Some physicians say that the challenge of being educated as a doctor is similar to mastering a foreign language. It’s certainly true that one’s vocabulary expands tremendously in medical school. To take the analogy a little further, languages and medical knowledge are both alive, meaning that they continuously change. I graduated from medical school in 1975. One word never mentioned was autoinflammatory. What is the distinction between autoinflammatory and autoimmune? Why is the concept of autoinflammatory relatively new? How does autoinflammatory apply to ankylosing spondylitis and related diseases?
To address these questions, I need to make each reader both a medical historian and a clinical immunologist. So be prepared for some complicated background information.
The major responsibility of the immune system is to protect you from danger such as a bacterial or viral infection. This is not a simple task. Your body plays host to trillions of bacteria. You also allow yeasts and a number of viruses to be passengers in your tissues. Your immune system must evaluate millions of signals from these microbes and decide which ones are potentially harmful and which are benign. It should not be all that surprising that there is an occasional mistake.
An antigen is a substance that can be recognized by the immune system. In an autoimmune disease, the body’s immune system targets an antigen that is produced by your own body. “Auto”, as in auto-immune, means self. For example, in rheumatoid arthritis many experts now believe that an autoimmune response to an antigen known as CCP in your joints and elsewhere causes rheumatoid arthritis. In a number of diseases ranging from Graves’ disease to lupus to myasthenia gravis, autoantibodies are detectable. An autoantibody means that your body’s immune system has recognized an antigen that is made by your own body. Not every autoantibody results in a disease. But unless autoantibodies can be detected, the term autoimmune should not be used to describe the disease. And autoantibodies are not a typical feature of ankylosing spondylitis or related diseases like inflammatory bowel disease (such as Crohn’s disease and ulcerative colitis) or psoriasis. The immune system is clearly involved in these diseases, but it is seemingly targeting something other than one of the body’s own proteins.
The technology to identify the specific cause of rare genetic diseases has progressed rapidly. In 1999 Dan Kastner, a rheumatologist at the National Institutes of Health, led a large group of scientists who studied a puzzling, rare inherited disease characterized by recurrent episodes of fever and inflammation. The group was able to show that the affected patients had an abnormality in the DNA that codes for the receptor for TNF, also known as tumor necrosis factor. TNF is the same protein that is targeted by many of the biologic drugs used to treat ankylosing spondylitis. For TNF to be active, it must be recognized by a protein known as a receptor on the surface of a cell. The inherited change in the TNF receptor caused inflammation because it resulted in TNF being overly active. In this case, the faulty receptor was like a faulty lock which left the door continually unlocked. Their discoveries were reported in the journal, Cell, and the title of the manuscript called this disease, autoinflammatory. The term was apt because the body was behaving as if it were responding to a danger signal, but no autoantibodies were present. Since this report, a growing number of inherited illnesses have been called autoinflammatory because they are characterized by recurrent episodes of inflammation and the absence of autoantibodies.
The immune system has an adaptive arm and an innate arm. The adaptive arm makes the antibodies which result in a highly targeted response like a perfectly aimed guided missile. But it takes time, a week or more, to make specific antibodies. So the body also has an innate arm which can respond more rapidly but less specifically. The innate arm is able to recognize and respond to bacterial and viral products. The innate arm makes proteins like TNF to respond to this potential danger. Autoinflammatory diseases are almost always caused by mutations in proteins that have a major role in the innate immune system.
So what about ankylosing spondylitis, autoimmune or autoinflammatory? The current thinking is: a little bit of both, as most diseases fall somewhere along a continuum from autoimmune to autoinflammatory. In some mouse and rat models that resemble ankylosing spondylitis, the disease can be transferred from one animal to another by taking the lymphocytes [a type of white blood cell] from the diseased animal and injecting them into a healthy animal. This argues in favor of an autoimmune disease because lymphocytes make the targeted response characteristic of the adaptive immune system. HLA-B27 affects how lymphocytes function and that also argues for an autoimmune disease. But bacteria are suspected by some to cause ankylosing spondylitis and that argues for an autoinflammatory disease. As does the absence of autoantibodies. And TNF is made by many cells, but mostly by cells like macrophages that are major contributors to the innate immune system. So if blocking TNF helps ankylosing spondylitis, some argue that ankylosing spondylitis must be autoinflammatory.
I think that what most of us have been correctly saying is, “Don’t call it autoimmune.” I agree with that advice, but the subtlety is that even though it should not be called autoimmune, there can be aspects of autoimmunity contributing to it. The terms, autoimmune and autoinflammatory, have become useful concepts as a way to try to understand immune-mediated diseases. But many immune system diseases do not fit into a perfect label; most show some aspects typical of autoimmunity and some aspects of autoinflammation. The concept is proving useful as a theoretical way to understand ankylosing spondylitis and related diseases like psoriatic arthritis and reactive arthritis.
And medical knowledge has thankfully progressed a great deal since the day I graduated medical school.
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