Science sub-journal interpretation! Revealing necrotum colitis, CD4-T cells migrate from the intestines to the brain, causing brain damage

January 12, 2021 // --- Doctors have long known that necrotizing colitis (NEC) is often associated with severe brain damage in surviving infants as a potentially fatal inflammation that destroys the gut walls of premature babies.
, however, the means by which the diseased intestine "communicates" its destructive "transmission" to the newborn's brain remain largely unknown.
now, in the first new study, researchers from the Johns Hopkins University School of Medicine in the United States and the University of Lausanne in Switzerland identified the missing link -- they say immune system cells migrate from the intestines to the brain and attack the cells there, rather than protecting them as usual.
study was published in the January 6, 2021 issue of the Journal of Science Translational Medicine under the title "Necrotizing enterocolitis induces T lymphocyte-mediated injury in the development of the processing of the cul-de-sein brain."
images from Science Translational Medicine, 2021, doi:10.1126/scitranslmed.aay6621.
NEC, seen in up to 12 percent of babies born weighing less than 3.5 pounds, is a fast-moving gastrointestinal emergency in which bacteria invade the colon wall and cause inflammation that eventually destroys healthy tissue in the area.
enough cell necrosis (death) to form holes in the intestinal wall, bacteria can enter the bloodstream, leading to life-threatening sepsis.
in a 2018 mouse study, researchers at Johns Hopkins University School of Medicine and the Fred Hutchinson Cancer Research Center found that animals with NEC produce a protein called toll-receptor 4, which binds to bacteria in the gut and promotes intestinal damage.
also determined that TLR4 simultaneously activates immune cells in the brain called small glial cells, leading to white blood loss, brain damage, and cognitive decline.
is not clear how the two are linked.
the new study, the authors speculate that CD4-T lymphocytes ---immune system cells, also known as auxiliary T-cells--- may be linked.
CD4-T cells are called "assistive" because they help another type of immune cell called B lymphocytes, or B-cells, respond to antigens on the surface of cells infected by foreign invaders such as bacteria or viruses.
When CD4-plus T cells are activated, immature B cells either become plasma cells, producing antibodies to mark infected cells in order to remove them from the body, or memory cells that "remember" the biochemical properties of antigens to respond more quickly to future invasions.
CD4 plus T cells also release chemical messengers that recruit another type of T cell, or killer T-cells, into the region to remove the target infected cells.
, however, if this activity occurs in the wrong place or at the wrong time, the chemical signals released may inadvertently direct lethal T-cells to attack healthy cells.
Co-author of the paper, Dr. David Hackam, a professor of surgery at Johns Hopkins University School of Medicine and chief surgeon at the Johns Hopkins Children's Center, said, "By comparing the brains of infants with NEC with those of infants who die of other causes, we know that the former has the accumulation of CD4-T cells and exhibits more small glial cell activity."
we guessed that these T-cells came from the NEC inflammatory region of the intestine and began using newborn mice as models for human babies to prove it.
in a series of experiments, the authors induced NEC in young mice and then examined their brains.
as expected, there was a significant increase in CD4 plus T cells in brain tissue, as well as higher protein levels associated with increased activity of small glial cells.
follow-up tests, they found that the blood-brain barrier ---usually prevents bacteria, viruses, and other harmful substances circulating in the blood from reaching the walls of the central nervous system--- are weakened.
they speculate that this may explain how CD4-plus T cells from the gut can travel to the brain.
, the authors determined that the accumulated CD4-plus T cells were the cause of brain damage seen by NEC.
first biologically prevented these auxiliary T-cells from entering the brain, and then in another experiment, they neutrally neutraled them by binding them to a specially designed antibody.
in both cases, the activity of small glial cells was inhibited and whites in the brain were preserved.
to further determine the role of CD4 plus T cells in brain damage, the authors collected T cells from the brains of mice with NEC and injected them into the brains of mice that also lacked both T and B lymphocytes.
mice that received these lymphocytes had higher levels of chemical signals to recruit lethal T-cells than mice in the control group who did not receive any T-cells.
also observed activation of small glial cells, inflammation of the brain and loss of white matter--- markers of brain damage.
Then, the authors tried to better determine how the accumulated CD4-plus T cells destroy whites--- in fact, a type of fat called myelin, which covers and protects neurons in the brain and promotes communication between them.
, they used brain-like organs, mouse brain cells grown in the lab, to simulate the entire brain.
add brain-sourced CD4-T cells from mice with NEC to brain-like organs in these labs and then examine them over several weeks.
Hackam and his colleagues found that as myelin levels decreased, a special chemical signal from these T-cells ---a cytokine called interferon-γ (IFN-γ) --- increased in brain organs.
this activity was not found in brain-like organs that added CD4 plus T cells from NEC-free mice.
addED IFN-γ individually to brain organs, the authors observed the same increased levels of inflammation and decreased myelin in NEC mice.
when they were added to ifN-γ and antibodies, the production of this cytokine was significantly reduced, inflammation was suppressed, and whites were partially restored.
The authors conclude that IFN-γ guides the processes that lead to NEC-related brain damage.
their findings were confirmed when they examined brain tissue in mice with NEC and found that IFN-γ levels were higher than those in mice without the disease.
, the authors looked at whether CD4-plus T cells could migrate from the intestines to the brains of NEC mice.
, they obtained CD4 plus T cells from the intestines of young mice with and without NEC.
both types of T cells were injected into the brains of two groups of young mice--- one group of young mice produced the protein Rag1 and the other group could not produce the protein.
mice with missing Rag1 did not have mature T or B lymphocytes.
mice with Rag1 were given intestinally-assisted auxiliary T-cells from NEC mice, showing the same characteristics of brain damage as observed in previous experiments.
T cells from mice with and without NEC did not cause brain damage in mice with Org1, nor did T cells from mice without NEC cause brain damage in mice without Rag1.
suggests that intestinally assisted T cells from NEC mice are the only cells that can cause brain damage.
second experiment, intestinal-source T cells from mice with and without NEC were injected into the peritoneal membrane of mice with and without RAg1.
only intestinal T cells from NEC mice caused brain damage.
this finding was confirmed by genetic sequencing of the same parts of brain-based and intestinally-sourced T lymphocytes in NEC mice.
there was an average gene similarity of 25% between brain-sourced and intestinally assisted T-cell sequences in NEC mice, while the average gene similarity of brain-based and intestinally assisted T-cell sequences in NEC mice was only 2%.
in the last experiment, the authors individually blocked the IFN-γ.
this has a significant protective effect on brain damage in mice with severe NEC.
authors say this suggests that a treatment could benefit premature babies with the disease.
T cells from the NEC-causing intestine can migrate to the brain and cause damage," said Hackam, a researcher at the Study Group.
mouse models in our study have previously shown a very consistent with what happens in human patients, so we believe this is a possible mechanism for NEC-related brain damage in premature children.
based on these findings, Hackam said interventions to prevent this type of brain damage, including treatments that block ifN-γ, are possible.
: 1. Qinjie Zhou et al. Necrotizing enterocolitis induces T lymphocyte–mediated injury in the developing mammalian brain. Science Translational Medicine, 2021, doi:10.1126/scitranslmed.aay6621.2.Diego F. Niño et al. Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain. Science Translational Medicine, 2018, doi:10.1126/scitranslmed.aan0237.3.Mouse Study Finds Link Between Gut Disease and Brain Injury in Premature Infants