From our tonsils through our intestines, the lining of our gastrointestinal tract forms a border between our body and the outer world. More than a static tissue, it is an active tissue constantly bombarded by exposure to foods, viruses, and bacteria. It houses more than 40 trillion of its own bacteria, known as the microbiome.
“Peyer’s patches serve as the immune sensors of the intestine and likely play a pivotal role in immune surveillance of materials within our digestive system,” says Frederick Alt, PhD, director of the Boston Children’s Hospital Program in Cellular and Molecular Medicine (PCMM), and senior author on a paper in Nature describing the findings. In new research, the Alt lab discovered that components within Peyer’s patches produce a core set of antibodies even in the absence of a known trigger. These antibodies may be responsible for maintaining healthy immune activity in the gastrointestinal tract.
When Peyer’s patches sense danger, they respond by forming so-called germinal centers, sites where antibody-producing B cells prepare to mount an immune response to infection. However, the Alt team wanted to know why germinal centers in the intestine linger persistently even in the apparent absence of any pathogen. These “chronic” germinal centers do not appear to have an off switch; they remain constantly active in producing antibodies in the absence of a known infection. But what is activating them? And what kinds of antibodies do they make?
A common subset of antibodies found
To answer these questions, researchers in the Alt laboratory studied Peyer’s patch germinal centers and antibody production in mice. They exposed the mice to many different types of gut microbes or non-microbial triggers and found that the mice were predominantly making a subset of the same kinds of antibodies — about 10 major types in total.
“This was surprising because there are literally billions of possible combinations that could be generated in mice when producing antibodies to different triggers,” says Alt. “The fact that several seemed to be selected for consistently could mean there are some common gut antigens which have not been known before.”
Gut antibodies mostly target bacteria, but not always
Of the 10 common antibody types produced, eight appeared to be targeted to bacteria. This may mean that these antibodies are constantly being produced as sentries in the gut to maintain a healthy balance between the host and the microbiome. Disturbances in this balance are known to have a role in the development of inflammatory bowel diseases and autoimmune diseases.
“We think the antibody collection in the gut may serve to interact with the microbiome to maintain a healthy balance so that one type of bacteria does not take over,” says Huan Chen, PhD, co-first author on the paper.
“Because most of the common antibodies react with gut pathogens, it may mean that the gut is continuously selecting a set of antibodies to protect us from disease-causing bacterial pathogens in the microbiome,” adds co-first author Yuxiang Zhang, PhD.
A couple of antibodies among the ten, however, appear to be unrelated to bacteria. Instead, their potential target may be either a food-derived antigen or a self-antigen. This finding may offer some new clues related to food allergy or autoimmune disease, but more work needs to be done to prove what these antibodies are reacting to.
“We hope that our new sequencing methods and pipelines may also contribute to vaccine development and therapeutic antibody studies,” adds Adam Yongxin Ye, PhD, co-first author.
A COVID-19 connection?
The Alt lab has been working on an HIV vaccine with the Duke Human Vaccine Institute using an approach that may have relevance for COVID-19 vaccine development. As described last year, they created a mouse model that replaced the mouse antibody-making system with a human version, enabling them to safely and quickly test vaccine strategies for HIV. In a paper published in Nature Communications in February 2020, the Alt laboratory reported they found a way to see if mice make antibodies that will kill, or neutralize, the infection.
“These same principles could be applied to COVID-19,” says Chen. Others on the Alt team are already collaborating with Duke on a COVID-19 vaccine project based on the same mouse modeling approach.
Looking to human disease, Zhang has done preliminary work with human tonsil tissue. Like Peyer’s patches in the gut, tonsil tissue is part of the body’s mucosal immune system. It also has a similar job: to detect pathogens and mount an immune response. Based on this new paper, the team will now focus on trying to find a related subset of antibodies in human tissues and hope to identify what is triggering them.
Relevant to the current COVID-19 pandemic, the SARS-CoV-2 virus that causes COVID-19 also infects intestinal mucosa, not just the respiratory system. As a result, a significant number of people sick with COVID-19 experience gastrointestinal symptoms, like loss of appetite, nausea, vomiting, and diarrhea.
Says Alt, “It appears the mucosal tissues are related to each other immunologically, and that might contribute to why some COVID-19 patients have gastrointestinal symptoms.”
Other contributors to the paper include Zhou Du, Cheng-Sheng Lee , Joyce K. Hwang , Nia Kyritsis, and Zhaoqing Ba from Boston Children’s Hospital; Mo Xu and Dan R. Littman from the New York University School of Medicine; and Donna Neuberg of Dana-Farber Cancer Institute.
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