack us

Molecular mimicry may be the root cause of both multiple sclerosis (MS) and rheumatoid
arthritis

MS usually occurs in young adults, and affects nerve cells in the central nervous system the spinal cord and the brain

The body doesnt directly attack the nerve cells

It attacks the delicate tissue that protects them, the myelin sheath

The myelin sheath protects the long nerve cell extensions called axons, which neurons
extend to communicate with one another
The immune system goes after special cells called oligodendrocytes, which maintain the
myelin sheath

Scars called plaques form in the damaged areas, and interfere with nervous conduction

Sclerosis comes from the Greek word skleros, meaning hard, hence multiple sclerosis,
lots of small hard scars on the nerve cell axon sheaths

Its as if an army of tiny mice were nibbling on the electrical wires in your house

You might still be able to turn on the lights, but all those exposed wires would soon start to
spark and sputter

Most of the actual damage is caused by cytokines and proteases released in the attack

A protease is an enzyme that breaks down proteins

This nerve damage proceeds very rapidly, affecting almost every part of the body, making it
difficult to diagnose
Victims steadily deteriorate some decline right away, some hold out for several years

Many alternate between relapse and remission, though all of them suffer the inevitable
progression of MS
There is no cure, and no effective treatment

Ex-mousketeer and movie star Annette Funicello is one of its most prominent victims - I
had a huge crush on her when I was eight years old

The disease is most common in Caucasian females from Northern European or North
American families
This strongly suggests a genetic or environmental component

But heres an interesting twist the disease becomes more common as you go from the equator
to the poles, in both hemispheres!

And to make things even more mysterious, if you move in either direction as a child, you
acquire the MS risk level that corresponds to your new home

So if you moved north as a child, you now have a higher risk, but if you moved south you
now have a lower risk
But if you move in either direction as an adult, you keep the MS risk level you had as a
child!

Your risk level is somehow locked in during childhood

Maybe theres some bacteria or virus in the north that people are exposed to in childhood,
that somehow increases their chance of getting MS in later life

Many viruses have been investigated as probable triggers of MS, but with little success,
though the Epstein-Barr virus is still a strong candidate
This virus has a series of protein subunits that bear an unfortunate resemblance to part of a
myelin sheath protein called Myelin Basic Protein (MBP)

An infection of Epstein-Barr could lead to the creation of antibodies that cant tell the
difference between the viral proteins and the proteins in human myelin

We can actually mimic the effects of MS by injecting Theilers virus into lab mice

Molecular mimicry has also been proposed to explain a real heartbreaker, juvenile
rheumatoid arthritis

Juvenile rheumatoid arthritis strikes children between 6 weeks and 16 years

It begins with vague symptoms of decreased activity, lethargy, and loss of appetite,
progressing to morning stiffness, joint pains, and limping

The ultimate cause is still a mystery, but juvenile rheumatoid arthritis may occur following
certain types of bacterial or viral infections, as can rheumatoid arthritis in adults

In the late 1980s, for example, 260 people got Salmonella at a banquet

Within a month, 19 of them developed rheumatoid arthritis

Coincidence, or cause and effect?

Consider the connection between autoimmunity and type A Streptococcus

We share several epitopes with Strep A bacteria

In rheumatic fever, the body makes antibodies against an antigen in the cell wall of the
Strep A bacteria
But these same antibodies also target the mitral valve of the heart, the joints, and nerve
sheaths

In the case of rheumatoid arthritis, some of the Salmolnella bacteriums own cell-wall
antigens appear to be shared by cells or structures in the membranes that line our joints

Rheumatoid arthritis strikes a little too close to home, for me

My favorite relative, when I was a little boy, was my maternal grandmother, Sadie
LaMere
I have an old photo of her standing proudly next to my mother and great-grandmother,
whos holding me in her arms

But I dont remember her that way

I remember her as that frail old lady in the wheelchair, her legs useless, her hands so
twisted, she could barely turn the pages of a book, her body so delicate that the smallest
bump or injury would create a massive, painful bruise

And yet, through all the agony she must have endured, she remained uncomplaining,
devout, loving, and independent

She was an inspiration to us all

Molecular mimicry may be the key that unlocks the mysteries of rheumatoid arthritis

One injection of mycobacterial antigens, from the genus that causes TB and leprosy, can
induce rheumatoid arthritis in lab rats

A similar relationship with mycobacterial infection has been observed in humans

Many different bacteria and viruses have been implicated in rheumatoid arthritis

But molecular mimicry is only one of several hypotheses about the cause of autoimmune
disease

Are they simply the result of a shared cellular heritage, or are they a clever strategy evolved
by microbes?
We just dont know

There are so many different kinds of autoimmune diseases, its difficult to find any
common cause or pattern

We know, for example, that there is a genetic predisposition to certain autoimmune

diseases, but the details are very poorly understood
We also know that up to 75% of autoimmune disease victims are female, so we assume that
there is a hormonal connection as well

But one common thread has recently emerged, special compounds called superantigens
(SAgs)

Superantigens are antigens that can activate many different types of T cells, and cause them
to start rapidly dividing

Normal antigens activate one in 10,000 to one in 1,000,000 T cells

Superantigens activate one in every 50 T cells!

Superantigens can turn on thousands of different T cells

Unfortunately, superantigens also seem to reactivate the silenced clones of self-reactive cells

In response to superantigens, tissues may be flooded with self-reactive cells, marked with
antigens from several different types of body tissue

This would explain why some autoimmune diseases can affect so many different parts of
the body at the same time

A superantigen has recently been isolated from an SIV viral infection, suggesting that
superantigens might even be a trigger for AIDS
If such a superantigen is expressed by HIV, it could trigger the activation of thousands of T
cells, setting the table for an AIDS viral feast

And it would explain the enigma that AIDS patients, whose immune systems are shattered,
can still get an autoimmune disease
Superantigens can trigger the formation of CD8 killer T cells without involving the
depleted CD4 helper T cells

Superantigens might also explain the pattern we see in systemic lupus erythematosus, or
SLE, one of the four types of lupus
SLE appears mainly in females between the age of 20 and 40, more frequently in AfricanAmericans

Stress, overexposure to sun, infections, birth control pills, and pregnancy can all bring on
an attack

It starts with a characteristic rash across the cheeks, called a butterfly rash

It progresses to extreme fatigue, arthritis, blood problems, organ inflammation, mental

problems, and many other varied symptoms
There is no cure

The actual damage in lupus is done by the accumulation of immune complex, the
combination of antibody and antigen
Macrophages usually clean up the mess, but because the alien cells are the bodys own, the
supply is essentially unlimited, and eventually the macrophages cant eat fast enough to
keep up

The same kind of damage occurs in rheumatoid arthritis and other antibody-mediated
autoimmune diseases
Lupus is a chronic disease, that often dooms its victims to a painful half-life

Its often misdiagnosed and mistreated, its victims accused of being slackers, or
hypochondriacs

Superantigens have been proposed as a cause of SLE, though theres no clear evidence yet to
support that hypothesis

It would explain, however, the cycle of flare ups and remissions that victims often
experience, as new sources of stress jump start the self-reactive cells

The causes of other autoimmune diseases are even more mysterious - many genetic and
environmental factors may be involved
Take Type 1 diabetes mellitus (T1DM), for example, which accounts for 5-10% of diabetes
cases

The body attacks and destroys the cells that make insulin, so victims cant control their
blood sugar levels

Symptoms include increased hunger, thirst, and urination, fatigue and weight loss

It all happens in the Islets of Langerhans, which sounds like an exotic tourist destination

But its really an area inside the pancreas, an organ that makes several important digestive
enzymes, including insulin
Viral infections with the Coxsackie B4 or with the Rubella virus, the cause of German
measles, may be involved, although the viral link is controversial

Not everyone infected gets diabetes, and we think that some victims might have a genetic
predisposition
Its sometimes called juvenile diabetes, because its so common in children, but almost half
the new-onset cases of Type 1 are in adults

Myasthenia gravis is another autoimmune disease in which the immune system targets a
specific type of cell
Like MS, the target is a neuron, but instead of attacking the nerve sheath, the antibodies
block nervous transmission

Our nerve cells never actually make direct contact with one another

There is always a short gap, called the synaptic cleft, between the tip of an axon and the
cells it communicates with

Its like a telegraph service where the wires dont run all the way there

To close the gap, youve got to hand the message off to the Pony Express

The ponies are tiny molecules called acetylcholine, a neurotransmitter which drift across
the gap and bind to special receptors on the other side, perpetuating the nervous signal
In myasthenia gravis, the body makes antibodies that bind to those same receptor sites,
blocking the nervous signal

Victims experience muscle fatigue, drooping eyelids - some may have difficulties talking,
swallowing, and even breathing as the disease progresses

Now, at this point, you may be starting to drift off, trying to absorb all this hard science at the
end of a busy day

Or maybe youve got narcolepsy

Ive often wondered if I have it, because I have a nasty habit of nodding off in lectures
not my own, of course

But it turns out that Im not diseased, just easily bored - a trait that I share with both
Darwin and Linnaeus
Victims of narcolepsy experience extreme sleepiness during the day, and cant sleep well at
night

50,000 Americans have narcolepsy, and the actual tally may be as high as 200,000

Some respond to extreme emotions by going into cataplexy, with blurred vision and slurred
speech, and sometimes total paralysis and collapse they freeze up!

The causes of narcolepsy are still poorly understood, but the autoimmune attack stops
production of a protein called Orexyn A, which is central to normal sleep patterns
Researchers in Australia in 2004 were able to induce narcolepsy by injecting antibodies
from narcolepsy victims, which strongly suggests that its an autoimmune disease

But the target of the antibody remains a mystery, though it may act to destroy a type of
brain cell called a hypocretin neuron, which is known to play a critical role in sleep cycles

Stimulants and other drugs can help victims live a normal life

Prominent victims of narcolepsy include the actor Morgan Freeman, and baseball superstar
Hank Aaron

There are no treatments for most autoimmune diseases, though a wide variety of
immunosuppressant and anti-inflammatory drugs are commonly prescribed

For most autoimmune diseases, all we can do is treat the symptoms as best we can

Autoimmune diseases makes an odd sort of evolutionary sense

Although the immune system sometimes fails, the occasional failure is worth the
evolutionary benefit when it works

In our next lecture, well look at what happens when the immune system responds all too
well, causing allergies and asthma
This has been quite a lot to absorb, I know - so if any of you nodded off in the process,
youre forgiven
After all, whats a little narcolepsy between friends?