Physicians have long known that necrotizing enterocolitis (NEC), a potentially fatal infectious condition that destroys the lining of premature babies, is often linked to the development of severe brain injury in these infants. surviving. However, it is not yet known how the diseased intestine communicates its destruction of the newborn’s brain.
Now, working with mice, researchers at Johns Hopkins Medicine and the University of Lausanne in Switzerland have identified that missing link – an immune system cell they say will travel from the slice to the brain and attack cells rather than the defense as usual. .
The team’s findings were published in the journal Science Translational Medicine.
Seen in as many as 12% of babies weighing less than 3.5 pounds at birth, NEC is a rapidly progressing gastrointestinal crisis in which bacteria invade the colon wall and causing inflammation that can destroy healthy tension at the site. If enough cells become necrotic (die) until a hole is formed in the intestinal wall, bacteria can enter the bloodstream and cause life-threatening sepsis.
Researchers at Johns Hopkins Medicine and the Fred Hutchinson Cancer Research Center found that animals with NEC produce a protein called 4-hole-like receptor (TLR4) that binds to bacteria in the gut and secretes out of the intestinal destruction. They also concluded that TLR4 simultaneously activates immune cells in the brain called microglia, leading to white matter loss, brain injury, and reduced mental function.
For this study, the researchers hypothesized that CD4 + T lymphocytes – immune system cells also known as helper T cells – may be the link. CD4 + T cells get the nickname ‘helper’ because they help another type of immune cell called B lymphocyte (or B cell) to respond to superficial proteins – antigens – on cells that under attack by foreign invaders such as bacteria or viruses.
Activated by the CD4 + T cells, B cells immediately turn into plasma cells that make antibodies to identify the infectious cells to get rid of the body or memory cells that remember the biochemistry of the antigen for respond more quickly to future attacks.
CD4 + T cells also send out chemical messages that bring another type of T cell – called a killer T cell – to the area until the targeted infectious cells are removed. However, if this activity takes place in the wrong place or at the wrong time, the signals can inadvertently direct the killer T cells to attack healthy cells in their place.
In the first of a series of experiments, the researchers stimulated NEC in infant mice and then examined their brains. As expected, the figs showed a significant increase in CD4 + T cells as well as higher levels of protein associated with increased microglial activity.
In a follow-up test, the researchers showed that mice with NEC had a weak blood-brain barrier – the biological wall that normally blocks bacteria, viruses, and other dangerous substances that infect circulation in the bloodstream from reaching the central nervous system.
Next, the researchers concluded that the accumulation of CD4 + T cells was responsible for the brain damage observed by NEC. They did this first by blocking the movement of the helper T cells into the brain and then in a separate test, neutralizing the T cells by binding them to a specially designed antibody. In all cases, microglial activity was controlled, and white matter in the brain was retained.
To further explain the role of CD4 + T cells in brain injury, the researchers extracted T cells from the brains of mice with NEC and inserted them into the brains of implanted mice. bred so that both T and B lymphocytes did not. Compared to control mice that did not receive any T cells, the mice that received the lymphocytes had higher levels of the chemical markers that attracted killed T cells.
The researchers then tried to better explain how the accumulating CD4 + T cells actually destroyed white matter, a fat called myelin covering and protects neurons in the brain and enables communication between them. To do this, they used organoids, laboratory-grown mouse brain cells to mimic the entire brain. CD4 + T cells derived from brains from mice with NEC were added to these laboratory “micro-brains” and then analyzed for several weeks.
After adding IFN-gamma to the organs, the researchers observed the same increased levels of inflammation and myelin reduction seen in mice with NEC. When they applied a neutralizing antibody IFN-gamma, cytokine production was significantly reduced, inflammation was reduced, and white matter was partially regenerated.
The researchers concluded that IFN-gamma directs the process leading to NEC-related brain injuries. Their finding was confirmed when a study of brain bones from mice with NEC showed higher levels of IFN-gamma than in interferons from mice without the disease.
Next, the researchers investigated whether CD4 + T cells could migrate from the cleft to the brain of mice with NEC. To do this, they obtained CD4 + T cells from the womb of infant mice with and without NEC. Both cell types were introduced into the brains of infantile mice in two groups – one set that could produce the Rag1 protein and one that could not. Rag1-deficient mice do not have mature T or B lymphocytes.
The Rag1-deficient mice that received gut-based T helper cells from mice with NEC showed the same features of brain injury seen in the previous trials. T cells from both mice with and without NEC did not cause brain injury in mice with Rag1, and T cells from mice without NEC did not cause in mice with Rag1 deficiency. This showed that the helper T cells derived from gut from mice with NEC were the only ones that could cause brain injury.
In a second experiment, gut-derived T cells from mice with and without NEC were introduced into the peritoneum – the membrane lining the abdominal cavity – of Rag1-deficient mice. Only brain intestinal T cells from mice with NEC caused brain injury.
This finding was confirmed by genetically following the same extracts from both brain and gut T-derived lymphocytes from mice with and without NEC. The sequence of T helper cells from mice with NEC was, on average, 25% genetically similar while those from mice without NEC were only 2% combined.
In a final test, the researchers blocked IFN-gamma by itself. By doing this it provided great protection against the development of brain injury in mice with true NEC. This suggests, the researchers say, a therapeutic approach that may be beneficial for premature babies with the condition.
Based on these findings, researchers said there could be measures to prevent this type of brain injury, including medications to block INF-gamma action.
(This story was published from a wire group group without altering the text.)
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