Immunity and sulfatides
Biologists have solved the main secret of innate immunity
For the first time, scientists were able 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 results of the study are published in the journal Proceedings of the National Academy of Sciences (Su et al., Sulfatides are endogenous ligands for the TLR4–MD-2 complex).
A key role in the work of innate immunity is played by two endogenous, that is, molecules produced inside the body – the membrane protein TLR4 (toll-like receptor 4) and the protein MD-2 (lymphocytic antigen 96). However, the molecular mechanism of their action has so far been completely unknown.
Researchers from the University of Texas Southwestern Medical Center, together with colleagues from Germany and Israel, have confirmed at the structural level that in mammals, innate immunity - the earliest reaction of the body to infections entering it – depends primarily on the effectiveness of the TLR4/MD–2 protein complex.
The team of scientists was led by Bruce Bettler, MD, Director of the Center for Host Protection Genetics at Southwest 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 pathogenic 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 out 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 has been no answer to the question whether endogenous molecules can activate innate immunity receptors," the press release says. Southwest Medical Center, the words of Professor Bettler. – Scientists have previously found out that our own nucleic acids can activate TLR receptors 3, 7, 8 and 9, causing inflammation and autoimmunity. Many endogenous ligands have also been proposed for TLR4, most of which are proteins. Our work demonstrates that TLR4 activation can indeed be triggered by endogenous lipids."
The authors note that this is the first work confirming the existence of such a TLR4 ligand, that is, a molecule that enters the receptor, using structural methods. X-ray diffraction analyses were performed at the Center for Structural Biology at Southwest Washington State University and at Argonne National Laboratory in Illinois.
At this stage, all the results were obtained on laboratory mice. Biologists plan to continue their research to find out if there are differences in how receptors are activated in mice and humans, and also 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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