Nature: Reveals the immune system produces a huge pool of antibodies to fight infection

, July 8, 2020 /PRNewswire/ --BioValleyBIOON/--- it has long been known that the acquired immune system can produce a large pool of antibodies (immune globulins) through genetic recombination in developing B cellsHowever, it is not known how these different immunoglobulin gene fragments can meet and recombine in the three-dimensional space of the B-cell's nucleus to produce functional antibody genesNow, in a new study, researchers from the Institute of Molecular Pathology in Vienna, Austria, have found that the transcription factor Pax5 plays a crucial role in promoting the interaction of immune globulin gene fragments through a ring extrusion mediated by a cohesinnThe findings were published online July 1, 2020 in the journal Nature, with the title "Wapl relis by Pax5 promotes V gene recombination by Igh loop extrusion"The paper's authors are DrMeinrad Busslinger, Senior Scientist and Deputy Director of Science, Institute of Molecular Pathology, Viennaimages from Nature, 2020, doi: 10.1038/s41586-020-2454-ywhen our body is confronted with an alien invader---
bacterialor viruses such as the new coronavirus SARS-CoV-2, it has several defense mechanismsThe congenital immune system provides the first line of defense, moving quickly and trying to contain the initial infectionThe adaptive immune system then comes into play, eliminating the pathogen within the next two weeksIts powerful weapons are highly selective and, in some cases, provide lifelong protection against infectious pathogensB cells are the main pillarof our adaptive immune systemThey develop in the bone marrow and then circulate in the blood B cells are responsible for producing antibodies against invasive pathogens (so-called antigens) Each B cell is highly specific to an antigen Antibodies are larger protein molecules called immunoglobulins that are secreted into the bloodstream They are also produced in the form of membrane binding and are present on the surface of B cells and are therefore called B-cell receptors (BCR) recombination ensures the diversity of antigens
in order to be able to fight a wide variety of antigens, B cells can produce an extremely diverse variety of B-cell receptors, about 1011 species That's far more than the 20,000 genes that exist in the human genome The solution to this problem lies in the modular structure of the receptor Its variable regions -- the parts that identify antigens -- are made up of fragments of V, D, and J genes that can be combined in almost endless ways through random recombination during B-cell development Importantly, 200 V gene fragments are distributed over a long piece of DNA in the genome However, all these V gene fragments must be involved in the V(D) J recombination process in order to produce a diverse pool of B-cell receptors To do this, all V gene fragments need to be recombined by physical interactions with D gene fragments, which are achieved by folding the immune globulin gene sites into ring structures and compressing them 2004, Busslinger and his team found that the transcription factor Pax5 plays a crucial role in the formation of these longer ring structures, which form early in B-cell development Sixteen years later, the Busslinger team now explains how Pax 5 regulates the formation of this ring-shaped structure Part of the study was carried out by the Busslinger team in conjunction with Jan-Michel Peters of the Institute of Molecular Pathology in Vienna The Peters team recently published a circular protein complex bonding protein in the journal Science as a molecular motor that drives chromatin ring extrusion (Science, 2019, doi:10.1126/science.aaz3418) "In our experiments with genetically modified mice, we found that the chromatin ring extrusion mediated by the adhesive protein did occur at the entire immunoglobulin gene site of the developing B cell," explains Louisa Hill, lead author of the paper and a ph.D student at the Vienna Institute of Molecular Pathology Given that the site spans a larger 2.8Mb area of DNA, the ring structure in B cells is much longer than most other cell types, because the ring structure is used to assemble and compress the genome "the length of the ring structure depends on the adhesive protein that acts as a ring extrusion factor As long as the adhesive protein resides in the chromatin, it continuously squeezes the chromatin ring until the process is actively stopped by removing the adhesive protein from the chromatin through the muscosing protein release factor Wapl B-cells re-arrange the entire genome
The number of Wapls controls the duration of the binder's stay on chromatin, which determines the length of the chromatin ring structure in a particular cell, as the Peters team has previously demonstrated Now, the Busslinger team found that Pax5 inhibits the Wapl gene, reducing the number of Wapl proteins in developing B cells, resulting in an extra-long chromatin ring structure at the entire immunoglobulin gene site, allowing all V gene fragments to participate in V(D) J recombination As a result, the chromatin ring in the entire genome of developing B cells also expanded, indicating that the entire chromosomal structure has changed to ensure that a diverse antibody pool can be produced to fight all possible infections "Our study is the first to show that wapl protein levels are regulated to control important biological processes such as V(D) J recombination," Busslinger said "
these new findings make an important contribution to our understanding of how adaptive immune systems work They provide us with valuable new insights into the generation of diverse antibody banks This antibody bank is the body's arsenal, ensuring that most people are able to fight pathogens such as COVID-19 infections (Biological Valley Bioon.com) References: 1.Louisa Hill et al.
Wapl relis by Pax5 promotes v gene recombination by Igh loop extrusion Nature, 2020, doi:10.1038/s41586-020-2454-y.
2 How the immune system generates a vast antibody repertoire to the