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Transcript
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 Reiter’s disease, or Reactive arthritis • • It has such diverse symptoms, that doctors recognize it by remembering “can’t see, can’t pee, can’t 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 aren’t even aware of the microbial bullets we’re 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 body’s 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, we’ll examine the nature of autoimmunity, and try to determine what causes diseases like multiple sclerosis, rheumatoid arthritis, and lupus In the lecture that follows, we’ll consider the role of the immune system in allergic reactions, and asthma The more you think about it, doesn’t the whole idea of autoimmune disease seem a little strange - how could the body not recognize parts of itself? And why hasn’t natural selection weeded out those individuals whose immune systems can’t 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 1970’s, 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 G’s: Glück, 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 Bordet’s 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 1960’s Now, autoimmunity isn’t 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 don’t seem to cause a big problem… • • • And it reminds us that autoimmunity is a normal, natural process It’s 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 mom’s and dad’s 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 aren’t sufficient to keep all of the fetal antigens out of the mother’s 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 can’t activate a T cell Self-reactive B cells, and maternal-fetal tolerance, remind us once again that autoimmunity is a fundamentally natural process • • • But it’s not enough to nip self-reactive cells in the bud, while we’re 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 I’m willing to bet you don’t know where it is, or what it does… • • • • • • Well, don’t feel bad – I had to look it up myself! It’s part of your immune system, and a very important part, at that…(it’s also a great Scrabble word!) … The thymus gland is located above the heart, at the base of the neck And while we’re 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 it’s 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 – it’s the college from which T cells have to graduate before going out into the body So it’s the logical place to give T cells their final exam, to detect and destroy any self-reactive 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 provocateur…I’ve 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 it’s 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 body’s 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 doesn’t 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 • • It’s 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 here’s 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 there’s 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 can’t tell the difference between the viral proteins and the proteins in human myelin • • We can actually mimic the effects of MS by injecting Theiler’s 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 1980’s, 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 bacterium’s 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, who’s holding me in her arms • • But I don’t 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 don’t know… There are so many different kinds of autoimmune diseases, it’s 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 (SAg’s) 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 African-Americans 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 body’s own, the supply is essentially unlimited, and eventually the macrophages can’t 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 It’s often misdiagnosed and mistreated, its victims accused of being slackers, or hypochondriacs • • • • • • • • • • • • • Superantigens have been proposed as a cause of SLE, though there’s 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 can’t 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 it’s 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 It’s sometimes called juvenile diabetes, because it’s 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 • • It’s like a telegraph service where the wires don’t run all the way there To close the gap, you’ve 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 you’ve got narcolepsy… I’ve 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 I’m 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 can’t 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 it’s 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, we’ll 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, you’re forgiven After all, what’s a little narcolepsy between friends? • •