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Pärt Peterson's article, "Estonian Nature" 03/2003


The author of the article, Pärt Peterson (1966), is an extraordinary professor of molecular pathology at the University of Tartu, researching the causes of autoimmunity.



The most important purpose of the immune system is to protect the body from pathogens, viruses, bacteria and parasites from the outside world. In addition, the immune system plays an important role in suppressing potential tumors. Because of these positive properties, we are used to thinking of the immune response as the body's defense. At the same time, the immune system can sometimes turn against the person as an enemy. Autoimmunity is a situation where the immune system is no longer able to distinguish between its own and a foreign one, and an immune reaction against one's own tissues develops.


The distinction between one's own and another is the result of complex selection processes, and therefore at first glance it is even surprising that the immune system can perform its given task normally. Molecules against which the immune system forms its response are called antigens. Most antigens are proteins that are similar in their biological structure in viruses, microbes and humans. Despite the fact that proteins are very diverse, they always contain similar amino acid sequences. Often proteins that function in the same way are structurally similar. Thus, it may happen that the proteins found in pathogenic microbes are similar in structure or amino acid structure to our own proteins.


The specificity of the immune system is based on accurate recognition of antigens and immunological memory. Normally, the immune system works precisely and is able to recognize even protein sequences only about ten amino acids long. Nevertheless, errors can occur in the recognition of antigens, which can cause so-called an autoimmune reaction in which a person's immune system attacks its own cells and tissues. An immune reaction against the body itself can have tragic consequences: it can cause chronic diseases and even lead to death.




There are many types of autoimmune diseases


Although the autoimmune response can be directed against almost any human tissue or organ, some of these diseases are affected more often than others. The most well-known autoimmune diseases are, for example, rheumatoid arthritis that damages the joints, multiple sclerosis that attacks the central nervous system, or childhood diabetes that destroys the insulin-producing cells of the pancreas. Even at the most superficial glance, it is clear that all these diseases are significantly different from each other, the consequences of damage are different and therefore require special treatment.


Despite the difference in outcomes, there are several similarities in the development of autoimmune diseases, suggesting that similar factors play a role in the causes and development of the diseases. Often, one patient has several autoimmune diseases or close relatives have different types of autoimmune diseases. This confirms the involvement of the same mechanisms in the development of diseases. In total, about 70-80 autoimmune diseases are known, but they probably also include several other diseases with unknown pathogenesis.



How Autoimmune Diseases Occur?


T-lymphocytes and antibodies play an important role in any immune response. T-lymphocytes are the basis of self and foreign antigen recognition. Together with the antibody-producing B lymphocytes, they are responsible for selective protection against proteins and other antigens from foreign microbes, while the antigens of the body are left intact. In the same way, they are central to the development of an autoimmune reaction, because in this case they have lost their "landmark" and behave contrary to the physiologically normal situation.


An example is diabetes (insulin-dependent or type 1 diabetes), which damages the insulin-producing beta cells located in the islets of Langerhans in the pancreas. The body needs insulin for carbohydrate metabolism: without insulin, the cells cannot acquire carbohydrates (sugars) from the blood and starve, while the blood sugar level is high. T-lymphocytes are formed in the blood of diabetics, which invade the pancreas and begin to destroy insulin-producing cells.


It turns out that such T-lymphocytes recognize proteins in beta cells as foreign, one of which is insulin itself. At the same time, other immune cells also invade the pancreas, further amplifying the inflammation that has started. In addition, under the influence of autoimmune T-lymphocytes, antibody-producing B-lymphocytes also become active, secreting antibodies against the same proteins, further exacerbating tissue damage.


As a result of such an inflammatory process, insulin-producing cells are destroyed and the pancreas loses its ability to produce insulin, which in turn causes the symptoms of diabetes. For some reason, an error in the specificity of T-lymphocytes and antibodies leads to self-destruction. Unlike diabetes, in which only one tissue is affected, in other autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple tissues can be affected at the same time. In SLE, an immune reaction develops against proteins that are found in most tissues of the body, and therefore many organs are involved in the disease.


Autoimmunity is primarily the cause of these various diseases. In this sense, autoimmunity is similar to another group of diseases of the immune system - allergies. Allergies can also be different forms of allergies, such as nasal (allergic rhinitis or hay fever), lung (asthma) or skin allergies (atopic dermatitis or eczema), but all of these diseases have the same cause or etiology. The same applies to autoimmune diseases: the etiology is the same, but the consequences are different. The only way to effectively treat such diseases is to deal with the causes of these diseases.


For several decades, efforts have been made to understand how such errors occur in the immune system. Several hypotheses and their combinations have been proposed, some of which have been confirmed. Autoimmunity development is probably a complex process: the interaction of several factors and disease mechanisms.



Interaction of genetic and environmental influences


Almost all autoimmune diseases develop as a result of the interaction of these two factors. Certainly, heredity plays an important role in the development of autoimmune diseases, although autoimmune diseases cannot be classified as classic genetic diseases.


In autoimmune diseases, there is usually no single genetic mutation that causes the disease. Instead, it is the interaction of many genes, and small differences or polymorphisms of different genes are important. In favor of genetic factors, the fact that one-third to one-half (different diseases vary) of genetically identical identical twins, one of whom is sick, also develops an autoimmune disease in the other twin also speaks in favor of genetic factors. But autoimmune disease can be different in twins. Therefore, it cannot be said that genes affect the development of a specific disease, rather it is a predisposition to autoimmunity, which in turn can develop into an autoimmune disease.


HLA (human leukocyte antigen) gene polymorphisms on the sixth human chromosome are of particular importance in the development of autoimmune diseases. The genes of the HLA group code for histocompatibility antigens (MHC I and MHC II) and are therefore responsible for the development of the immune response and are the basis for inter-individual differences that prevent tissue transplantation from one person to another. Tissue compatibility required for transplantation is possible only if the polymorphism of HLA genes is similar between two people. All major autoimmune diseases are also associated with polymorphism of certain HLA genes.


Thus, both autoimmunity and transplantation involve an immune reaction that uses HLA molecules. For example, 90-100% of patients with insulin-dependent diabetes mellitus have pronounced polymorphism of certain HLA genes. Despite such a correlation, it does not work the other way around, since the same diabetes-specific HLA gene polymorphism is known in almost 20% of people in the population, of whom only a few develop the disease.

Apart from HLA genes, other polymorphic genes have also been found. One example is the CTLA-4 gene, which, like HLA, is responsible for controlling the immune response. There are probably about 20-30 genes involved in various autoimmune diseases.


It is believed that if genetic factors create a predisposition, environmental influences often act as so-called. as a trigger, as a result of which the disease is triggered. Unfortunately, it is still largely unclear how exactly environmental factors work. It is known that some medicines can affect the development of diseases. In addition, viral and bacterial infections are also associated with the development of several autoimmune diseases. Proteins from viruses and bacteria, which are often similar in structure to human proteins, cause an immune response. Later, if the similarity of the proteins proves to be sufficient, the immune reaction can be transferred to the body's proteins, thus initiating an autoimmune reaction.


Stress or trauma can also cause an autoimmune disease. As one theory, it has been proposed that the basis of the autoimmune process is local stress in the tissue or organ, which generates a kind of danger signal to which the immune system reacts. Stress is also associated with hormonal fluctuations.


The risk of developing autoimmune diseases is significantly higher in women than in men. Thus, Sjögren's syndrome (damages the lacrimal and salivary glands) manifests itself ten times more often in women than in men. The reason for the higher proportion of women is primarily the female hormone estrogen. Fluctuations in other, especially steroid hormones, can also affect the development of autoimmune diseases.


Any autoimmune reaction does not always result in disease. Most people have some form of autoreactive T lymphocytes, or autoantibodies, but never develop the disease. This makes it difficult to diagnose autoimmune diseases. However, patients with autoimmune diseases clearly have a strong autoantibody response. Nowadays, analyzes based on genetic markers are increasingly used in diagnosis, for example, HLA polymorphisms are determined.


Current treatment of autoimmune diseases mainly deals with the consequences. The goal of the future is to better understand how the immune system works and how such diseases arise. By better understanding the autoimmune mechanisms, new opportunities will emerge to fully treat and more effectively prevent these diseases.





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