Not an unnecessary detail
Siberian scientists have come closer to understanding the mechanisms of multiple sclerosis
Yulia Klyushnikova, "Science in Siberia"
Multiple sclerosis is a severe autoimmune disease, the causes of which have not been sufficiently studied to date. New data from Novosibirsk biochemists may be useful for identifying the factors and mechanisms that lead to the occurrence of pathology. The work was published in the Journal of Cellular and Molecular Medicine.
The staff of the Laboratory of Repair Enzymes of the Institute of Chemical Biology and Fundamental Medicine of the SB RAS, under the guidance of the head of the laboratory, Doctor of Chemical Sciences Georgy Alexandrovich Nevinsky, together with colleagues from the Research Institute of Fundamental and Clinical Immunology, are studying experimental autoimmune encephalomyelitis (EAE) in mice, which is a model of human multiple sclerosis (MS).
In multiple sclerosis, the immune system mistakenly destroys myelin (the substance that forms the sheath of nerve fibers) in the brain and spinal cord. As a result, the body begins to fight with itself, producing antibodies or aggressive clones of lymphocytes. Since this process occurs gradually, the disease may not manifest for a long time, besides, there are currently no reliable methods for its prediction and treatment.
"Multiple sclerosis in humans and experimental encephalomyelitis in mice have similar signs," comments Ksenia Sergeevna Aulova, an employee of the IHBFM SB RAS and a graduate student of Novosibirsk State University. – In both cases, there is an increase in the level of antibodies to myelin proteins in the blood. Also, in both diseases, antibodies with unusual catalytic properties are found in the blood serum: like enzymes, they can cleave various molecules – for example, fragments of their own DNA that have entered the extracellular space during cell death. DNA is present in the blood of healthy donors, and in various infections and autoimmune pathologies. However, antibodies that cleave DNA are absent in the blood of healthy patients and are markers of pathological processes."
To "trigger" the disease in laboratory animals, they are usually injected with a myelin protein that provokes an immune response. Scientists activated EAE in mice with the help of three different antigens (substances that the body considers as foreign or potentially dangerous – ed.), presumably involved in the development of MS: the protein myelin-oligodendrocyte glycoprotein (MOG), as well as a DNA fragment from the calf thymus in combination with two different types of proteins (bovine serum albumin and histones).
The experiment was carried out for 60 days. Every two weeks after the introduction of foreign substances, scientists analyzed various parameters of the disease in mice, such as weight, proteinuria (protein level in urine), the level of antibodies to myelin and DNA proteins, as well as the level of apoptosis (death) and proliferation (division) of lymphocytes isolated from animal organs: thymus, spleen, bone marrow, lymph nodes. In control (non-immunized) mice, the same parameters were studied throughout the entire duration of the experiment.
The scientists also studied hematopoietic bone marrow stem cells in animals, which are responsible for the formation of all types of blood cells. "It is believed that various pathologies and anomalies in autoimmune diseases originate in the bone marrow. Various disorders in the formation of blood elements can lead to the formation of "harmful" lymphocytes, leading to the destruction of myelin, and other undesirable reactions in the immune system," explains Ksenia Aulova.
Lymphocytes are always present in the body of healthy people, but are under strict control of the immune system. In a gland called the thymus, these cells undergo "training" aimed at preventing autoimmune reactions. But sometimes there are failures in the learning mechanisms. This can lead to the fact that some of the lymphocytes that consider their own body tissues as "enemies" become the cause of diseases.
The study showed that all three antigens contributed to the development of experimental encephalomyelitis, but for two of the three antigens, immunization led to a delayed manifestation of signs of the disease. "The appearance of antibodies with catalytic activity that cleave DNA is one of the early symptoms of an autoimmune disease. With the introduction of MOG, this activity occurs in mice in the early stages: after 6-8 days. And when using DNA complexes – much later: after 22 days, that is, in fact, after the acute phase of the disease," says Ksenia Aulova.
The staff of the IHBFM SB RAS plan to continue research on transgenic lines of mice in which some parameters of the immune system are genetically conducive to the development of EAE.
"The work was supported by an RNF grant (No. 16-15-10103). By conducting such an experiment, we can understand that the reaction of immune system cells is capable of initiating the disease not only to myelin proteins (normally they should not react to them), but also to their own DNA, which can also play a significant role in the development of autoimmune pathologies such as EAE and MS. Thus, the contribution of DNA to the formation of encephalomyelitis in mice and, probably, MS in humans was studied for the first time. This fundamental work may lead to a better understanding of the mechanism of the origin of this insidious disease," says Ksenia Aulova.
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