[메디게이트뉴스 배진건 칼럼니스트] British cellist Jacqueline Du Pré has been holding cellos since the age of 5 and has been active since the age of 15. At the Royal Festival Hall in England in 1962, Jacqueline played Elgar’s Cello Concerto with the BBC Symphony Orchestra, causing an explosive response to critics and the public. In 66 he met Daniel Barenboim and married at the age of 21. Thanks to the combination of a genius conductor and cellist, their concerted performances were praised for excellence anywhere in the world. In 1971, while actively active, Jacqueline suddenly complained of systemic pain and abnormalities, and was diagnosed with multiple sclerosis (MS). In 1975, he was paralyzed, and in 1987 he died. Multiple sclerosis retired in his late 20s, the peak of his career as a performer, and died young at the age of 32.
Multiple sclerosis is a refractory central nervous system disease. The brain is made up of many cells. The connection point between neurons, neurons, which are thought to contain our memories and information, is a synapse. Synapse is a combination of the Greek words’syn- (together)’ and’haptein (to combine)’. If neurons are responsible for transmitting signals to individual target cells, synapses are the tools that allow neurons to do that. Glia (glial cells) is a term for non-neuronal cells in the central nervous system. It is composed of cells with functions.
Synapses, which are the connection points between nerve cells, show structural plasticity in which creation and extinction itself are dynamic. Synapse extinction is not only a key mechanism for remodeling neural networks that occur continuously in the brain, but also a pathological phenomenon occurring in the early stages of degenerative brain disease. If there is a problem with synapse extinction, it has a great adverse effect on the development of the brain and maintenance of homeostasis, and is thought to act as a direct cause of various brain diseases.
Just as cytotoxic T cells directly attack and kill cancer cells or virus-infected cells, microglia move around the brain, act as a monitor, and are responsible for the primary immune response in various situations. Since astrocytes are in physical contact with most of the synapses, it is thought that they will be able to respond primarily to microglia when the synapses are structurally destroyed by changes in neuronal activity. Cells called astrocytes have numerous twigs, through which one astrocyte embraces 4 neurons, 600 neurons, and tens of thousands of synapses at the same time, and is known to interact with neurons. In the past, most opinions were that the role of astrocytes was only passively supporting the survival and function of neurons, but recent studies have shown that astrocytes directly induce synapse formation and function enhancement.
Contrary to the conventional perception that microglia is the only one with phagocytic capacity in the normal brain to destroy synapses or perform other cleaning tasks, a specific astrocyte, which occupies the largest number of cells in our brain, receives the instructions from the intestine and ‘Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+anti-inflammatory astrocytes’, a paper that physically eliminates inflammation of the body, was published on January 6th. Published in Nature.
Autoimmune encephalomyelitis (EAE) is an animal model similar to human multiple sclerosis. Unlike multiple sclerosis in humans, EAE in rodents clearly shows progressive muscle paralysis, suggesting that an inflammatory response targeting the spinal cord actually exists. Researchers used instruments that analyze genes and proteins to identify specific astrocyte subsets. Control mice and EAE mice (Aldh1l1EGFP) were compared through fluorescence activated cell sorting (FACS) analysis, and cerebrospinal fluid astrocytes were screened using 266 antibodies. High-throughput FACS was added to single-cell RNA sequencing and genetic manipulation using CRIPR-Cas9. It’s a really great hand.
Meninges (腦膜, meninges) refer to all three membranes that surround the brain and the central nervous system (CNS). Inflammation occurs in the meninges, or blood vessels in the meninges sometimes burst. When meningitis is inflamed (meningitis), cerebrospinal fluid (CSF) is extracted and tested because the pathogen or virus is fatal when it reaches the brain. Astrocytes near the meninges found a subset of astrocytes that simultaneously contain LAMP1 (lysosomal-associated membrane protein 1) and TRAIL. TRAIL is attracting attention as a protein that protects normal cells and has tumor selective killing ability thanks to a unique receptor system called death receptor (DR5) and decoy receptor (DcR1, DcR2). ‘LAMP1+TRAIL+astrocytes’ blocks inflammation of the central nervous system by inducing the death of T cells that cause inflammation. In antigen-induced models, an inflammatory response occurs in the brain, not the spinal cord. The specific inflammatory sites occurring in the central nervous system suggest the potential to influence the specificity of the astrocytes subset antigen and the ability to produce IFNγ.
To determine what LAMP1+TRAIL+astrocytes do in the brain, the researchers conducted a number of experiments using the genetic scissors’CRISPR-Cas9′. As a result, it was found that interferon gamma (IFNγ) in particular regulates the expression of TRAIL protein. Microbiome is a combination of’microbe’ and’biome’ that inhabit the human body, and refers to 38 trillion microbes and their genes in the body. Moreover, when NK (natural killer) cells, which are directed by the intestinal microbiome, go around our body and reach the meninges, they immediately cause IFNγ protein expression, allowing astrocytes to act as anti-inflammatory. The expression of TRAIL in astrocytes is caused by the action of IFNγ, and meningeal NK cells directly produce IFNγ. In addition, the expression of IFNγ in NK cells is regulated by the intestinal microbiome. TRAIL, a brain inflammation killer, is the spy of a spy under the direction of the intestine.
Multiple sclerosis is a demyelinating disease (demyelinating disease) of the central nervous system. It is the most common type of disease in which myelin sheath, an insulating material surrounding axons of nerve cells, falls out, and is a chronic inflammatory disease that occurs mainly in younger age groups. It is an autoimmune disease that can even cause death: A better understanding of the pathway by which LAMP1+TRAIL+astrocytes blocks inflammation could lead to the development of new drugs to treat diseases such as MS, for example through regulation of the colonic microbial ecosystem. Probiotic candidates could be identified.
Leading researcher, Dr. Francisco Quintana of Brigham Women’s Hospital in Boston, USA, found an increase in certain bacteria in the gut of MS patients in a previous study in 2016, but this study goes a step further and how the bacteria affect the brain’s immune system. Studied.
Dr. Quintana said, “So far, many labs, including myself, have concluded that astrocytes play an important role in causing neuropathy. This paper demonstrates that at least some’a subset astrocyte’ plays a role in blocking inflammation. It was the first time I showed it. The reason I haven’t seen this phenomenon so far is because I thought that these cells were uniform cells, but now I have the technology to separate the differences between these cells.” Through the experience of single-cell sequencing, they are slowly getting out of the frame of thinking that it is a single cell.
Another recent study by the research team is that certain tumor cancers are evading the body’s immune response using the pathway they discovered. Therefore, the microbiome can also be used to develop immunotherapy that protects against cancer attacks. Dr. Quintana said, “The research results show that a subset of astrocytes regulated by the microbiome has anti-inflammatory activity in our nervous system and is important. The’gut-brain axis’, which the gut controls inflammation in the brain, is important,” said Dr. Quintana. “It is an important concept that exists and will guide new treatments for brain lesions in the future, especially brain tumors.” This study is likely to be a monumental study.
The gut, the digestive organ, and the thinking brain appear to be separated from the body, but this study shows that they are actually directly connected to special neurons and the immune pathway, the gut-brain axis. Microbiome is a field that has been studied a lot in recent years and has been widely studied because it has the effect of preventing or treating various diseases such as dementia, Parkinson’s disease, cancer, and obesity. But I still have a lot of questions personally. Is the positive emotions of healthy people without disease also related to the gut microbiome? The microbiome is mostly present in the gut, but can it travel out of the gut tissue to the brain? Conversely, how does the microbiome recognize what signals from the brain and train NK cells in the intestines to become spies ready to kill? After knowing that the brain-inflammation killer is a spy who was instructed by the intestine, I have to manage the gut better.
※The column is the columnist’s personal opinion and may not match the editorial direction of this magazine.