STUDY. In a new study, recently published in Nature Communications, researchers at Sahlgrenska Academy show that B cells that mature into IgA-producing plasma cells in the intestine differ from other B cells in having a special ability to react to the intestinal contents. These findings have a bearing on further development of vaccine taken orally and absorbed by mucous membranes.
The study demonstrates that, of the B cells that mature in the specialized intestinal membrane structure known as Peyer′s patches (PPs), most lack the GL7 activation marker on the cell surface that is a feature of activated B cells in, for example, the spleen.
”We show that Peyer′s patches, that activate immune responses in the gut, function differently from the lymph nodes that control production of IgG and IgM antibodies elsewhere in the body. We also show how B cells in the intestine can recognize and acquire the right type of antigen, transporting it from the intestine to the germinal centers where the antibody genes are improved during an immune response,” says Mats Bemark, a researcher at the Department of Microbiology and Immunology. Bemark and Nils Lycke are the joint last (supervisory) authors of the study.
“The conclusions from the study are very important for development of mucous membrane vaccine,” Bemark continues.
“There are only a small number of vaccines that can activate the mucosal immune system in the intestine. It would be good if more could be developed, since they can give immunity that protects the body even before the infectious material gets through the membrane and into the body.”
Right antigen
With genetic studies, the researchers show that a protein called CCR6 occurs mainly on activated B cells that lack the GL7 marker. The CCR6 protein has previously been shown to be important for B cells in the gut when an immune response starts, allowing them to move to a particular area in Peyer′s patches that is in close contact with the contents of the intestine. The study now published showed that activated B cells with CCR6 on their surface, too, migrate to this area; there, they contact cells of another type — M cells — that transport material from the intestine into the tissue. When the M cells take up antigen, the B cells can bind to it and then migrate away from the M cells. Through advanced microscopy inside living mice, the research group has then also been able to show how, after that, the B cells transport the antigen to germinal centers.
”The intestine contains a huge number of different antigens, and it’s important for the right antigen to be transported to the germinal center so that it doesn’t drown among all the other antigens,” Bemark says.
The special area in the Peyer′s patches where M cells transfer antigen to the B cells is called the subepithelial dome (SED). The study shows that this area plays a key role not only at the beginning of an immune response, when B cells are first activated by the antigen, but also later, to make the immune system as effective as possible.
Advanced methods
The study is based on methods that the research group in Gothenburg spent several years developing. They make it possible to follow the B cells that bind to a particular antigen in the intestine.
“Using one of these methods, we transfer colored B cells that can bind the antigen, so that we can then follow them when they are activated and become IgA-producing plasma cells that migrate out into the intestine.”
Bemark mentions that the group in this report has developed the technology further, so that they can see not only which cells might bind to the antigen but also investigate where and when they do so.
To gain access to ultramodern microscopy technology, the group collaborated with researchers at the Weizmann Institute of Science in Rehovot, Israel.
”With a technique that enables us to observe marked cells in the tissue, using a strong laser light, it’s been possible for us to follow how cells migrate for several hours in the tissue in live mice. In this way, we’ve been able to observe how cells move in Peyer′s patches during an immune response,” Bemark says.
The current publication is the second based on this collaboration. It also, as recently as in March 2019, culminated in another article in Nature Immunology. In it, the researchers rigorously investigated where antigen-specific B cells were located in Peyer′s patches, using a newly developed method that makes it possible to use 3D microscopy of whole organs.
Articles:
Activated Peyer′s patch B cells sample antigen directly from M cells in the subepithelial dome
https://www.nature.com/articles/s41467-019-10144-w
BCR affinity differentially regulates colonization of the subepithelial dome and infiltration into germinal centers within Peyer’s patches: https://www.nature.com/articles/s41590-019-0325-1
TEXT: ELIN LINDSTRÖM
