Autoantibodies: find and prevent future illness

Galina Kostina, Expert Magazine N edavno in Moscow passed II 

International Conference "Natural immunity in norm and pathology". Like the first one — two years ago — it was organized by the leading Russian center for the study of autoantibodies of the IC "Immunculus" with the support of the I. M. Sechenov MMA. One of the main topics is autoantibodies as harbingers of diseases. The conference was attended by world authorities in this field. It is significant that prior to these conferences, "auto-builders" did not gather in such a company.

If antibodies appear as a reaction to antigens of foreign substances or organisms — bacteria, fungi, viruses, then autoantibodies (autoimmune antibodies) are formed during the development of autoimmune disorders and act on the components of the body's own tissues.

Now there is no doubt that the functions of the immune system are much broader than previously thought. Ilya Mechnikov also expressed the idea that the cells of the immune system are not only "gendarmes", but also regulators. Today it is known that some autoantibodies serve as "scavengers", sending old or unusable cells for recycling, others, on the contrary, "bodyguards", in particular, for hormones, and others regulate biochemical reactions in the cell.

"Scavengers", perhaps, were the first to draw attention to themselves, since their number could be an indicator of the onset of some disease that no one suspects yet. The topic of autoantibodies, raised by scientists thirty years ago, was overshadowed by genomic research and the large-scale Human Genome project. Paying tribute to the results of this global project, many participants of the conference said that such a project on autoantigens and autoantibodies could become much closer to medical practice. When the human genome was deciphered in 2003, the world press was full of headlines about deciphering the book of life and a new era in biology and medicine. But it was still necessary to find out what all these genes are, how the proteins encoded by them form a biological portrait of a person, how genes participate in numerous chemical reactions. It was assumed that ways to many incurable diseases would be found. However, the level of "genetic frustration" turned out to be quite high, if only because only in isolated cases a breakdown in one gene was enough for the development of the disease. In most cases, whole ensembles of genes and a lot of incoming factors are involved in the development of the disease. At the same time, research in the field of immunology, which for a long time was only the stepdaughter of microbiology, studying viruses and bacteria, brought it to a new level. 

The recognition of the position that the immune system is not so much a "gendarme" for viruses and bacteria, but also a regulatory system, and its elements, in particular autoantibodies, are able to "talk" about the state of the body, brought fundamental science closer to practice. It became clear that a broad study of autoantibodies will help predict various diseases. And such work can be done only by joint efforts and subject to large investments.

And the initiator of international conferences in Moscow on natural immunity, the head of the Immunculus Center, Professor Alexander Poletaev, like many of his colleagues from other countries, believes that a large joint program on autoantibodies is needed

"Such a project cannot be raised alone. "Together we can assign roles, get access to information and those banks of blood serums that have been stored for more than ten years. Then our joint work will be more effective, and success will be shared. So far, we have agreed that as a minimum program for the next conference, we will write a book together with active participants from different countries, and as a maximum program, we will prepare a draft version of a large program on preventive medicine and autoantibodies."

Poletaev himself has been conducting autoantibody research for twenty years. Together with colleagues, he identified about 50 autoantibodies-markers that can indicate a person's state of health. Since autoantibodies are like a mirror image of autoantigens that are characteristic of certain organs and tissues, their number and totality reflect the overall picture. It is known that in healthy people, the number of certain autoantibodies is approximately the same. A prolonged increase or decrease in their number, according to Poletaev, indicates problems in the relevant authorities. Externally, a person can look healthy until he has no clinical manifestations of the disease, and autoantibodies can already "declare" the beginning of some disease.

Alexander Poletaev is convinced that autoantibodies are harbingers not only of autoimmune diseases, but also of many others, in particular cardiovascular diseases, diseases of the gastrointestinal tract, kidneys, liver, lungs. The Immunculus Research Center has prepared a number of test panels approved by the Ministry of Health of the Russian Federation and used for diagnostics both in the Immunculus itself and in other medical centers. Tests that determine women's reproductive health are particularly popular. In 2007, the Immunculus project on autoantibodies — harbingers of diseases received the Grand Prix at the Russian Innovation Competition held by our magazine since 2001, and was recognized by experts as the best in the "Success Story" nomination. Now Professor Poletaev is working on expanding the panel and completing research on creating oncotests.

Alexander Poletaev understands that even 50 tests for a general immune portrait of a person is not enough. To create a complete picture, you need to study thousands more proteins and choose from them the "harbingers" of many diseases. This is what joint efforts of scientists are needed for.

One of the most famous immunologists and propagandists of the Autoantigenom project, Abner Notkins from the US National Institutes of Health, is convinced that it requires the combined efforts of specialists from world laboratories. "This is a new and good idea," a professor of medicine from University of California San Diego Wolf Palinski. — I think that the results of such a project would justify the efforts spent on it. But first we need to build a foundation for this project — organizing conferences, symposiums, formulating a project strategy, preparing many publications on this topic." Leonid Churilov, head of the Pathology Department of the Medical Faculty of St. Petersburg University, also believes that it is necessary to create a society headed by such authorities as Abner Notkins, Ruiz Arguelles, Yehuda Schoenfeld. Hilmar Lemke from The Institute of Biochemistry at Albrecht University (Germany) also believes that joint efforts will help to better coordinate the work of specialists, at least in order not to perform identical studies in different laboratories. A professor of medicine at Tel Aviv University (Israel) is also in favor, although he believes that it will be easier to find funding for more private projects in this area.

Abner Notkins gave an interview to our magazine.

— Mr. Notkins, at one time the topic of autoantibodies was "unfashionable". Why is there increased attention to her now?

— This topic is becoming more and more relevant because the whole paradigm of modern medicine is changing: there is a turn from treatment to prevention and prevention of diseases. The impetus for the beginning of broader research in the field of autoantibodies was given by the human genome study project, during which scientists hoped to learn how to predict a person's condition by linking mutations in genes with the subsequent development of diseases. However, everything turned out to be more complicated: many genetic diseases, in particular autoimmune diseases, depend on the complex interaction of many genes, and mutations do not always mean the future development of the disease. Some scientists have concluded that autoantibody analysis is more important in predicting these diseases than genes. The appearance of new data as a result of research indicates the important role of autoantibodies as predictors of the processes developing in the body.

There is a strong opinion that the immune system, which has been formed for hundreds of millions of years, is designed to protect us from extraneous aliens — bacteria and viruses. This is true. However, sometimes, for reasons not entirely clear, it begins to attack its own tissues, which leads to the development of autoimmune diseases. One of the most common of them is diabetes, affecting millions of people worldwide. It is known that the immune system attacks beta cells of the pancreas, and lymphocytes and antibodies are involved in this. Scientists have found that a lot of autoantibodies circulate in the blood of patients with type I diabetes mellitus. The search for beta-cell autoantigens began. There were three of them. One of them — IA 2 was isolated in my laboratory. We determined its sequence, created a method for detecting autoantibodies to this antigen and screened several thousand serums from patients with type I diabetes and healthy people for control. We found autoantibodies to IA 2 in 70 percent of patients, and there were practically none in healthy patients (less than one percent).

— These studies have shown that autoantibodies accompany diabetes. How did you find out that they appear long before the first clinical manifestations? And how much time passes before the onset of the disease?

— To get such information, our and other laboratories have engaged in research of more than twenty thousand people. Moreover, the observations lasted ten to fifteen years. We took the blood serums of these people. And upon detection of each new case of type I diabetes mellitus in these groups, we extracted the stored sera and the results of their study and tested them for the presence of autoantibodies to three known diabetic antigens, including the IA 2 we identified. Such long studies and tedious waiting were rewarded. We found that the presence of autoantibodies to at least one antigen indicates the risk of developing a clinical form of diabetes over the next five years in 10 percent of the subjects, in the presence of autoantibodies to two types of antigens — in 50 percent, and three types — in about 70 percent.

Prior to this discovery, it was impossible to predict the development of type I diabetes mellitus. Meanwhile, in the United States, the risk of getting it is estimated as 1 in 400.

Previously, it was generally believed that diabetes develops rapidly. Our research has shown that years pass before the first symptoms appear. Thanks to these studies, type I diabetes mellitus has become a vivid example of how the level of autoantibodies can predict the disease in ten to fifteen years.

— In one of your publications in Scientific American magazine, you said that 40-80 autoimmune diseases are known today. Why is there such a spread in the assessment and which of them have learned to predict autoantibodies?

— Such a spread exists because not all the details are known about many diseases yet. In general, approximately 7 percent of the world's population suffers from various autoimmune diseases. They are third in the "popularity" rating after cardiovascular and oncological. As far as I know, most of the research has been done on only a few diseases, in particular, rheumatoid arthritis, systemic lupus erythematosus, thyroiditis and celiac disease.

— Why so little?

— I have already told you about research on diabetes: you need to involve a lot of people, wait ten to fifteen years, respectively, it takes a lot of money. Not necessarily the harbingers of other diseases manifest themselves so long ago, but it needs to be found out. For example, some studies have shown that rheumatoid arthritis can be caught about ten years before the appearance of clinical signs (in different groups, they manifested themselves in 40-90 percent of those observed). Signs of lupus appeared in 30-80 percent of the subjects after an average of 9.4 years, celiac disease or gluten disease — in 80 percent seven years after the corresponding autoantibodies-precursors were identified. I want to emphasize that the percentage of cases is still approximate due to the limited number of studies and the small number of patients. But in general, the trend of such a correlation is encouraging.

— Autoantibodies can only be precursors of autoimmune diseases?

— I used to think so. Now several laboratories are considering the link between autoantibodies and oncological diseases. If it is detected, autoantibodies can become early markers of tumor development. There are studies that predict the risk of stroke based on the presence of certain autoantibodies in patients with atherosclerosis, and predictors of thrombosis or miscarriage in patients with antiphospholipid syndrome are also being studied. Now there are many groups working in the world that are looking for autoantibodies as markers of other diseases.

— What does this knowledge give to doctors and patients? Is it possible to start treating a particular disease when there are no manifestations of it yet? Should there be special therapy for the early stages?

— It is still unclear how you can prevent the development of diabetes mellitus. But it has already been found out that early treatment of rheumatoid arthritis helps to avoid a more severe stage of the disease. In the case of celiac disease, for example, it is possible to establish a regime that will not allow the disease to develop. It is known that this disease is associated with gluten intolerance, which is found in grain crops. If you exclude all grain products, as well as other products — some sauces, ice cream and even meat products that contain gluten, the immune system will have nothing to attack. It is harder with those diseases for which there are no effective treatment methods yet. But this is also the importance of predictive medicine, that it gives us the opportunity to start looking for treatment methods, since there are still several years before the appearance of the disease itself.

— You have already spoken more than once about the Human Autoantigen project. How do you think it should develop?

— The first step is the compilation of the "genome" of human autoantigens, their identification — for which everyone is responsible. It is known that almost every disease has several types of autoantibodies. In general, it is necessary to examine up to 50 thousand proteins on serums with various diseases. The second step is to determine which of these autoantibodies are predictors. To do this, you need to conduct long-term studies, going back to the results of ten or fifteen years ago, to understand which autoantibodies were present at the very beginning. The third step is to learn how to treat the patient at the pre—pain stage and prevent the development of the disease. And the fourth — many ethical questions need to be answered. Who should be tested? What is better — ignorance or a "painful" test result and fear of the future, especially if a decent therapy is not offered for the disease? Will there be problems with health insurance for people with disease precursors? Wouldn't the results of such tests be a problem when applying for a job?

— Many scientists say that such a grandiose project will be difficult to raise financially. Have you tried to raise the question of such a project at the National Institute of Health — the main source of budget injections into fundamental science in the United States?

— I can't put the question like that myself, since I work in a state institution. But I communicate with different scientists and companies. Such international meetings are also important, when more and more information is gathered about research in this area. In the USA and Europe, scientific research is mainly funded by the state. But in such a project, I think various funds and private investors could also join it. I think the project will take place in one form or another. Coordination of actions and a common platform for scientific research will contribute to this.

— Does it exist in USA autoantibody diagnostics and are you familiar with the works of Professor Alexander Poletaev, who has developed relatively large panels for the study of various autoantibodies and their association with various, including non-autoimmune, diseases?

— There is no special diagnosis for many diseases. As for the individual ones, Wasserman's familiar reaction is the first example of such a diagnosis. Many laboratories make some panels, but they are used only for research purposes, not in medicine, although there are individual doctors who use these panels in consultation with the patient. Here, in my opinion, a long and painstaking work is still needed. We have been corresponding with Alexander Poletaev for only a year, and I expect in Moscow to get a closer look at the results of his work.

Portal "Eternal Youth" www.vechnayamolodost.ru20.10.2008