That's not the way genetics works in autoimmune disease. In autoimmune disease, multiple genes are involved; we have genes that collectively increase the vulnerability or susceptibility to autoimmune disease. What is inherited is not a specific gene that causes a specific defect in metabolism; several genes increase vulnerability or susceptibility to autoimmune disease.

     How do we know that there is a genetic basis of autoimmune disease? I can cite three kinds of evidence. The first is autoimmune diseases tend to occur in families. If there's one case of autoimmune disease in the family, there's likely to be another case.

     However, it is not a particular autoimmune disease; it is generally a tendency to autoimmunity. One family member may have lupus, another family member may have Sjogren's disease, a third member of the family may have rheumatoid arthritis. That's one bit of evidence for genetic involvement, and we've known this for a number of years. If we ask patients when they come to us, "Is there other autoimmune disease in your family?"--and we actually have to mention them because people don't know these are all autoimmune diseases--they will usually say, "Yes, my aunt had thyroid trouble...my grandmother had that disease...my grandmother had Crohn's disease...."

     But we call this soft data in science because families share genes and that's some indication of genetics; but families share other things.

     So we need to look further. The second thing we do is to look at twins. We compare two kinds of twins. There are twins that are genetically identical, and there are twins that are non-genetically identical. If something is caused by an environmental factor, there should be no difference between identical twins and non-identical twins. If there's a difference, it suggests that genetics plays a role. These studies have been done for a number of autoimmune diseases, and the answer has always come up about the same. Genetic components represent something in the order of half of the risks. In other words, if you have a genetic predisposition to autoimmunity, you may have twice or five times as much chance of developing autoimmunity as someone else--not 100 times, but not zero. So genetics plays an important role.

     One group of genetic factors is particularly important. One of the things that immunology has taught us through the years is obvious but needed some kind of physical basis, it is simply that every human being is different from every other human being (unless you have a genetically identical twin). Every person is a little different from everybody else; we know that for certain when we try to transplant tissues, like kidneys or hearts. In general you cannot accept a kidney or heart from someone else unless we dampen your immune response.

     There clearly are significant physical differences between different people. And we call the substance that causes that difference histocompatibility complex. We call the genes that provide that difference "major histocompatibility complex genes". Everybody abbreviates that long tongue twister by just saying MHC; and every species has an MHC, a major histocompatibility gene. In a human we call it HLA.

     HLA is the major group of genes that distinguishes one human being from another. It is important in transplantation, and we do HLA typing regularly. It's important to us in autoimmunity because susceptibility to autoimmunity is associated with the HLA type. It represents the most important single genetic trait in estimating susceptibility to autoimmune disease.

     There are three kinds of information that tell us if autoimmune diseases are genetic. I've mentioned two. One is family clustering; the second is the association with HLA. What's the third?

     The third is that autoimmune diseases occur in animals as well as in human beings. With animals we can do the breedings that are necessary.

     We can infer the same must be true in humans. In animals the equivalent of HLA determines susceptibility. In animals this trait is actually predictive. In humans we aren't yet at that point because we don't have enough information from humans to say, "Because of your HLA factor you're going to develop an autoimmune disease." We can, however, say that you have a greater likelihood of this happening.

     So we're getting to a point where we can almost predict who is more likely or less likely to develop autoimmune disease. Now this, again, is an example of how very basic research on a molecular level or on a genetic molecular level is beginning to pay off in human medicine.

     I would like to conclude with the second half of the story. I've said that genetics accounts for about half of the risk that you develop an autoimmune disease.

     The other half is the agent in the environment which triggers the process. Unfortunately, we do not know very many of the triggers. We know there are certain drugs that can induce lupus. We know there are certain environmental substances like silica that can induce scleroderma. We suspect that there are certain dietary substances, such as iodine, that can exacerbate thyroid disease. So we're beginning to define the other half of the story, the environmental half. It is going to be, I think, an equally fascinating chapter in the saga of autoimmune disease in the next decade.

     So, in summary, that's what autoimmune diseases have in common. That's why we feel very strongly there should be a society like the American Autoimmune Related Diseases Association that brings together all of the research and all of the investigators and all of the physicians as well as all of the patients interested in autoimmune diseases. Let us begin to get to questions of etiology, to get at the root causes of these diseases, rather than being left at the superficial level, that is, treating the symptoms after the disease has had its destructive effects.

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