New immunopathology
Immunologists have identified a weak link in the body's defense system
Immunologists from the Medical Research Center at Cincinnati Children's Hospital (USA) have described an unknown part of the molecular mechanism whose failures lead to a weakening of immunity.
A young man suffering from leukopenia – a decrease in the number of leukocytes (white protective blood cells) was admitted to the hospital – and splenomegaly – pathological enlargement of the spleen.
The decoding of all protein-coding genes (exome) in the DNA of this young man showed that he is a carrier of a point mutation in the gimap5 gene, leading to an almost complete absence of the protein of this gene.
The results of the tests interested the immunologists of the medical center, because they had been conducting research on this gene for a long time. It encodes the GIMAP5 protein, whose main role is interaction with guanosine triphosphate (GTP), it participates in immune processes.
It was known that the lack of this protein is associated with a decrease in the viability of lymphocytes (the main cells of the immune system), a decrease in their level, the occurrence of autoimmune diseases and colitis (inflammation of the intestine). But the molecular mechanism of the effect of the gimap5 gene on immune processes has not yet been established.
For experiments, scientists have bred a special line of mice, called "sphinxes", with a mutation in the gene gimap5. In the cells of mice, the GIMAP5 protein was not produced, and, as a result, the level of T-lymphocytes in the line was lowered, maturing in the thymus gland, or thymus (hence the "T" in their name), and then spreading through the body.
The clinical picture of pathologies in these mice resembled the diseases diagnosed in the young man: reduced resistance to infections and a violation of the structure of the spleen. The researchers began to reveal the cause of the lowered level of T-lymphocytes in the body by assessing their "release" by the thymus.
Comparison of "sphinx" mice with wild-type mice (without mutation) showed that the thymus works normally. Then scientists began to look for the reasons for the deficiency of protective cells on the periphery of the body and found out that after meeting T-lymphocytes with a foreign substance, they are not able to reproduce in the line of "sphinx" mice, although "on duty" they are obliged.
Microscopic image of a healthy mouse T-cell. The protein Gimap5 (green area in the upper right corner) and the enzyme GSK3 (red area) intersect in small cellular structures-vesicles (yellow area). This happens before GSK3 enters the cell nucleus (blue). This is an important step to prevent DNA damage in active T cells during their growth. Image: Cincinnati Children's
It was possible to establish the mechanism during the study of signaling pathways: the content of one of the factors responsible for the beginning of reading the DNA code in the line of "sphinxes" was too low, and its regulation was carried out by the enzyme glycogen synthesis kinase-3, or GSK3