Unexplained recurrent fever may be a genetic mutation in "disruption"

Spending most of my time in the hospital since birth and fever a few days a week..Because the genetic mutation changes its coding protein, leading to inherent immune dysfunction and cause systemic inflammation, coupled with its genetic characteristics, many young people shortly after birth, have to endure the torture of their own inflammatory diseasesas early as the beginning of the 20th century, as a kind of self-inflammatory disease, familial Mediterranean fever (FMF) has been in the news, until 1997 when scientists discovered its disease-causing gene - the Mediterranean thermogene MEFV, humans and self-inflammatory diseases beganFor more than 20 years, the academic community has been exploring auto-inflammatory diseases and their disease-causing genes, Zhou Qing, a researcher at Zhejiang University's Institute of Life Sciences, said in an academic article published online in the international leading journal Nature that by analyzing the molecular mechanisms of the onset of a child with an auto-inflammatory disease, they have for the first time found that human receptor-interaction protein kinase (RIPK1) mutations can lead to auto-inflammatory diseases, and that the child has found a disease-causing mechanism that is expected to provide a more accurate treatment plan for the clinical diagnosis and treatment of such auto-inflammatory diseasesfound genetic mutation sites from patients
" many self-inflammatory diseases are a single-gene genetic disease, about 40 disease-causing genes have been found, in addition to periodic, repetitive fever, but also accompanied by rashes, arthritis and other symptomsZhou Qing explained to science and technology daily reporters, there are many unexplained cases of fever, generally believed to be caused by infection, rarely linked to genetic diseases, so in the treatment of antibiotic-based drugs, but no effectit is understood that because of the symptoms of self-inflammatory disease involving multiple systems, a variety of manifestations are not unique, patients often because of unexplained fever, rash or arthritis and other symptoms to and from the infection department, dermatology, immunology, hematology and other departments, but also due to the lack of diagnostic means of the disease, clinicians lack of understanding, many patients long-term misdiagnosis or missed diagnosis"A small patient we admitted last year, in the absence of infection, repeated periodic fever, after receiving full exoon sequencing test is still unable to confirm the cause, the traditional treatment has not been ideal." Wang Xiaochuan, director of Fudan University's affiliated pediatric hospital, told reporters that they speculated that the child was likely to have an auto-inflammatory disease and that a new genetic mutation had not yet been detected or clarifiedWith the guardian's consent, the hospital referred the child's genome data to the Zhou Qing laboratory team for re-analysisthe experimental team found that the RIPK1 gene in the child's body mutated, resulting in its coded RIPK1 protein in the protease Caspase-8 cutting site amino acid changes, making RIPK1 can not be cut normally, this change destroys the normal activation mode of RIPK1, its activity increased, to some extent promote the apoptosis and procedural necrosis of the cell"RIPK1 protein is a key molecule that regulates apoptosis, cell procedural necrosis and inflammatory signaling pathways, participates in embryo development, hematopoietic system development and immune steady state maintenance and other important biological processes, because the 'life and death' balance of cells is broken, the level of inflammatory factors in children abnormally elevated, and spontaneously produce fever and other inflammatory phenotypesZhou Qing said the team also found that different types of cells in children had different responses to the same RIPK1 mutation, suggesting that different tissues and cells in the human body could exhibit very different phenotypes under the same genotype, a finding that enriched the role of human RIPK1 in regulating cell death in different types"easy capacity" escape of RIPK1 causes cell death
previously, international authoritative academic journals have reported that the mouse RIPK1 mutation can lead to embryonic death, mouse RIPK1 protein cutting plays an important role in inhibiting apoptosis and necrosisThe effects of variation on the control of cell procedural death and human health have not been reported for the variation of human RIPK1 cutting sites "Under normal circumstances, this protein will be cut without an inflammatory reaction, and the RIPK1 protein, which cannot be cut properly, will cause an increase in its own kinase activity, which in turn leads to an increase in its mediated apoptosis, an increase in cell procedural necrosis, which causes the release of inflammatory factors, leading to an inflammatory response." Zhou Qing introduced, just like the snake hit seven inches, to cut RIPK1 protein this "fuse" must also be accurate to the cutting point "The human RIPK1 protein has a cutting site called protease Caspase-8 in the intermediate structure of the human ripK1, where RIPK1 is cut into two short segments and no longer has kinase activity , the human body under normal circumstances, full length and cutting RIPK1 co-existence, no health problems In patients with THE mutation of RIPK1, the proportion of full-length RIPK1 protein increased and the cut of RIPK1 decreased In the study of disease-causing mechanism, the researchers found that the patient's RIPK1 protein in this site has an amino acid mutation, so that it should have been cut it "unscathed", still in the full-length protein state, like doing a cosmetic surgery, "cutting machine" can not recognize also no way to start " the pathogenesis of this new type of self-inflammatory disease is a vicious circle Zhou Qing said that because of the genetic mutation caused the RIPK1 protein can not be precisely targeted by protease cutting, so that it continues to be in an active state, resulting in more apoptosis and necrosis, apoptosis and necrosis of cells can activate the release of inflammatory factors, increased inflammatory factors further promote cell death researchers found higher levels of inflammatory factors in the study of serum and peripheral blood mononucleocells in the child "The levels of inflammatory factors such as IL-6 and TNF are super high, especially when patients have a fever "It was also found in mouse cells that mice with RIPK1 site mutations are more sensitive to stimulation, release higher levels of inflammatory factors, and tend to die in cells." ", "We also got a family of Canadians with similar disease sleustics: a 35-year-old woman and her three sons with an unexplained recurrent fever, accompanied by swollen lymph nodes, enlarged liver and spleen, and so on The analysis of the whole exon sequencing data showed that the RIPK1 gene in the family line also carried mutations with the same site Zhou Qing said the team's data analysis and functional experiments on both family genomes showed that RIPK1 was caused by functional mutations at the site leave the hidden "rare disease" without a place to in this study, the researchers found that the inflammatory factor IL-6 in the patient's body a large number of expression and its triggering mechanism, so in the clinical use of the il-6 receptor inhibitors In fact, a number of different bioinhibitors have been developed to treat different inflammatory response pathways for their own inflammatory diseases "If you can determine which inflammatory factor or which inflammatory signaling pathway causes the disease, it means you can prescribe the disease." Zhou Qing introduced, the team further found that the skin fibroblasts, RIPK1, TNFR1 and other protein expression levels significantly reduced, the cell's reduced glutathione (GSH) content is high, the reactive oxygen (ROS) content is low, these changes partly explain the cell's resistance to different forms of death This phenomenon suggests that in order to cope with the high sensitivity to various stimuli caused by RIPK1 mutation, the child's fibroblasts develop a variety of compensation mechanisms to maintain the body's steady state ": "The current situation is that the overall clinical awareness and diagnosis level of self-inflammatory diseases needs to be improved before formal treatment Wang Xiaochuan said that although the self-inflammatory disease is difficult to cure because of its hereditary nature, but found the pathogenic mechanism of the drug, patients through regular medication can also work normally, life ", the academic community is strengthening the exploration of the pathogenesis of auto-inflammatory diseases, this study is the first to find that cell necrosis, apoptosis causes auto-inflammatory diseases, follow-up is expected to be derived from more clinical cases due to apoptosis caused by the disease of disease-causing genes, improve the family lineage of disease-causing genes Zhou Qing said self-inflammatory diseases are called rare diseases, but there are also relatively large groups Zhou Qing said that he had done another study of cavalstroke and nodule polyartery (DADA2) cases, initially only 9 patients, but after the publication of the paper, the world has found more than 400 cases "It could be hundreds of thousands of patients based on the frequency of its genetic mutation sites in Chinese groups " ",。 Zhou Qing said that in the face of endless "genetic mysteries", not only need top technical support, but also need the joint social forces to jointly promote scientific research and clinical development, the benefit of more patients suffering from their own inflammatory diseases.