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Unraveling the Mystery of Autoimmunity

Everybody wants to have a strong immune system. The immune system is the body's own personal Department of Defense, protecting its health and integrity from invading armies of harmful viruses and bacteria. Its specialized cells, called lymphocytes, normally do a fine job of keeping illness at bay, but sometimes they slip up, sending us home with the flu.

Even with all the smart weaponry at its command, the immune system can sometimes go awry, attacking targets inside the very body it was designed to protect. This is the explanation behind over 80 suspected autoimmune diseases, including psoriasis, rheumatoid arthritis, multiple sclerosis and juvenile diabetes.

Noel Rose, MD, Professor in the Department of Pathology at Johns Hopkins School of Medicine and Director of the Johns Hopkins Center for Autoimmune Disease Research, has spent the better part of his distinguished career following the common thread that weaves these diseases together. In the following remarks, he shows how autoimmune diseases of the skin, joints, nerves and pancreas are fundamentally linked.

What is autoimmunity?
Traditionally, the immune response has been understood as the body's method of defending itself against disease, which it does by identifying and destroying foreign invading microorganisms. By contrast, autoimmunity involves an immune response to something within the body itself.

We all produce lymphocytes that are potentially capable of recognizing and even attacking "self." Normally, these cells are either deleted very early or they're held in check by regulatory controls. When these safeguards fail us, so-called autoantibodies develop. All of us have autoantibodies - antibodies in our blood that react with something in our own bodies.

Are you saying that autoantibodies and autoimmunity are normal?
Autoimmunity is mostly harmless. Some immunologists even believe it may be helpful. Autoantibodies may help to remove worn out or dead cells, but firm evidence for this is not yet at hand. Clearly, though, an autoimmune reaction can go too far, and that's where the problem begins.

What is autoimmune disease?
The definition of an autoimmune disease is sometimes very hard to pin down. There is no universal agreement on which diseases are autoimmune and which are not autoimmune. Autoimmunity may be present in the disease, but may not be actually causing it.

What causes some people to develop autoimmune diseases in the first place?
The tendency to develop an autoimmune disease has roots in both genetics and the environment. Autoimmune diseases are different from other genetically determined diseases that we're more familiar with, like sickle cell anemia, where there's a single gene and either you have it or you don't. In autoimmune disease, there's an accumulation of a number of different genes that, when added together, give a heightened probability that you will develop an autoimmune disease. About a third of the risk of developing an autoimmune disease is inherited. That means the other 66% is environmental. Even if you inherit a genetic predisposition, the autoimmune disease will not occur unless there's an environmental trigger.

What are some conditions that are now considered autoimmune diseases?
Interestingly, back in the 1960s, many of us suspected that Type 1 diabetes might be an autoimmune disease, but we couldn't really find substantial evidence to support our suspicions. Later, it emerged that the autoimmune form of diabetes is the insulin-dependent form, sometimes called juvenile diabetes or Type 1, which affects about 10% of patients with diabetes. So that was a major surprise.

According to the current view, psoriasis is now considered an autoimmune disease involving an immune response that results in lesions in the skin. For example, they may have been exposed to an infection, and the infecting organism may have had an antigen - a substance that resembles a component of the skin. Whether psoriasis is caused by an internal or external stimulus, the upshot is that there is an immune response to something in the skin.

Another example is rheumatoid arthritis, a very common disease. Patients with rheumatoid arthritis have autoantibodies. We still don't know for certain whether the autoimmunity we see in the disease is actually causing the disease. That having been said, virtually all of us now accept rheumatoid arthritis as an autoimmune disease. Still, there's a little uncertainty in the back of our minds that there could be a virus, or something else, that's causing the disease, and that the autoimmunity is merely an accompaniment.

Is it important to establish the ultimate cause of rheumatoid arthritis in order to treat it effectively?
At present, the ultimate cause is not a matter of overwhelming importance, because what we treat are its symptoms. The kinds of drugs we use today block the substances that are produced during an immune response, substances that are actually causing the pathology of the disease. These drugs work. It's not relevant whether the immune response that we're blocking is actually a true autoimmune response or whether it's a response to a hypothetical virus that we've never found.

Finding the actual cause of the autoimmune disease will probably become more of an issue in the future years. We hope to see a whole new generation of treatments based on a more advanced understanding of autoimmunity as an underlying disease process.

Once a patient has a full-blown autoimmune disease, what are today's preferred methods of treatment?
In some cases, we can treat an autoimmune disease by replacing a lost function. That's what we do when we give insulin for diabetes or thyroid hormone for Hashimoto's thyroiditis. When these symptomatic remedies fail, however, we must turn to immunosuppression in order to down-regulate the entire immune system. Obviously, this approach is hazardous, because it makes people susceptible to infection, plus most immunosuppressant drugs have severe side effects. They're a last resort. Most physicians give them with great reluctance.

We would much prefer to have a more targeted type of therapy - one that turns down the disease-inducing, damaging autoimmune response without interfering with general immune function. Some of the newer biologic drugs are an improvement over traditional immunosuppressants, since they focus on the inflammatory consequences of the autoimmune reaction. But they still may have adverse effects in heightening susceptibility to certain types of infection.

How would you assess the pace of medical discovery in the field of autoimmunity? Is substantial progress being made?
We're getting closer and closer to the root cause of autoimmune disease. My vision is that someday we'll identify the substance that gets the harmful autoimmune disease process going. The goal is to make people unresponsive to their own excessive autoimmune response. We need to learn a lot more about how to identify these offending antigens in people and how to make people immunologically unresponsive. The fact that we can do it in animals shows that it's possible.