Autoimmune diseases (1)

Anna Petrenko, Copper News 

When the immune system rebels against its own body and its cells cause an immune response instead of pathogens, this is called an autoimmune disease.

There are several mechanisms of such a reaction. The first is the production of antibodies by cells of the immune system against their own molecules, which in this case are called autoantigens. The second is that other immune cells destroy whole cells of some organ: either because they did not recognize them as their own, or because some proteins of these cells accidentally turned out to be similar to pathogen molecules. Since it is impossible to remove the "irritant" from the body, the treatment usually takes on a chronic character.

The general treatment of systemic autoimmune diseases includes immunosuppressants and anti-inflammatory drugs, which can themselves harm the body. For some diseases, therapy is not aimed at eliminating the cause, but at alleviating its symptoms. For example, this is the case with diabetes: the patient is prescribed insulin injections. They are trying to overcome the situation with gene therapy. Another promising approach is the use of monoclonal antibodies.

Many have been known for a long time, but their autoimmune nature has been revealed recently.

Suffer from these diseases much more often than it seems: at least 5% of the inhabitants of Europe and North America, and two thirds of them are women. It is difficult to assess in total how acute the social significance of autoimmune diseases is in comparison with others – for example, age–related neurological diseases. Some diseases are extremely severe, others, on the contrary, are easily tolerated. However, they are clearly not the last in terms of financial costs for society. The burden of treatment for arthritis alone is estimated at $65 billion. In addition, the patient may have several autoimmune diseases at the same time, and the treatment is always prolonged. In addition, these diseases often accompany primary immunodeficiency and complicate diseases with non-immunological etiology, for example, Duchenne muscular dystrophy and atherosclerosis.

In addition, as a recent study by the American Autoimmune Disease Related Diseases Association (AARDA) has shown, the life of patients is complicated by a severe form of fatigue. 7838 people participated in the online survey. As it turned out, fatigue affects almost all aspects of life: its overall quality, career, ability to work, romantic, family and professional relationships, mental and emotional well-being. Despite the fact that most patients discuss these problems with doctors, many are not prescribed additional treatment.

Autoimmune disease is considered local if the damage is concentrated in individual organs. This is a case of multiple sclerosis, where cells of the central nervous system are affected, and type I diabetes – the pancreas is destroyed. Other diseases are systemic and affect the entire body. These are, for example, systemic scleroderma and lupus erythematosus with connective tissue changes.

The diagnosis of autoimmune diseases includes specific methods for detecting autoantibodies in the blood. For example, this is a test for antinuclear antibodies (ANA test) – a large group of antibodies directed at DNA, histones and other components of the cell nucleus.

In addition, since inflammatory reactions develop in the body, a complete blood test, determination of the level of C-reactive protein, erythrocyte sedimentation rate (ESR) and other general methods of detecting inflammation are used in clinical practice.

Even the brilliant Paul Ehrlich (Paul Ehrlich) at the beginning of the twentieth century wrote about the impossibility of "autotoxic horror" ("horror autotoxicus"): immunity, in his opinion, protects only from external agents, and harm can never be inflicted on one's own body. In theory, this is true, and this phenomenon is called "auto-tolerance". Cells of the immune system, prone to taking "their own" for "strangers", are destroyed by the body itself at the stage of development. In addition, a small amount of autoantigens is usually present in the human body, but their concentration is insufficient to trigger an immune response.

By 1957, Frank McFarlane Burnet had formulated a clonal-selective theory in which he showed how some lymphocytes with mutations could avoid destruction and cause autoimmune disorder.

Reproducible experiments and models of animal studies appeared in the 1960s. For example, at this time autoantibodies were described that appear in Sjogren's syndrome, in which the salivary and lacrimal glands are mainly damaged. At the same time, a hypothesis was first put forward about the connection of autoimmune diseases with viral infections. In the early 1970s, molecular details began to appear. By the 1980s, the similarity of the symptoms of autoimmune disease and the side effects of bone marrow transplantation was being discussed. A decade later, the idea arose to apply the principles of autoimmune disease as contraception – as immunization against spermatozoa.

Animal experiments and family analysis have made it possible to study DNA mutations that lead to disruption of the functions of cells of the immune system. In addition, genetic studies help to identify homologies between proteins of pathogens and internal molecules of the body. For example, one of the autoantigens, the sodium–iodine symporter NIS, has homology with three other thyroid antigens: thyroglobulin, thyroperoxidase and thyrotropin receptor. The researchers showed that NIS has significant local homology with at least 11 proteins of bacteria and viruses, for example, with streptococcus and herpes. Thus, if the human body is fighting herpes, then at the same time it can destroy thyroid cells.

Finally, new therapies based on molecular research have appeared. Last year's discovery by researchers from the University of Bristol (University of Bristol) It can help in the treatment of many autoimmune disorders, for example, multiple sclerosis, type I diabetes mellitus, Graves' disease and systemic lupus erythematosus. Scientists have found out how antigen-specific immunotherapy affects gene expression, as a result of which cells switch from attacking body tissues to protecting them.

Academic work is also actively underway to deepen knowledge about the nature of autoimmune diseases. Usually, after meeting with a pathogen, B cells return to the germinal centers of lymphoid tissue, where they shuffle their genome so as to create highly specific antibodies against a specific antigen of a virus or bacterium. At this point, lymphocytes change their structure and later become plasmocytes, which produce antibodies in huge quantities. In addition, they immediately react to a repeated encounter with the same "stranger" and thus form the memory of the immune system. Unfortunately, in some cases, unwanted DNA mutations may occur in such a situation.

This year, researchers from the Garvan Institute of Medical Research in Australia said they had found a group of cells that could start producing autoantibodies and dubbed them "Rogue germ center B cells." But then what is holding back the development of the disease normally? Scientists believe that this is a FAS receptor (a death receptor leading to cell death – apoptosis) on the surface of "rogue" B cells. As shown in the mouse model, FAS mutations lead to the appearance of an unusually large number of plasma cells from the "outcasts". The antibodies produced by them, contrary to the norm, were worse bound to the antigen, and many turned out to be autoantibodies at all.

In the next articles of the series, we will talk about the molecular mechanisms of the development of autoimmune diseases.

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08.08.2015