Biologists have solved the main secret of innate immunity
For the first time, scientists managed to find out which compounds activate the protein complex responsible for innate immunity. The authors believe that their discovery will help create new treatments for a number of autoimmune diseases. The research results are published in the journal Proceedings of the National Academy of Sciences.
The key role in the work of innate immunity is played by two endogenous, that is, produced inside the body, molecules – membrane protein TLR4 (toll-like receptor 4) and protein MD-2 (lymphocyte antigen 96). However, the molecular mechanism of their action was still not fully understood.
Researchers from the University of Texas Southwestern Medical Center, together with colleagues from Germany and Israel, have structurally confirmed that in mammals, innate immunity – the earliest reaction of the body to infections that enter it – depends primarily on the efficiency of the TLR4 / MD-2 protein complex.
The team of scientists was led by Bruce Bettler, MD, director of the Center for Host Defense Genetics at Southwestern Medical Center. In 2011, he received the Nobel Prize in Physiology or Medicine for his research on the immune system. It was he who discovered receptor proteins that recognize disease-causing agents and are responsible for innate immunity.
Now, for the first time, researchers have discovered compounds that activate the TLR4 / MD-2 complex. We are talking about sulfatides – natural membrane glycolipids containing a sulfate group in their composition. Using X-ray crystallography methods, the authors found that sulfatides bind to the TLR4 / MD-2 protein complex as ligands, and this binding triggers biological pathways that lead to an inflammatory response of the body to infections.
“For many years, there was no answer to the question of whether endogenous molecules can activate the receptors of innate immunity,” Professor Betler said in a press release from the Southwestern Medical Center. “Scientists have previously figured out that activate TLR receptors 3, 7, 8 and 9, our own nucleic acids can induce inflammation and autoimmunity. Many endogenous ligands have also been proposed for TLR4, most of which are proteins. Our work demonstrates that endogenous lipids can actually trigger TLR4 activation. ”
The authors note that this is the first work to confirm the existence of such a TLR4 ligand, that is, a molecule that enters the receptor, using structural methods. X-ray diffraction analyzes were performed at the Center for Structural Biology at Southwestern Washington State University and at Argonne National Laboratory in Illinois.
At this stage, all results have been obtained in laboratory mice. Biologists plan to continue research to find out if there are differences in how receptors are activated in mice and humans, and to study how the chemical composition of individual sulfatides can affect interactions with the receptor complex in order to activate or, conversely, suppress the immune response.
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/Biologists have solved the main secret of innate immunity/