tyrinryan wrote: ↑Sun Oct 09, 2022 11:33 am
Terrific and so well written! Could you expand on the paragraph "This was the year....". Macrophages, I guess, only attack the infected regular cells? are there other immune cells or even regular cells that are part of the equation to create the cytokine storm? etc.? or is it only these macrophage explosions? What would be the purpose of a non-neutralizing antibody?
The immune system is enormously complicated and I don't pretend to understand all of it. But I think I can give a little summary. I am not going to cover things like interferon, by which an infected cell can tell its neighbors to shut down their machinery because there are viruses around, but am going to concentrate on the immune cells themselves. I will just note there was a fascinating study in a petri dish with nasal cells which showed they cleared rhinovirus (a type of common cold) infections by themselves - with no immune cells present.
Your immune system has two "teams" called the innate immune system and the adaptive immune system. The innate immune system is designed to be a first responder to anything bad going on, but is not particularly specific. It has a number of different kinds of cells, like neutrophils, which attack bacteria, and natural killer cells, which attack human cells which appear infected, and macrophages, which are monocytes which travel in the blood to an infected organ and then turn into macrophages ("big eaters") which go around trying to eat bad things, like viruses or the detritus of dead cells. The innate immune system has ways of causing "inflammation" which is actually part of the damage response and healing process, it brings more blood, and thus more oxygen, nutrients, immune cells etc to a trouble spot to stop the problem and begin repairs. If you've sprained your ankle, the resulting swelling is your innate immune system bringing in repair crews to fix the damage.
The innate immune system also produces symptoms. The purpose of this is to make you lie down and rest. The way the body's energy budget works is active tasks, like thinking and moving muscles, spend energy from the daily budget immediately as they occur. The immune system gets what is "left over" as a budget surplus so to speak. That is why you will do worse if you try to remain active through an illness. Feeling bad is the innate immune system's way of forcing you to lie down and not do anything so it has plenty of energy from the surplus. Those muscle aches, headache, fatigue etc? They're the innate immune system trying to get you to hand over the energy. Of course you can override this (what if there's a lion over there?) but you shouldn't unless you have no choice.
Other less pleasant symptoms like nausea, vomiting and diarrhea are the body's way of trying to flush bad things out of the digestive system and make you stop eating whatever noxious substances you ate.
Fever has a special purpose, it changes the body temperature which in turn impacts enzymes (organic catalysts). Enzymes are designed to operate at a particular temperature and biological processes are absolutely dependent on them. Warm blooded animals have mostly enzymes which work at a particular temperature and they regulate their body temperature to maximize enzyme activity by keeping things at the ideal temperature for their enzymes. Cold blooded animals have groups of enzymes, some of which work at this temperature, some at that, so they can tolerate a wide range of internal temperatures and their metabolism does not stop if they get cold (like ours does), but on the other hand, when they get cold only a portion of their enzyme set works so they are sluggish, while our bodies would spend energy to maintain our temperature at a constant point and remain just as active when it's cold out as when it's warm since all our enzymes are always available at full capacity. Make us too cold internally and all the machinery stops though.
Bacteria and viruses tend to like it colder than we do in terms of their enzyme activity. If you raise the temperature via a fever, their activity tends to slow. They reproduce more slowly. Thus a fever can often slow down a disease by interfering with the activity level of the enzymes the pathogen uses to infect cells and reproduce itself. This is why fever reducers are seldom a good idea. They are making things more pleasant for the disease organism. One study showed that people who took aspirin during a common cold had a 50% longer duration of the cold than people who didn't.
Which brings us to the main point of the innate immune system in a situation like a viral infection: to buy time. The innate immune system is not "smart" and just tries to attack obviously bad things, increase the temperature, make you feel crappy so you rest, and create inflammation in attacked areas to bring in reinforcements. It is just stalling for time for the other team to do its thing.
Calling for backup is another job of the innate immune system. There are innate immune cells, called antigen-presenting cells, such as dendritic cells, whose job it is to patrol the body and look for alien stuff, namely antigens, floating around. Anytime there are viruses or bacteria there are pieces of protein, lipoproteins etc from them floating around for various reasons. Antigen is short for "antibody generating." It is a substance defined by the fact it evokes a response from the adaptive immune system because the body recognizes it as alien. Dendritic cells like to hang out in muscles among other places which is why intramuscular shots are given for many vaccines.
The adaptive immune system is the precise one. It contains two general classes of cells, T cells and B cells. You could think of the innate immune cells as street cops walking beats all over the body and the adaptive immune system as a SWAT team in reserve, much more powerful but it has to be summoned to where the trouble is and told what it is so it can prepare.
When an antigen-presenting cell like a dendritic cell finds something weird and alien, like a viral protein, it goes to the lymph nodes where the T cells and B cells hang out. If I recall correctly it hands off what it found to a type of T cell called a helper T cell. Then this cell goes looking for what are called naive T and B cells. Naive cells are not specialized, they are essentially recruits who have not been trained yet. But they each have a unique pattern on their outside. The helper cells holds out a chemical signal which corresponds to the antigen that was found, to find naive cells who "match" it to some degree. You can think of this like a peg and hole sort of arrangement, or a lock and key. The helper cell tries to find T and B cells whose surface pattern roughly fits the antigen. This pattern is a protein called an immunoglobulin and the T and B cells display it on their surfaces so the helper cells can try to find cells that match the antigen the helper cell is carrying around.
Matching cells become "activated" and begin a remarkable process called somatic hypermutation and affinity selection. This means they begin dividing and deliberately inducing very high rates of mutation in the sections of their DNA that code for their unique immunoglobulin. This produces lots of slightly different cells with a huge array of variations of their immunoglobulin, some of which will fit the antigen better and some worse. The helper cells keep fitting their little key to the locks of the immunglobulins of these new cells. If a cell is a bad fit, it is told to self destruct and it drops out of the competition. If it is a good fit, it continues in this process, which simulates mutation and natural selection in the environment, producing generation after generation of these mutated cells, trying by chance to get better and better fits to the antigen, with the losers of each round self destructing and the winners dividing again with more mutations. This goes on for days, even weeks. At some point cells whose immunoglobulins are a more or less perfect match, along with other ones which are close, are produced. The body has thus produced immune cells whose immunoglobulins match the antigen almost exactly, along with variations just in case the virus mutates. These cells now follow one of two paths: they become memory cells to keep in reserve for the next time this antigen is seen so the process goes much faster, or they go to war.
(This process actually continues over time after the infection is over, and again upon re exposure, such as a second vaccine shot, but that's another story.)
T cells that go to war are called cytotoxic T cells and their job is to look for their matching antigen or a fragment of it (they are very good at recognizing variants of their immunoglobulin) on the surface of a human cell. Human cells always have a little escalator inside that runs up samples of everything it is making and displays them on its surface in something called the major histocompatibility complex or MHC. The T cells float around and sample the MHCs of everything they bump into to see if anything there matches their immunoglobulin. If it does - it means the cell is making viral proteins! It is infected! The T cell has ways of destroying human cells, such as apoptosis, where the infected cell is ordered to self destruct. The T cells go around killing the human cells which have been co-opted into becoming viral factories. This is the only way to end an infection - destroy all the infected cells. T cells stop the infection at its source, the infected cells which are making more viruses.
B cells that go to war are called plasma cells. They begin manufacturing enormous quantities of their immunoglobulins and releasing them into the bloodstream. These free floating immunoglobulins are more widely known as "antibodies." They have been crafted through the mutation and selection process to chemically match and stick onto the antigen. The blood becomes filled with these antibodies and viruses displaying the antigen find themselves covered in a fuzz of antibodies blanketing them like iron filings on a magnet.
Now the B cells produce antibodies to whatever they are shown by the helper cells. Some antigens, like the tip of the fusion proteins of viruses like covid, are required to be functional and exposed for the virus to be able to infect a cell. If you cover them with antibodies, the virus is neutralized and cannot infect anything. However, other antigens, like other substances on the virus surface, or parts of the spike protein not near the tip which are not essential to have exposed in order to infect a cell, are not used in the infection process and it doesn't neutralize the virus to cover them. The B cells have been shown all sorts of antigens by helper cells and make antibodies to them all. Some are neutralizing, some are not, depending on exactly what antigens they were shown, which is going to be a wide array of fragments of various substances produced by the virus.
Macrophages know what antibodies are, if they see something with antibodies sticking to it, they know it is something alien to be eaten and dissolved. This works fairly well most of the time, but there are certain viruses like dengue and HIV which use something called "antibody dependent enhancement" or ADE. For them, this means the person was infected with one strain, produced antibodies to it, and then later was infected by another strain. The antibodies to the old strain are close enough to the new strain to stick to it, but not well enough to neutralize it. This results in "marked" viruses that immune cells try to eat, but the virus is still active and infectious, so it infects the immune cell. This is bad. This is why a second dengue infection is often far worse than the first. This also happened when researchers tried to make a vaccine for RSV - to make a long story short the vaccine produced lots of antibodies which were not neutralizing, and children getting the vaccine actually did far worse than the control group. The RSV debacle gave a lot of lessons which made the covid vaccines possible.
Covid, to my knowledge (which is limited) is the first virus to use ADE in the initial infection, such that early antibodies (which might not fit as well as later, more refined versions, or else target unessential parts of the virus) enable the virus to infect macrophages. The virus gets eaten, but it breaks out of the endosome the macrophage stores it in, so instead of being destroyed, it infects the macrophage. Macrophages know this trick and self destruct rather than let themselves be used as a virus factory, but in doing so they send up a big flare that hey, this is serious, this pathogen is infecting the immune system itself, send help now. This is a major form of inflammation which results in more immune cells coming in, some of which get infected the same way and it's like a chain reaction in a nuclear bomb. Innate immune cells are not the trained snipers of the adaptive immune system, and in a situation like this with flares going up saying "Emergency!" and without the specificity of the trained T cells, they can start killing everything in sight, including uninfected lung cells, and "destroy the village in order to save it."
I should note that one of the things the adaptive immune system does, when it is ready to fight, which is typically 14 days after infection, is tell the innate immune system to stand down. Turn off the fever, the inflammation, the body aches etc the situation is now under control, we got this. Except this doesn't work in a cytokine storm of the type produced by the infected macrophages. It can be very difficult or impossible for both the body and for doctors to stop the runaway cytokine storm once it starts. I don't think covid is the only virus that can cause this situation but it certainly is the first widespread one that I know of.
Future infections by the same pathogen result in a similar but shorter process where the antigen presenting cells find an army of memory cells already waiting and trained on this particular antigen. Chances are the virus has mutated a bit since last time so some more refinement might be needed, but the antibodies start getting churned out in days rather than weeks. For most viruses, this response is faster than the virus' incubation time, which means the body gets it under control before the virus can reproduce enough to trigger symptoms and you never know you even were reinfected. This is what the "lifetime immunity" we associate with things like measles and smallpox is. You don't get these diseases twice, once your immune system is trained it can squash any future infections quickly. Covid unfortunately now has such a short incubation time that it can outrun even a trained immune system before the memory cells can get fully into gear, although your chances are still much better of avoiding a bad outcome if you have had prior exposure to the antigen and have memory cells standing by.
Hope that was helpful and that I didn't make too many mistakes. I think the immune system is second only to the brain in terms of complexity, it truly is amazing and I am not an immunologist.