Scientists from Australia and the United States have discovered and identified the genetic cause of a previously unknown human auto-inflammatory disease. The hhalazgo has been published in the magazine «Nature».
The researchers determined that the autoinflammatory disease, which they called CRIA (excision-induced RIPK1-induced autoinflammatory syndrome), is caused by a mutation in a critical component of cell death called RIPK1.
The research team was led by Dr. Najoua Lalaoui and Professor John Silke of the Walter and Eliza Hall Medical Research Institute, Australia; and Dr. Steven Boyden, Dr. Hirotsugu Oda and Dr. Dan Kastner, from the National Human Genome Research Institute of the National Institutes of Health (NIH), USA.
Dr. Lalaoui explained that the research team identified a new human auto-inflammatory disease and the associated mutation in a critical cell death molecule that promotes the disease.
"Cell death pathways have developed a series of built-in mechanisms that regulate inflammatory signals and cell death, because the alternative is very dangerous," he said. "However, in this disease, the mutation in RIPK1 is overcoming all the normal checks and balances that exist, resulting in uncontrolled cell death and inflammation," he warned.
Auto-inflammatory diseases are caused by abnormal activation of the innate immune system, which leads to recurrent episodes of fever and inflammation that can damage vital organs. In the document, the researchers describe patients from three families with a history of episodic high fever and swollen and painful lymph nodes. The patients, who were diagnosed with a new auto-inflammatory disease (CRIA syndrome), had a number of other inflammatory symptoms that began in childhood and continued into adulthood.
Dr. Boyden said the first clue they found that the disease was related to cell death appeared when they delved into the exomes of the patients, the part of the genome that encodes all the proteins in the body.
"We sequenced the complete exome of each patient and discovered unique mutations in the exact same amino acid of RIPK1 in each of the three families," said Dr. Boyden. «It is remarkable, like a lightning strike that hits three times in the same place. Each of the three mutations has the same result: it blocks the cleavage of RIPK1, which demonstrates the importance of the cleavage of RIPK1 to maintain normal cell function, ”he added.
Dr. Lalaoui noted that the Walter and Eliza Hall Institute researchers confirmed the link between RIPK1 mutations and CRIA syndrome in laboratory models. "We showed that mice with mutations in the same location in RIPK1 as in patients with CRIA syndrome had a similar exacerbation of inflammation," he said.
Dr. Dan Kastner, considered the "father of auto-inflammatory disease," explained that the NIH team had treated patients with CRIA syndrome with a series of anti-inflammatory medications, including high doses of corticosteroids and biological products. Although some of the patients improved markedly with an interleukin-6 inhibitor, others did not respond as well or had significant side effects.
"Understanding the molecular mechanism by which CRIA syndrome causes inflammation provides the opportunity to get directly to the root of the problem," said Dr. Kastner, adding that the discovery of this new disease also suggests "a possible role for RIPK1 in a broad spectrum of human diseases, such as colitis, arthritis and psoriasis ». . (tagsToTranslate) discover (t) new (t) human disease (t)