Chapter 9: Humoral Immune Response
What do B-cells need for activation? B-cells need their receptor crosslinked, they need a second signal coming from other molecules like B7 engaged and they need cytokines. The standard T-cell dependent antigens, and this chapter will distinguish between the 95 or more percent of T cell antigens from the T-cell independent antigens which are highly repetitive. When a B-cell gets all the necessary signals it starts to divide and differentiate, it makes more antibody, it secretes antibody, it will undergo class switching and somatic hypermutation, and then it achieves terminal differentiation and is a plasma cell and will take up residence in the termini of long bones. Plasma cells are different from B-cells, they don’t express MHC, they don’t express surface immunoglobulin, they don’t undergo class switching or affinity maturation.
So, if you have an antigen that enters and elicits an immune response, what can an antibody do? The antibody can coat the invading pathogen, so that receptors on that bacteria that would normally bind a cell surface molecule to be able to develop an invasive infection are not available. Antibody can also bring bacteria to a macrophage which is capable of binding the antibody and get rid of the pathogen by phagocytosis. Generally, the lysosome is able to fuse with the phagosome and the bacteria can be digested. Antibody of certain subclasses is able to bind complement components and trigger the complement cascade, and if the bacteria has a membrane and only the gram negative bugs do, it can punch a hole, otherwise if the complement cascade starts, complement receptors can bind the pathogen which has been opsonized by complement.
Most antigens are T-cell dependent, and thymus depleted or T-cell compromised individuals can’t make antibody to those things. However, this is a very primitive immune response, and this is largely germline in nature, the antibody molecules that are on these B-cells that are capable of seeing these thymic independent antigens do not undergo affinity maturation, they are germline in sequence, they bind repetitive antigens which are usually found on bacteria. These B-cells tend to live in cavities like the peritoneum and they are there as a backup, but the thymus dependent ones rely on many other signals to be activated.
B-cells are very good at presenting their own antigen. While their receptor may bind a small epitope on the pathogen, they can endocytize the entire pathogen and present peptides to T-cells. When the T-cells recognize the antigen they activate the B-cell, and instruct the B-cell to make more antibody. B-cells can see not only protein determinants but also nucleic acids, lipids and carbohydrates. T-cells can only see peptides but there are lots of proteins that have polysaccharide tails, proteins with lipid tails, proteins bound to nucleic acids and all of these can be brought in by the antibody molecule on the B-cell and processed and presented. This is a potential problem: if this is a rogue antibody, one that had not been eliminated so that those self-reactive B-cell antibody receptors are present, and if this sees something in the nucleosome for instance and it brings in those antigens, and it gets activated, it can generate more self reactive antibody and there are several autoimmune diseases in which antibody recognizes self molecules. You will not get that self-reactive response however unless you have a T-cell that instructs the B-cell to make more antibody, so in order to treat the disease you must remove the antibody, but also eliminate the T-cell responses.
There are some bacteria that have a wonderful carbohydrate shell, some bacteria are encapsulated in carbohydrate, and the vaccines that are generated against bacteria like this i.e. pneumococcus are directed against the carbohydrate shell. In order to do that, you need to introduce the carbohydrate on a protein, and that protein is sometimes diptheria toxin, tetanus toxin, so its conjugated carbohydrates, because your T-cells can’t recognize that carbohydrate but they can recognize the tetanus toxin or diptheria toxin. So the B-cell presents the tetanus toxin peptide to the T-cell and the T-cell instructs the B-cell to make more antibody which might have interacted with the carbohydrate, and in that manner you can be protected against those carbohydrate encapsulated bacteria.
This (pg. 4 slide 1) is really similar to what happens when a CTL recognizes its target. There is an interface between the T-cell and the B-cell and in the center is the T-cell receptor and the MHC and ICAM and further out there are co-receptors like CD40, and this interaction tells the T-cell to activate the microtubule organizing center, which brings vesicles to the site and they are released, and with respect to T-cells helping B-cells make antibody, the vesicles release cytokines that are going to trigger the differentiation and division of that B-cell, one of which is IL-4.
So where do T-cells encounter B-cells? They don’t encounter them in blood or skin, they generally encounter them in lymphoid organs. The dendritic cell comes in from whatever tissue and that dendritic cell goes to the T-cell zone of the lymph node and the T-cells enter from the blood and look for their antigen on the dendritic cell, and when they do get activated they divide and differentiate and they recruit B-cells. If the B-cell is recruited and its surface is not crosslinked, then that B-cell begins to divide and differentiate and move into the germinal center, produce antibody, induce the formation of memory cells, possibly differentiate into a plasma cell which will then go to the bone marrow.
Plasma cells are devoid of MHC and they express virtually no surface Immunoglobulin. Resting B-cells have to, that’s their receptor, that’s how they get stimulated, and the cells that are their immediate descendents, the activated B-cell also have antibody on their surface because they need further affinity maturation, further triggering and activation. The memory cells will also maintain high levels of antibody on their surface. A resting cell has not differentiated to the point that its making antibody, it just has that one form on the surface, it doesn’t have antibody in vesicles, but once it gets triggered it starts making that antibody and releasing it.
Plasma cells are the terminally differentiated cells, they are not waiting for any further signals. A resting B-cell is primed to wait for triggering and when triggered some will differentiate into memory cells which will be quiescent but inducible. So a memory cell is just going to wait until the next time you see that antigen. Somatic hypermutation goes on once a cell has been triggered in both resting cells and memory cells. The resting cell is probably going to be a surface IgM cell and when it gets triggered, depending upon the milieu it will switch classes and that depends on what cytokines that T-cell is activating is secreting.
Any activated cell has to either become a memory cell or die, there is activation induced cell death. There is an expansion of a response and then there is a retraction. It is only when you have a chronic condition, like hepatitis C or cytomegalovirus infection, where you are constantly stimulating the immune system that you expand tremendously the population of cells that are specific for that, and you are constantly stimulating it so that as the contractions occur there is further stimulation. When people are persistently infected with cytomegalovirus 10% of their T-cells may be specific for CMV. With HIV, although you are constantly stimulating, HIV kills so many cells that they are not there for the expanded response.
So once you get an activated cell they generate antibodies but once the infection is gone those cells that were in the primary or secondary germinal center are going to contract and some of the daughter will be memory cells and some will be plasma cells, but the intermediate cells will die. You will still have resting cells because you will continue to generate new B-cells in your bone marrow and obviously there will be B-cells of the same clonotype in a different lymph node that did not get activated.
This (pg. 7 slide 1) is a reiteration of the class switching, first you get the VDJ recombination and after the VDJ recombination a constant domain is selected. During class switching, a constant domain is swapped out, and the one selected depends upon the milieu during activation of the B-cell. If IL-4 is present you IgG1 or you can get IgE. If you happen to make lots of IgE antibody to rose pollen then you develop type I hypersentivities, the classic spring fever allergy to that antigen. If the IgE is to something you eat then you develop a food allergy, because the mast cells that line the gut will be sensitized to that allergen. The original VDJ can be to anything, and depending on which constant domain is attached to it, the biologic repercussions are different. For instance, if you have a VDJ region against rose pollen, but it is on an IgG2, you will not get allergies, and that class switch is IFNγ dependent. So one strategy used to treat type I hypersensitivities, is to give injections of allergen in the form that they hope will stimulate TH1 cells instead of TH2 cells. TH1 cells are going to find new cells that have the appropriate VDJ recombination, induce class switching, and you won’t have as much IgE made in the future, it can be swapped out for IgG2. Once you have a cell that is making IgG1, when the microenvironment that surrounds the cell when it is restimulated, changes, you cannot go back to an IgM or IgD or IgG3 because the intervening DNA during the first class switch has been lost.
This (pg. 7 slide 2) distinguishes the kinds of antibody responses that the different cytokines make. So IL-4 induces IgE and IgG1 and IFNγ induces IgG3 and IgG2, there is more IgG2 made than IgG3, and IgG2 fixes complement. TGFβ induces IgG2B and IgA. IFNγ suppresses IgE production. Remember that IgM is stuck in blood, unless you have a lot of vascular permeability because you have a huge inflammatory response, you will not get that IgM out of the blood whereas the other classes can. IgG3 is very good at crossing the placenta so it protects babies. IgA is important for mucosal immunity.
Thymic independent antigens are highly repetitive and stimulate latent cells which make the response and these responses are important in babies and the peritoneum but the highly repetitive antigen are critical for those responses. When a B-cell is activated by a thymic independent antigen and a dendritic cell is activated on its PRRs or TLRs by the same antigen it can secrete BAFF. BAFF is part of the TNF family of cytokines, and it is involved in the activation of thymic independent 2 (TI2) B-cells that see the highly repetitive antigens, and the BAFF secreted by the dendritic cell can stimulate the class switch to IgG1 secreting cells.
Pg. 10 slide 1 – We talked about the standard antigens which elicit thymic dependent responses, these responses are found in infants, and they require T-cell priming and include a wide range of different antigens and pathogens. The TI-1 antigen, thymic independent 1, is an early response in infants, and it is there before you see much of the adaptive response, you can find these responses in individuals who are thymic deficient, you get polyclonal B-cell activation. TI-2 are found in thymic deficient individuals, they have the repeated epitopes, and it is polysaccharides that are largely able to stimulate these responses.
This table (pg. 10 slide 2) recapitulates a lot of the things that we have already discussed. An antibody can bind a pathogen and neutralize it if it can prevent it from binding onto a cell, and most classes of antibody are capable of doing that. IgM is not listed because IgM is not available in tissue, it can opsonize, but IgG1 and IgG3 can opsonize as well. Sensitization for killing by NK cells is antibody dependant cell mediated cytotoxicity ADCC. You must have an Fc receptor on a cell for the antibody and the Fc receptor is on the NK cell and the antibody binding site is directed at something else and this reaches the NK cell to that cell and enables the NK cell to kill in the absence of the other NK cell activating receptors that we talked about. Only IgE sensitizes mast cells, it would be nice if we could replace it, but the ε receptor is such high avidity and is so characteristic of mast cells that only IgE matters there. Complement activation is important and there are three subclasses that are capable of that. Getting across the epithelium is critical for mucosal immunity. Crossing the placenta protects the baby. Diffusion into extravascular sites, all antibodies but IgM can get across the vasculature. Now this last line, there is only a hint that at any time there was IgE in the blood because the affinity of the IgE receptor on mast cells is so high that as soon as IgE is made it is taken out and sensitizes those mast cells, whereas other antibodies can have other levels.
You have a plasma cell which is making IgA and the IgA is a dimer with a joining chain and there is a receptor on these (see pg. 11 slide 1) cells that specifically binds that joining chain and takes it up into a vesicle and in the vesicle the receptor gets cleaved, and the vesicle opens up on the luminal side and releases that IgA to that luminal area, whether it is your nose, lungs, genital urinary system, breast secretions, gut secretions, this is how it works. There is a fraction of that receptor that moved the antibody complex across that remains in contact with the IgA and that is called the secretory piece. Once this antibody dimer with the secretory piece is on the luminal side it is relatively protected from the proteases that are found in the gut or other regions of the body and the antibody is going to sit and wait for a pathogen or a toxin. The way that many bacteria cause disease is to release toxins, so you want antibodies that can bind those toxins and neutralize them. We have been immunized against many things to make antibodies against toxins i.e. tetanus, diptheria, cholera. The disease causing part of anthrax are two toxins, the new generation of vaccines against anthrax are toxin directed. Most of the bugs that cause gastroenteritis and other things actually stay in the lumen and secrete toxins. The way cholera causes disease is the toxin changes the permeability of the epithelial cells and causes the smooth muscle cells to contract giving you diarrhea, water fluxes out, so you need electrolytes to replace those that are lost, and the smooth muscle contractions are also going to cause cramping.
Where is IgA important in terms of protecting mucosa? The orapharynx the lungs, the GI tract, the genital urinary tract, it is secreted in collostrum. IgE is found wherever mast cells are found, and they are in skin, in the GI tract. IgG is everywhere but the brain does not have any antibody and normally you don’t find antibody in CSF and normally you don’t find antibody in the brain parenchyma. If there is a huge inflammatory response caused by infection or a traumatic event, you can get local release by increasing permeability in the brain hypervascular endothelial cells. In individuals that have a chronic inflammatory disease in the brain a tertiary lymph gets set up there, and the tertiary lymph node has the same structure of the secondary lymphoid organ and there you get B-cells secreting antibody locally, and because of the fluid flow in the brain which is rostral to caudal, gets collected in CSF and if somebody has a lumbar puncture, you will find antibody, but it will be selective, it will not be the same distribution of affinities that are found in the blood but it will reflect what is going on in the brain.
As said before, lots of bacteria make toxins and the toxins cause disease and depending upon the toxin, you get different kinds of disease. Tetanus toxin causes lock jaw by causing muscle contraction. Botulism causes the release of acetyl choline. Scarlet fever, one of the toxins causes vasodilation and when you have vasodilation the skin looks red. TSS is a disease that was recognized about 30 years ago. When the staph aureus that has the plasmid that makes the toxic shock syndrome toxin, TSST-1, they release it in high quantities and this toxin is a superantigen. Superantigens cross link T-cells and APCs and so even though you don’t have T-cell specificity you get wholesale activation of T-cells which releases tons of cytokines and thus you have a flood of cytokines which causes the toxic shock.
Many toxins but not all have two chains, and one of the chains binds a receptor, which leads to receptor mediated endocytosis, and when that occurs the other portion of the protein is able to enter the cell and affect it. Cholera toxin affects the adenocyclase which controls the flow of fluids on epithelial cells. One of the anthrax toxins results in the cleavage of MAP kinases, blocking signal transduction. Different toxins have different activities but they often have one chain that binds the cell surface receptor and the other chain which has the intracellular activation. So if you want to make a vaccine, you only need to clone and express just the portion of the protein that binds to the receptor, and if you do so, there is no danger of the disease associated with the toxin, you will just block the receptor binding capacity, and if you block that ability the toxic molecule can’t get into the cell.
Viruses bind cells by receptors and viruses have hijacked important cell surface molecules, which determines the cell specificity of the virus. So the virus binds and gets in somehow, sometimes by receptor mediated endocytosis, sometimes by fusing to the cell surface. The virus begins making their products and are released and infect new cells. Viruses cause disease in a wide variety of ways, if you have an antibody that can block the receptor on the virus you can block the virus from getting into cells, and that is how many vaccines work. The vaccine against influenza, which is an injection works by generating antibodies against the hemoglutanin of the virus, and that is the same for the vaccine against polio virus and the measles, vaccines that are live attenuated viral vaccines vs. dead virus or proteins derived from the virus, elicit TH1 cells and CD8 cells which are able to recognize virus infected cells and kill them whereas immunization against a piece of the virus is only going to give you antibody which can neutralize the virus and not the entire spectrum of immune responses to that virus. Where you immunize is also important. Having antibody against polio virus in the foot is not helpful. Polio is transmitted by the oral-fecal route, so you want antibody in the gut in order to prevent the initial infection, and the oral live attenuated virus vaccine protected the population by having antibody in the gut and generating T-cells. The salk vaccine which was killed virus, insured antibody in the blood which prevented transport of the virus across synapses. Once the initial infection in the gut took place it had to enter neurons and then the brain to cause poliomyelitis, but if you have antibody present in blood you can prevent that transmission from the gut to neurons, so individuals who were immunized with the killed virus vaccine still replicated virus in their gut and still spread it in the community but they didn’t get the disease.
Most of us have lots of bacteria on all of our surfaces and these are tame bacteria, they are normal flora, they are commensal. They do several things, they provide a barrier and they generally stay outside. So if they are colonizing your skin or gut should a pathogenic bacteria come in, the region is already crowded, and the pathogenic bacteria is not easily going to be able to get in and cause disease. In mucosa there is also a huge barrier of mucous, and there are cilia that are constantly moving the mucous, and that is another important bacteria that protects you. There are some pathogenic bacteria that are able to get through the barrier of commensal bacteria and the barrier of the mucous and bind cell surface receptors and some of them enter into cells, and some of them simply cross cells and enter blood and cause sepsis. If you have antibodies you can prevent the receptors from binding and the bacteria from causing disease.
If antibody is going to bind onto a cell there has to be a receptor for antibody and these receptors bind the constant domains, and that is why they are called Fc receptors. They come in a wide array but most have immunoglobulin like domains and many of them have secondary associated molecules which are important for signaling because not only do they need to bind stuff, they need to signal to the inside. The ITIM domains are inhibiting receptors, so that receptors with an ITIM domain will not induce phagocytosis. FcεR1 is the receptor on mast cells responsible for binding IgE and it is a complex series and there is a new monoclonal antibody that can bind that and not trigger and thus protect from allergies.
Bacteria get opsonized, they get internalized, the lysosome fuses with the phagosome and you get elimination.
Pg. 17 slide 2 shows you how large some parasites are, as you can see it is decorated with eosinophils. So these parasites can be huge, and in fact something like tape worm can be half the length of your gut, others are very tiny, but parasites come in all sizes. Obviously, something like this is not going to be phagocytized by one macrophage, it is not going to be eliminated in the same way and one of the things that can be done is these cells can bind and inject molecules that can kill the parasite, the eosinophils can bind and secrete things which will induce expulsion from the gut, and those are some of the ways you get rid of parasites.
ADCC was mentioned earlier, these Fc receptors on the NK cells bind the antibody which is binding the target cells and activate the NK cell.
We will talk much more about mast cells when we talk about allergies in a couple of weeks, but a resting mast cell is full of dense vesicles, and in these vesicles are many different mediators which cause the symptoms you see as allergy, it’s not just histamine, if it was just allergy any over the counter antihistamine can treat the symptoms of allergy, and we will talk about the rest of those molecules when we discuss allergies. But this, pg. 18 slide 2 is a resting mast cell, and next to it is a mast cell that has encountered the antigen which was cross linked by its receptors and you can see it is devoid of its vesicles because they are released at once.
Chapter 11: Mucosal immunity
This is a completely new chapter, any one who has the old textbook does not have this mucosal immunity, it took them 7 editions of Janeway to develop a chapter on mucosal immunity.
We have just talked about how IgA is important where the mucosa is, in the pharynx the lungs, the GU system, the mammary glands, eye secretions and salivary glands.
Why do we talk about mucosal immunity at all? Many infections that are important infect mucosal tissues. There are many things that cause respiratory infections, gastrointestinal infections, STDs, infections of the eye, and some of these can cause death and some of these are just an inconvenience. Others are a serious issue in the developing world, but acute respiratory infections take place throughout the world in diverse stratifications and populations. Diarrheal diseases can be lethal in children, some can be lethal in adults, mostly they are just debilitating. Tuberculosis can kill if you don’t have the right antibiotics. Measles can be completely prevented, hepatitis B vaccine is to a small peptide in hepatitis B, it is not a good vaccine but it does work. Hepatitis B causes infections in many people and it can cause death, the deaths are from acute destruction of the liver, cirrhosis or scarring of the liver, and the third cause of death is the development of hepatocellular carcinoma. Whooping cough is a disease that we have all been immunized against, however there are a number of parents in the U.S. who decided they didn’t want their children to receive the vaccine against this because a very small fraction of people developed a reaction to the vaccine which caused a seizure. As a result there have been mini epidemics of whooping cough which could have been virtually eliminated. It wasn’t recognized because doctors weren’t trained to recognize whooping cough because it is not endemic. Whooping can be treated with antibiotics but it can kill. Acute respiratory diseases can kill children, the elderly and immunocompromised individuals. Diarrheal diseases in an infant without supplementation with electrolytes can cause the infant to die of dehydration.
Mucosal infections can be severe and can kill and they are prevalent everywhere.
Janeway talks a lot about the gut, they don’t talk about the structure of the lung or the GU system in this chapter. The gut has some very specific features, it has long projections which have crypts in between them, it has specialized lymph nodes called peyer’s patches. In the gut you must distinguish between the commensal bacteria and the pathogens. There are many bacteria in the gut and these are important in digesting food, but you must be able to detect and react to pathogenic bacteria.
The vili have an epithelium and the epithelium has lots of cells with cilia which will be kneading the mucous. You need all the surface area increase offered by the villi in order to efficiently absorb the nutrients from food. There is lymph and blood vessels in the epithelium as well. In the mouth, in the oropharynx there are several different kinds of lymph nodes. Years ago, it was standard that when kids got inflamed tonsils, to remove them. The lymph nodes are there to deal with infections that enter through the mouth, to generate T-cells that respond to the viruses, antibodies are made there, and they are very important. Pg. 4 slide 1 shows an inflamed tonsil, the purple area represents dividing B-cells and T-cells.
Pg. 4 slide 2 shows increasing magnification of the peyer’s patch. There is an M cell on the surface. The M cell samples the contents of the lumen of the gut and transports antigens across where a dendritic takes up what has been sampled by the M cell. The dendritic cell processes and presents what has been sample by the M cell to T lymphocytes in the Peyer’s patch. If the M cell samples a commensal organism, it induces the dendritic cell to have an anti inflammatory phenotype so it will not turn on inflammatory T-cell responses. If this were a pathogenic bacteria it would turn this dendritic cell onto an activated inflammatory dendritic cell and turn on T-cell responses. Dendritic cells can also sample antigen in the gut directly by reaching across the epithelium.
Pg. 7 slide 1 lists some of the cells that are found on the villi. There are cells inside, in the lamina propria of the villi, and there are cells that go through the epithelial cell layer. The columnar epithelial cells are essential to the villi. There are cells that make mucous and immune cells as well. There are cells making IgA in the lamina propria, and that will be transported across the villi to the lumen. There are mast cells in the lamina propria that are waiting for food allergen to come, there are macrophages that are waiting for bacteria to enter, there are CD4 and CD8 T-cells and there are γ δ T-cells.
When the M cell samples pathogenic bacteria, the T-cells are activated by the dendritic cells that process the antigen. When the T-cells are activated they leave the lymph node and enters the lymph and enters the blood stream and then circulates to look for activated capillaries. If someone has an activated phenotype for that dendritic cell whether it is because of pathogenic bacteria, and you have a series of activation to normal commensal bacteria, you develop inflammatory bowel disease or crohn’s disease. To treat these diseases you want to arrest this interaction and block the T-cells from coming back into the endothelium and allow the gut to heal and recover. Crohn’s is treated with remicaid and anti TNF molecules. Another method of treating this is to use the monoclonal antibody that binds the integrin and prevents T-cells from entering from the blood.
Remember that to go into the lymph node the T-cell must bind the HEV, to go into other tissues you have other recognition molecules. For instance, L-selectin binds MadCAM and this α4:β7 receptor recognizes MadCAM as well but it recognizes the immunoglobulin domain and not the lectin component. MadCAM takes the T-cell out of blood and into tissue.
IgA is released into collostrum at the time of birth and is also introduced into bile and from bile is released into stomach contents. IgA binds bacteria, toxins and neutralizes toxins.
If you get a viral infection in the gut it can result in gastroenteritis, the virus infects and causes dysfunction of the epithelium you get acute gastroenteritis, T-cells kill the virally infected cells, but most of the gastroenteritis is the host response to the infection. T-cells recognize virally infected cells and kill it and NK cells can do the same thing. Gliadin is a peptide associated with one of the food allergies, it is found in wheat products. Ciliac disease is a reaction to Gliadin.
What are some pathogens that cause disease? Norwalk virus has been caused the cruise ship virus, it goes through dormitories and hospitals, it causes acute and violent gastroenteritis and vomiting. It is a small virus, it spreads through the oral fecal route, it has high titers and a capsule, not an envelope so soap and water is not enough. There are many serotypes, and when it is around the area must be completely disinfected. Salmonella, cholera, yersinia enteritis, clostridia perfingins, there are even mycobacterial infections of the gut. Helicobacter is associated with ulcers. There are also protozoa, like Giardia, entamoeba is amoebic dysentery, tape worm. How do pathogenic bacteria cause disease, besides those that release toxins. Some bind receptors on cells and enter cells, and they trigger TLRs. There are those that are able to leave endosomal vesicles and enter cytoplasm and there is a series of damage receptors of the NOD family, and another member of the NOD family is a transcription factor, critical for class II gene expression and an absence of that transcription factor can lead to bare lymphocyte syndrome. The NOD familiy has a signal transduction cascade which results in activation of those cells and they make cytokines and chemokines and interferons which starts an inflammatory response. Other bacteria can get into blood and cause sepsis.
In mice, we found a phenomenon that if you feed mice the initial time they are exposed to an antigen orally as opposed to by the respiratory route or injection you can get what is called oral tolerance. This is due to the induction of T regulatory cells specific for that antigen. There is a little IgA made, there are T-cells made but they are T-regs, not effector T-cells. If you inject that antigen by another route you don’t get an immune response. People thought this was a way to treat autoimmune disease; if you oral tolerize to collagen you cannot elicit collagen induced arthritis, however people already had many clones of pathogenic T-cells specific for the collagen antigen and oral tolerance does not work after the fact, you need T-regulatory cells to shut down those autoimmune inflammatory processes but it doesn’t work with oral tolerance.
Normally there is a great commensal bacteria layer, but if you get strep or you have an abscessed tooth and you get a prescription for an antibiotic, that antibiotic will kill commensal bacteria as well. This will destroy the barrier of commensal bacteria, and pathogenic bacteria will have the opportunity to cause gastroenteritis, and that is not uncommon after antibiotic treatment. Once you get rid of the pathogenic bacteria and replace it with the commensals you will recover. You can eat yogurt to replace commensal bacteria.
Pathogenic bugs come in and activate mucosal dendritic cells which activate the T-cells, whereas the commensal bugs give an anti inflammatory signal.