Wang Shuo: Researcher at the Institute of Microbiology, Chinese Academy of Sciences, head of the intestinal mucosal immunity and disease regulation research group of the Key Laboratory of Pathogenic Microbiology and Immunology, Chinese Academy of Sciences
Introduction: Researcher at the Institute of Microbiology, Chinese Academy of Sciences, Ph. long. He graduated from Zhejiang University with a bachelor's degree in bioengineering in 2006, and obtained a doctorate degree from the Institute of Biophysics, Chinese Academy of Sciences in 2012. In 2019, he joined the Institute of Microbiology, Chinese Academy of Sciences as the research team leader. He is mainly engaged in the research on the regulation and immune response of intestinal innate immune lymphocytes . As the first/co-first and co-corresponding author, he has published more than 10 research papers in Cell, Immunity, Nature Immunology, Cell Stem Cell and other journals. In 2017, he was awarded the Outstanding Youth Science Fund of the National Natural Science Foundation of China.
Hello fellow colleagues. I am Wang Shuo, a researcher from the Institute of Microbiology, Chinese Academy of Sciences. I am very happy to come to the Rexinchang Research Institute to share some knowledge about intestinal mucosal immunity with you.
I believe that you have learned a lot about intestinal disease and intestinal flora in some previous reports, so how does the intestinal mucosal immunity that is closely related to them work? Let's find out.
My sharing includes the following four aspects: the development history of mucosal immunity, the composition of the intestinal mucosal immune system, digestive tract diseases and mucosal immunity, and intestinal flora and mucosal immunity.
Let us first take a brief history of the development of mucosal immunity.
The history of immunology is also the history of our human struggle against disease.
Smallpox is very familiar to everyone. This is a very potent pathogen that once caused a very serious impact around the world.
And in China ancient times, there was such a technology that can prevent smallpox, which is the picture on the left. What are they doing? It is to grind the pox scabs of smallpox patients into powder and blow it into the nasal cavity of healthy people to prevent healthy people from contracting smallpox virus . This is also called "vaccination without acne", and such a immune method is also based on the protective immunity obtained from the nasal cavity mucosal . When
arrived in the UK, Dr. Jenner invented the vaccination method of vaccinia , which eventually led to the development of vaccinology.
With the development of microbiology , French scientists Pasteur have developed many attenuated vaccines, including various attenuated vaccines for rabies, which has promoted the development of vaccinology.
Dr. Pasteur established Pasteur Institute , and under the impetus of Pasteur Institute, another Russian scientist developed a method of oral bacteria for immune protection, which is what we call Oral vaccine . In fact, this way is to mediate a protective immune response through the mucosa of the digestive tract.
In the development of oral vaccines, the most successful one should be the oral vaccine of polio , which is the familiar sugar pill . The success of the oral polio vaccine greatly suppressed the development of polio.
With the development of various vaccines, mucosal immunology has gradually developed.These include the discovery of intestinal Peyer's patches, the discovery of intestinal Paneth cells, the discovery of intestinal mucosal tolerance mechanisms, the identification of secretory and serotype IgA, and the discovery of intestinal M cells in 1982.
With the development of modern immunology, the development of intestinal mucosal immunology has also been greatly promoted, so we know that mucosal immunity is closely related to disease and physiology.
In terms of the regulation of pathological , many pathogens -- should be said to include more than 90% of the pathogens, all infect the human body through the mucosal system. Among them, viruses include the well-known respiratory viruses - new crown, influenza , etc., as well as enterovirus . The same is true for bacterial infections, both tuberculosis and salmonella enter our bodies through the mucous membranes. Mucosal immunity is also closely related to inflammation and tumor.
In addition, mucosal immunity also plays a very important role in physiological regulation. It can interact with symbiotic bacteria , mediate the regulation of immunity and nerves, and mediate the regulation of immunity and metabolism, and immune tolerance is also an important scientific issue in mucosal immunity.
So, how is the intestinal mucosa immune system composed?
Before introducing the composition of the intestinal mucosal immune system, I would like to introduce the barrier structure of the intestinal mucosa epithelium .
Above is a schematic diagram of an colonoscopy of the intestine, and below is a schematic diagram of the small intestine and colon.
There is a very tight connection between the intestinal epithelium, and there is a mucus layer outside the intestinal epithelium.The mucus layer contains many small molecular substances, such as antimicrobial peptide , defensin , etc., as well as macromolecular substances such as IgA and so on. And of course the gut microbiota we are familiar with.
The barrier structure composed of epithelium and mucus layer can defend most pathogenic from invading . If the intestinal barrier is breached, after the pathogen invades our intestine, the immune system of the intestine will build a protective barrier.
The mucosal immune system of the gut is mainly gut-related lymphoid tissue, including Peyer’s patches, mesenteric lymph nodes, the lamina propria under the intestinal epithelium, and some independent lymphoid follicles. . They are interconnected and independent of each other, forming the barrier of intestinal immunity.
The picture on the right is an H&E-stained section of the mouse intestine, and such a raised part is the Petri’s lymph node.
Let's find out what is a Peyer's patches.
In the picture on the left, Peyer's patches are raised lymphoid tissue located on the intestinal wall. It is very similar to the organization of lymph nodes, it has lymphoid follicles and T cell areas.
And the Peyer's patches have a very unique place, that is, at the top of it - that is, the part near the intestinal lumen, there is a very special epithelial cell - the microfold cell, or M cell for short. This cell is able to capture the antigen and deliver the captured antigen to DC cells (dendritic cells), which further present the antigen to T cells, mediating an adaptive immune response.
Therefore, Petri's lymph node is a very important site for the induction of intestinal mucosal immunity.
Beneath the intestinal epithelium is the intestinal lamina propria.The lamina propria contains numerous immune cells , including T cells, B cells, ILC cells—that is, innate lymphoid cells, as well as DC cells, macrophages , granulocytes , and so on. A large number of immune cell groups build a strong barrier for intestinal mucosal immunity.
The picture on the right is a fluorescently stained section of the mouse intestine that we have made, in which we can see the distribution of numerous immune cell types.
In addition to the lamina propria, there are also some lymphocytes between the intestinal epithelium, called intraepithelial lymphocytes.
They are mainly located between epithelial single cells, mainly including some naturally occurring intraepithelial lymphocytes, including αβ T cells and γδ T cells, and some inducible T cells.
Their main function is to remove pathogens and ensure the integrity of epithelial cells. Of course they also lead to chronic inflammation on the other hand.
Through some of the above introductions, we have learned about the composition of the intestinal mucosal immune system. These include lymphocytes within the epithelium; the lamina propria below the epithelium, which contains T cells, B cells, DC cells, macrophages, ILC cells, granulocytes, etc.; The induction site of intestinal mucosal immunity, including M cells, T cells, B cells, etc.
When encountering pathogen invasion, the first defense against pathogens is the intestinal barrier structure. If the barrier structure is damaged, then our intestinal mucosal immune system will be activated.
M cells capture the antigen and deliver the antigen to DC cells, which further present the antigen to T cells , mediating T cell activation. At the same time, DC cells and T cells can activate B cells and turn them into plasma cells .Activated B cells and T cells are also able to migrate into the lamina propria and mediate immune responses.
This is also a relatively preliminary working mode of the intestinal mucosal immune system.
So, what is the relationship between intestinal diseases and intestinal mucosal immunity? In fact, there is a close relationship between the homeostasis balance of intestinal mucosal immunity and intestinal diseases.
This is a very simple pattern diagram for a balanced seesaw.
When the pathogen invades the intestinal tract, our immune effector cells will increase rapidly, leading to the elimination of the bacteria. If the pathogenic bacteria are eliminated, the effector cells will be reduced, thus reaching a steady state equilibrium.
But homeostasis is disrupted if effector cells are not reduced in a timely manner, or remain highly activated, or are continually stimulated by pathogen invasion.
On the other hand, if immunoregulates cells, such as a suppressor cell like TReg (regulatory T cell), its function is impaired or inhibited, such a balance will also be disrupted, resulting in intestinal disease.
In the process of intestinal bacterial infection, how is the intestinal mucosal immunity regulated?
When encountering pathogens, DC cells can capture the antigens of pathogens through epithelial cells, and then process them. The processed antigens are presented to T cells and mediate the activation of T cells. Activated T cells promote the secretion of antimicrobial peptides from epithelial cells by secreting some cytokines .
On the other hand, T cells and DC cells can also activate B cells, so that B cells become plasma cells capable of producing IgA, and the IgA secreted by plasma cells can also resist the invasion of pathogens.
In this process, we can see cytokines secreted by T cells and many immune cells, which are also inflammatory cytokines.
That is the second issue we want to discuss - Intestinal inflammation and regulation of intestinal mucosal immunity.
Inflammatory bowel disease IBD Everyone is familiar with it, so how is mucosal immunity regulated during the occurrence and development of IBD? Its regulation is divided into the following 4 stages.
The first is the destruction of the intestinal mucosal barrier. Due to some genes or external environmental factors, after the intestinal barrier is damaged, some bacteria and pathogens can enter our intestinal tract, causing an acute inflammatory response .
Immune cells can eliminate bacteria or pathogens due to an acute inflammatory response. If in this process, immune cells continue to activate or pathogens continue to stimulate the immune system, on the other hand, the function of regulatory cells is inhibited, then such an immune homeostasis will be broken.
Persistent inflammation can lead to intestinal inflammation, or inflammatory bowel disease.
On the other hand, intestinal tumors are also closely related to the regulation of intestinal mucosal immunity.
The occurrence and development of intestinal tumor is also divided into many processes.
First, as just introduced, due to the destruction of the intestinal mucosal barrier, pathogens enter the intestinal tract, and then the intestinal immune system will produce a series of immune responses to resist the invasion of pathogens. On the other hand, the immune system can also mediate the repair of intestinal epithelial cells by secreting some cytokines.
During this process, if some genomic mutations or other factors are encountered, the epithelial cells are mutated, which will eventually lead to abnormal proliferation of epithelial cells. And dysplasia cells can be recognized by some like NK cells and CD8[+] T cells at the initial stage, and eliminated by immune surveillance.
However, due to some changes in the immune microenvironment or the induction of a persistent inflammatory microenvironment, the function of immune cells has undergone some changes, such as the expression of some inhibitory molecules, or the secretion of cytokines that promote epithelial cell proliferation. Such an immune cell can promote the occurrence and development of intestinal tumors.
That is to say, in the occurrence and development of intestinal tumors, immune cells, especially intestinal mucosal immune cells, play a very important role in this process.
Then I would like to share with you about the regulation of intestinal flora and intestinal mucosal immunity.
I believe that many of the previous reports have learned that the intestinal flora has a very important regulatory effect on the intestinal tract and other tissues outside the intestinal tract, so what kind of regulatory role does it have on the intestinal mucosal immune cells?
The first is that gut microbiota can regulate the differentiation and function of T cells.
Intestinal flora can stimulate DC cells or macrophages by secreting serum amyloid, and the DC cells and macrophages can further activate TH17 and TH1 cells and so on. TH17 and TH1 cells are two important types of inflammatory cells and immune effector cells, which can stimulate epithelial cells to secrete antimicrobial peptides and mediate the clearance of pathogens.
On the other hand, intestinal flora can also activate another group of DC cells and macrophages by secreting some short-chain fatty acids or polysaccharide , by secreting retinoic acid or IL-10 and so on. Cytokines, promote the activation of regulatory T cells, mediate immune regulation.
That is to say, the gut microbiota can regulate immune effector cells on the one hand and immunosuppressive cells on the other hand.
In terms of B cell differentiation and function, intestinal flora can mediate B cell activation by acting on intestinal epithelial cells and promoting intestinal epithelial cells to secrete B cell activating factors, or by activating DC cells. Activation of B cells, into plasma cells and type switching of IgA.
Therefore, there is also a very close regulation and mutual connection between the intestinal flora and intestinal immunity.
In addition to regulating the intestinal tract, the intestinal flora can also regulate some other tissues and organs, such as what we usually call the gut-brain axis, the gut-lung axis, the gut-liver axis, and so on.
In fact, in this process, these immune cells in the intestinal tract can also regulate the tissues and organs outside the intestinal tract.
For example, in the process of multiple sclerosis , TH17 cells can also migrate to the central nervous system; and in the development of rheumatoid arthritis , TH17 cells can also migrate to joints, inducing inflammation In addition, during allergic reactions, sensitized NKT cells and B cells can also migrate to the lungs and mediate allergic reactions in the lungs.
That is to say, the flora in the gut and the immune cells in the gut can interact with each other and jointly regulate the homeostasis of the human body.
I also want to emphasize that in the process of studying the intestinal flora, we must not forget the regulation of intestinal immune cells.
That's all I share. Finally, thank you again for the invitation of the Enthusiast Research Institute, thank you!
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