| **FUTURE RESEARCH DIRECTIONS**

**Dr Blumenthal’s Introduction ofAnthony S. Fauci, MD**

Dr Anthony Fauci, an internationally renowned expert onimmunology, has been the Director of the NationalInstitute of Allergy and Infectious Diseases since 1984.

A brilliant scientist and gifted leader in the researchcommunity, Dr Fauci is at the forefront of our fight to better understand autoimmunediseases and to share with us what must be done to increase knowledge about theseillnesses. In fact, when he initially joined the staff of the National Institutes ofHealth, autoimmune diseases were among his first areas of research focus. I can think ofno more talented researcher to focus his energies and thoughtful dedication on the issueof autoimmunity than Dr Tony Fauci. It is my great honor and pleasure to introduce him toyou.

**Anthony S. Fauci, MDDirector, National Institute of Allergy and Infectious Diseases**

I know that when I walked in the door and people saw me,those who recognize me were wondering why an AIDS expert would be here talking aboutautoimmune diseases. There really is a very good reason conceptually for that, in additionto the fact that, as Dr Blumenthal said, I have been involved in the study of autoimmunediseases for some time before anyone ever even heard of HIV and AIDS.

I am here to talk to you because of my interest and thework that I’ve done over my professional career on the immune system. In fact, thecommon thread between HIV/AIDS and autoimmune diseases is that both are diseases of theimmune system. That is one of the things I think we need to get people to understand whoare trying to comprehend autoimmunity. The immune system is a system as complex and aselegant as any of the systems of the body—the cardiovascular system, the hematologicsystem, the neurological system, or the endocrine system, or the endocrine system. It isvery finely tuned and very finely regulated, and you have diseases of that system the sameway you have diseases of every other system of the body.

For example, you can have tumors of the immune system likeHodgkin’s disease and other lymphomas which are actually neoplastic transformationsof lymphoid tissue. You can have deficiencies of the immune system. Physicians, likemyself, might unavoidable have to make people immunosuppressed by giving them drugs, forexample for cancers, that are necessary to kill the cancer cells. And there are acquiredimmunodeficiencies, the major prototype of which is AIDS.

On the other side of the coin, when the immune systemoverreacts for a variety of complex reasons, you have hypersensitivity diseases orautoimmune diseases.

Now, the important thing about the immune system is thatour understanding of it is ever-unfolding. In my mind, the process is an unfinished mosaicin that we learn more and more and more about it. So you could step onto the stage in thefirst act of this play and find out that we know very little about the immune system andyou can be discouraged. You may say, "Well, we’re not going to solve any of themysteries of the autoimmune diseases," and essentially lose that drive or that energythat you need to get something done scientifically.

I devoted the first 13 years of my career to autoimmunediseases. I think it is important for all of us to make sure that we keep our eye on thegoal and realize that what we knew about the immune system in 1968 and 1969 waspractically nothing compared to what we know about the immune system now. Attitudes aboutthe impossibility of solving the riddles and the problems of autoimmunity in 1968 aretotally nonapplicable right now. They are totally not applicable to what went on in 1970or 1975 or 1980, or even in 1990. As the field evolves, the opportunities emerge more andmore.

There is a scientific solution to every problem. We justneed to find it. What you’re doing is increasing the awareness and understanding ofthe importance of this problem.

The message that I would like to leave you with is thatwhat you are doing, what all of you are doing, is extraordinarily important. It is one ofthe main motivations which drives people like myself and my colleagues to put the energyand the intense drive toward solving these riddles, which I will assure you are solvable.

**Dr Blumenthal’s Introduction ofDr Stephen I. Katz, MD, PhD**

Dr Stephen Katz is the distinguished director of theNational Institute of Arthritis and Musculoskeletal and Skin Diseases at the NationalInstitutes of Health and has served as Chief of the Dermatology Research Branch of theNational Cancer Institute for over 15 years. An internationally recognized leader in thefields of arthritis and musculoskeletal and skin diseases, Dr Katz has been at theforefront of the National Institutes of Health research efforts on autoimmune disorders.We are honored to have him share with us new research and treatment strategies forautoimmune diseases.

**Stephen I. Katz, MD, PhD**

What I will present to you this morning is the view fromthe NIH of the global concerns that relate to autoimmune disorders. What I mean by globalis all aspects of biomedical research, going from genetic predisposition to genderpredisposition, to what are the trigger factors that cause autoimmune disease, to what arethe targets of autoimmunity, to what causes the destruction of the autoimmune process, andfinally what is the treatment of the autoimmune process.

We are really in a very exciting time. Maybe people havebeen saying this for years, but now there is a convergence. There is a convergence ofimmunology, there is a convergence of biochemistry, and there is a convergence ofmolecular biology that enables us to probe some of the new approaches to diagnosis andtreatment for autoimmune disease.

There are many diseases where if one gene is mutated, itresults in a certain disease. That gene usually encodes for a very important protein,whether it’s on a cell or in a cell. We know now that with many of these autoimmunediseases there is not a single gene defect, but there are probably multiple genes that areinvolved in determining that genetic predisposition. But we now have the wherewithal withthe Human Genome Project to look globally at the entire genome to identify the multiplesites within the genome that may predispose to certain types of diseases. Dr Buyon’sreport describes to us the current work on the factors associated with genderpredisposition and the hormonal factors that are involved in treatment considerations inpatients with autoimmune diseases.

What are the trigger factors? If a person is predisposed,what triggers the autoimmune response? Namely, the body’s attack of itself, either ofa specific organ, whether it’s a kidney in lupus erythematosus, or the entire body inlupus erythematosus or various organ systems in scleroderma. Is the trigger factor abacteria? Is it some form of virus? We don’t know yet, but we have many of thecapabilities to look at these questions.

What is the target for the autoimmune process? Within thelast 5 years, an enormous amount has been learned about the targets in every one of thesediseases. For example, in multiple sclerosis, it is the myelin basic proteins. Inrheumatoid arthritis, what is it in terms of the synovium? What is on the surface of thecells in diseases such as lupus erythematosus? And there are other diseases in thespondyloarthridities, diseases of the spine. What is it that is the specific target?

In many autoimmune diseases the targets have beenidentified. In myasthenia gravis we have identified the target. In a disease calledpemphigus, a devastating skin disease, we know the target. This knowledge helps us togenerate very specific therapies.

And how does the destruction occur? We used to be limitedto looking at a biopsy. But now, with molecular biological techniques, we have the abilitynot only to look at cells, but to understand what those cells are doing at the site ofprimary disease.

We are also concerned at the NIH with studies on thepsychosocial effects of these chronic diseases. Although much of the NIH is concerned withdiseases which ultimately cause death, we are also concerned with the chronic, common,crippling, and costly aspects of these diseases for patients, their families and forbiomedical research. We’re trying to identify gaps in knowledge. In identifying thosegaps in knowledge, we are also trying to identify opportunities to learn.

With regard to treatment approaches, you have heard from DrCoyle and from the others that there are many different approaches to therapy. On the onehand, with autoimmune disease, we do have the ability to generate specific therapies thatare specifically geared toward fooling the immune system so that it will no longer destroythe myelin basic protein. It will be fooled into interacting with something that we use asa substitute for myelin basic protein. In rheumatoid arthritis, from studies conductedaround the country, we know what some of the target antigen is. We know if we feed acertain type of protein, we can try to fool the system into reacting to that benignprotein rather than reacting to something in the body’s system. If an antibody or aprotein is what really is causing the disease in the individual, we can take that proteinand fool it into reacting with something other than the body itself. Or, if there is acell that is ending up reacting against the body and causing the inflammation, we aretrying to "fool" that cell into reacting to something other than what we have inour body.

There are also nonspecific treatments that are beinggenerated. Dr Hahn talked about some of the devastation that comes from these nonspecificanti-inflammatory treatments, whether they are the more benign type, the nonsteroidalantiinflammatories, or whether they are the immunosuppressive agents that can increase therisk for infection or even secondary cancers in some individuals. Today, we have theability to utilize certain molecular and genetic techniques to generate certain types ofproteins which will cause the body to change the process of inflammation. It’sconsidered nonspecific because it will work in many autoimmune diseases to alter the formof inflammation that takes place in the body.

There are many new approaches to treatment with substancesthat are called cytokines, that are normally produced by cells. Now, with molecularbiological techniques, the bioengineering companies are producing mounds of thesesubstances for use in human beings. There are many other genetic approaches, includinggene therapy. This is just at the beginning in terms of thinking about altering thebody’s immune response.

Last year there was a workshop entitled "Gender andAutoimmunity," and as a consequence of the workshop, there are initiatives comingfrom all sides of the NIH, working together in cooperation between the various institutes.For example, the National Institute of Allergy and Infectious Diseases and the NationalInstitute of Arthritis and Musculoskeletal and Skin Diseases have put out an initiative,and a call for researchers to submit their novel ideas on why many of these diseases aremuch more common in women than in men. There must be some clue, and that clue will notonly help women who have these diseases, but also men who have these illnesses.

I hope that this talk has provided you with a broad view ofour approach to generating new and exciting research at the NIH. 

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