Nature sub-journal: Peripheral immune cells "kill" the brains of dying patients.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, also known as progressive freezing. It is a rare disease characterized by progressive degeneration and death of motor neurons.the ice bucket challenge, which swept the world in 2014, let more people know about this rare disease and raise money to help treat it.the famous British physicist, Hawking, not only has made great contributions to the scientific community, but also is the longest surviving patient with cryophilia.NK cells (natural killer cells) are an important class of innate immune cells, accounting for 2% - 18% of peripheral blood lymphocytes. NK cells play an important role in early anti-tumor and anti-virus by directly killing target cells.in addition, NK cells can produce a variety of pro-inflammatory cytokines and immunosuppressive cytokines after activation, which play an important role in innate and adaptive immune response.cohort studies have shown that the number of NK cells in peripheral blood of ALS patients is increased, but the role of NK cells in the immune regulation of ALS is not clear.on April 14, 2020, Cristina limatola, a research team from the Department of physiology and pharmacology of Sapienza university students in Rome, Italy, published an article in the journal Nature communications, revealing the specific mechanism of the degeneration of motor neurons caused by NK cells in ALS.the researchers detected increased levels of natural killer cells (NK) in tissue samples from the spinal cord and cerebral motor cortex after ALS death, but not in the control group.this confirms that peripheral immune cells can enter the brain parenchyma of ALS patients.using the motor cortex of the hsod1g93a transgenic mouse model (ALS disease model), researchers found that NK cells were at high levels in the early stage of the disease, and then gradually decreased.what exactly makes NK cells in the peripheral system enter the brain.after blocking the antibody with CCL2, the level of NK cells decreased, indicating that the recruitment of NK cells in the cerebral motor cortex was mainly dependent on the chemokine CCL2.then whether reducing the release of NK cells can improve the related symptoms.anti NK1.1 antibody can delay the onset of dyskinesia and increase the average survival time.these results suggest that NK cells may play a role in the disease process of ALS.NKG2D is an important activating receptor in innate immune system. It can activate NK cells and kill cells with NKG2D ligand expression after binding with ligand.therefore, the researchers found that the expression of NKG2D ligand in the spinal cord neurons of ALS disease model mice was increased by molecular biological detection, and the co labeling of neurons and NKG2D ligand was also increased by immunofluorescence test. after the virus silencing NKG2D, the number of motor neurons in ALS model mice increased. These results indicate that NK cells exert cytotoxicity on motoneurons expressing NKG2D ligand. like other central nervous system diseases, immune cells microglia of central nervous system play protective or harmful functions in different disease stages according to the characteristics of cell autonomy and local microenvironment. previous studies have shown that NK cells regulate microglial phenotype in glioma. what happens when peripheral immune cells and central nervous system immune cells meet in ALS. in terms of structure, the number of spinal microglia decreased, the volume of cell body decreased and the branches increased in ALS model mice after NK cells were removed. The expression of IL-6, IL-1 β, TNF - α and NOS2 increased in microglia of ALS model mice, while the expression of these proinflammatory factors decreased and the expression of anti-inflammatory factors increased after NK cells were removed. that is to say, the clearance of NK cells makes microglia have a protective phenotype. in general, we found that the level of NK cells increased in ALS patients and animal models, which was dependent on the chemokine CCL2. NK cells play a killing role by recognizing and expressing NKG2D ligand motoneurons. at present, the mechanisms of the disease are mainly reflected in the following aspects: 1. Gene mutation, which accounts for about 5% - 10%; 2. Neurotransmitter imbalance: high glutamate content in ALS patients; 3. Immune response disorder; 4. Protein processing abnormalities such as c9orf72. at present, the drugs used to treat the disease are mainly riluzole, which can reduce the damage of motor neurons by reducing the level of glutamate. Another drug is edaravone, a free radical scavenger. in recent years, stem cell therapy has also achieved good results in animal experiments. References: natural killer cells modular motor neuron immune cell cross talk in models of amyotrophic lateral sclerosis