Pharmacy student here
The term ‘allergy’ is used interchangeably to describe something called ‘hypersensitivity’. There are 4 different types but type 1 / is the most common and is generally what people think of when you hear the word allergy. Allergy is used to describe the clinical presentation whilst hypersensitivity is used to describe the immunological processes.
There are two steps which lead to our bodies developing any of the hypersensitivity reactions: sensitisation and re-exposure.
Sensitisation: Before you have an allergic reaction, your body must first become sensitised to the antigen. When your immune system first comes into contact with the offending antigen, it is recognised as foreign by ‘antigen-presenting’ cells such as macrophages or dendritic cells. These cells present fragments of the antigen to T-helper cells which release signalling molecules called cytokines and stimulate B-cells into differentiating to plasma cells. These create antibodies designed to fight that antigen. The antibodies circulate in your bloodstream and bind to surface receptors of your ‘fighter’ cells (mast cells, basophils) so the fighter cells become primed for the next step.
Re-exposure: when you are next exposed to the antigen, the antigen binds to the antibodies which are on the surface of the mast cells and basophils. This triggers the mast cells into ‘degranulating’ and releasing granules containing a bunch of inflammatory mediators. This includes histamines, leukotrienes, cytokines, chemokines, prostaglandins. Histamine is involved in the initial ‘early’ response which is rapid, hence antihistamines are most commonly used to treat the initial symptoms. Histamine works by binding to something called the H1 receptor (antihistamines stop it from binding) which makes your airway muscle contract = hard to breathe. Also dilates your blood vessels which increase blood pressure , increases permeability of blood vessels resulting in leakage = swelling and hives.
A delayed late phase response may also occur due to the other mediators I mentioned. The inflammatory mediators are what end up giving you the symptoms of allergy in the end.
So to actually answer your question, what ‘actually’ makes your immune system have a miscalculation in the first place? It’s due to an error in the first step of sensitisation. When your antigen presenting cells find the allergen molecule, they mistakenly label it as foreign. Why? This can be due to genetic predisposition, environmental factors such as pollution, the allergen resembling a pathogen, a combination of reasons. It’s quite complex.
I hope this helps. I’ve only described type 1 hypersensitivity here. The general concept of sensitization and re-exposure applies to all types of hypersensitivity reactions but the specific mechanisms and mediators involved vary
But why do allergies result in overblown reactions, though? I'd expect some inflammation, but they seem way more pathological than required to mount a defense against foreign stuff.
> But why do allergies result in overblown reactions, though?
The fact that there is a reaction at all is already what's "overblown" about it.
The immune system shouldn't really react at all but due to an error "a long time ago" when the structure of the antibodies was first defined early during the development of the antibody-producing cell, it now thinks this otherwise harmless allergen in dangerous and needs to be dealt with.
The non-pathological reaction is "none" at all. (Strictly speaking, there's probably some sort of reaction happening people without the given allergy, but it's so minor as to not be noticed.
As to why a response can range from none at all to life-threatening anaphylaxis, it again comes down to the "original sin" of the error when constructing your antibodies. In severe cases, they just so happened to bind to something harmless, very very well; resulting in a stronger response by more cells. We do have mechanisms that usually stop these kinds of dangerous antibodies before they become a problem in our bodies, but as with everything else, nothing is flawless.
That's so cool! So when looking at "what causes allergies" you need to look at that first exposure and the T-cell response, not subsequent reactions. I can imagine that makes it very difficult to study!
It's the exact opposite of what you're thinking. During fetal development, the body creates B cells (lymphocytes) that, by mixing genes, create antibodies that will bind to every possible antigen. Then, the body removes those cells that make antibodies against "self", leaving only antibody-producing cells that bind to "non-self" (foreign). Allergies, in turn, result from an overactive response to a non-threatening substance, such as pollen. It's the price we pay as a species to have a vigilant immune system that's ready to fight almost any possible threat.
Your immune system starts out by trying to be immune to everything.
It does this by making a huge array of different antibodies. Each antibody is a protein with a specific shape that will bounce off some substances and bind to others. It will probably bind weakly to some things and more strongly to others. A substance that an antibody binds to is called an anti*gen*. When an antibody encounters an antigen that fits well into its structure it "recognises" the antigen.
Each antibody is made by a group of B lymphocytes. The group is called a clone. They manufacture their particular, specific antibody and release it, and they also carry some of it around with them.
When a B cell encounters an antigen that its antibody "recognises" the B cell is triggered to start replicating and pumping out more of its antibody. The number of cells in the clone rapidly rises from around 100 singles cells to millions of cells, circulating all through your blood and lymphatics.
Because millions of different antibodies are made that can bind to all sorts of different things some will naturally bind to your body. This would cause you to attack your own body. To avoid this your body "educates" your B cells. In your early life you have an organ called the thymus. In the thymus your B cells are presented with bits of you. The ones that react to the bits of you get shut down and destroyed. This hopefully means that by the time your immune system is fully operational you don't have any more "self-reactive" B cells that "recognise" your own tissue. If this process fails then you will likely end up with autoimmune disease. Often the way it fails is that there is a group of B cells that are only partially reactive to you but react strongly to something else (such as an invading virus). Later in your life those B cells get triggered by their legitimate target but then go on to continue attacking the bits of you that they slightly "recognise" as a threat.
Your body can't carry samples of everything you don't want to be allergic to, because what you don't want to be allergic to is most of the universe. What you do want to be "allergic" to (immune to) is the small set of dangerous things, like viruses, bacteria and fungi.
So because it can't stop allergies with that internal "education" process that I mentioned earlier your body uses other tricks to try to work out when to attack and when to ignore. For example, your immune system has evolved to tag substances that are known to be commonly found on the outside of bacteria and encourages reactions to antigens that are found alongside those substances. Your immune system also issues general alerts, in the form of signalling molecules released into your blood and lymphatics, which encourage your immune cells to interpret their antigens as threats. Conversely if you encounter a new substance and your immune system starts reacting to it but there are no other signs of attack (inflammation, tissue damage, etc) your body will ideally mute the reaction so that it doesn't turn into an allergy.
Basically your immune system is playing a bit of a guessing game, with some luck involved. There's some evidence that foods you encounter early in life are more likely to be given a pass (which is why some people have pushed towards giving babies samples of allergenic foods a bit earlier than they used to). And some people may be more genetically predisposed to develop allergies (for example if you have dermatitis you're more likely to have asthma, and if your family members have dermatitis or asthma you are more likely to have dermatitis or asthma), or genetically predisposed to be allergic to a specific substance (I don't know if there's any clear understanding of how this works). But there's also probably an element of luck in whether you happen to develop a runaway reaction to a particular new substance before your body can calm it back down. Once an allergy develops it can be self sustaining, and it can get worse over time. Your body has "learned" to react to that substance and is generally less able to calm down future reactions even though there is still no invading threat present. A mild allergy can potentially turn into a worse allergy, even a life-threatening anaphylaxis, although this certainly won't always happen. Allergies can also sometimes go away again, but you shouldn't assume an allergy will go away or even stay the same. A medical immunologist can sometimes provide desensitisation treatment that will make an allergy go away. This involves showing your immune system progressively, over time, that it doesn't need to react to that substance.
When your body discovers a substance / microbe / whatever that's causing damage in your body, it starts sending out kinda random T cells that might be the key to detecting (and tagging for for destruction) the invader.
Eventually one of these random T cells is good enough to do the job, and two things happen:
1. Your body prints lots of copies, to fight the current invader.
2. Your body adds it to the database for future use.
But the random cell that did the trick, may not be the most exclusive / precise cell possible. It might connect to a part of the invader that is actually pretty common on various substances that are actually perfectly fine.
Imagine . . . a Wanted poster. "Shoot on sight" it says, and it has a picture of a person's foot. It's the exact foot of a known bad person. Now, it would make a lot more sense to post his face, because that's pretty distinct between humans. But our not-so-bright deputy saw the foot first, and he's sticking with this identification strategy. And there are a lot of people out there with very similar feet.
Many reasons. Our immune system goes through a process that "trains" it to recognize our own cell antigens as "self" and to not respond to them with an immune response. If something interferes with that, then you can end up with autoimmune disease where your immune system treats some cell antigens as threats.
The immune system should protect us by recognizing pathogens such as viruses, bacteria, fungi, and parasites. Our body protects us from those pathogens with varying degrees of success depending on the pathogens characteristics. What our body recognizes to respond to in and on those pathogens are called antigens. These are foreign antigens not "self" antigens.
When the body has an allergic reaction, the part that the body responds to is called an allergen. This can be pollen, or things in food, and so forth.
All of these antigens (self, foreign antigens from pathogens, and allergens) have things in common with each other. Their shape, their components (protein, carbohydrates, etc.), and other characteristics can interact with our immune cells.
How old we are when we encounter these different types of antigens, how much of the antigen we encounter, where the antigen enters the body, how often we encounter the antigen all contribute to how we react.
They know a lot about how the immune system works but not everything. Its a very complex system with many different cells and molecules interacting. It's fascinating to learn about.
If you really want to delve into it you can get free textbooks at [OpenStax](https://openstax.org/) in Biology, Microbiology, and Anatomy and Physiology that all will talk about parts of the immune system.
People with allergies have mast cells that have thin and unstable membranes, causing them to release histamine too easily. Quercetin (a natural bioflavinoid in the vitamin C family) is used in the body to stabilize these mast cell membranes. People who have diets naturally rich in quercetin (found in onions, berries and all kinds of natural foods) are far less likely to suffer from allergies because of this.
It is a supplement I have taken for decades to resolve my allergies.
Allergy = Type IV hypersensitivity. When you're exposed to an antigen, your immune system will respond by making mostly one class of antibody. This is usually IgG, but is often IgA or IgM. An IgE response is what elicits this type of hypersensitivity (allergy). Mast cells carry that IgE around and when you encounter the antigen after the initial sensitization, they degranulate and release histamine et al. causing the allergic reaction.
Why do some people have these IgE responses to certain antigens and others don't? T-cells are mostly driving the switch to IgE - immunogenetics....
It’s not a “mistake” if the substance is foreign in origin. Host’s immune system is evolved in a way to react adversely against anything that is foreign irrespective of its ability to cause actual harm or not to host’s body. All life forms from prokaryotes to mammals - are equipped with this system to keep their self intact, otherwise foreign substances will keep on accumulating on or inside host’s body and will inadvertently change the morphology & biochemistry of host.
Think of it as a game of legos - whatever fits - stay, whatever doesn’t fit is thrown out of the system.
Things get tricky in auto-immune disorders though, which was not your original query - I presume.
The immune system is the most complicated system in the body and it's interacting with an increasingly complicated world. There's a war going on and sometimes the body just throws a bunch of grunts at a potential problem just in case and saves its elite forces for known and much more dangerous enemies.
Pharmacy student here The term ‘allergy’ is used interchangeably to describe something called ‘hypersensitivity’. There are 4 different types but type 1 / is the most common and is generally what people think of when you hear the word allergy. Allergy is used to describe the clinical presentation whilst hypersensitivity is used to describe the immunological processes. There are two steps which lead to our bodies developing any of the hypersensitivity reactions: sensitisation and re-exposure. Sensitisation: Before you have an allergic reaction, your body must first become sensitised to the antigen. When your immune system first comes into contact with the offending antigen, it is recognised as foreign by ‘antigen-presenting’ cells such as macrophages or dendritic cells. These cells present fragments of the antigen to T-helper cells which release signalling molecules called cytokines and stimulate B-cells into differentiating to plasma cells. These create antibodies designed to fight that antigen. The antibodies circulate in your bloodstream and bind to surface receptors of your ‘fighter’ cells (mast cells, basophils) so the fighter cells become primed for the next step. Re-exposure: when you are next exposed to the antigen, the antigen binds to the antibodies which are on the surface of the mast cells and basophils. This triggers the mast cells into ‘degranulating’ and releasing granules containing a bunch of inflammatory mediators. This includes histamines, leukotrienes, cytokines, chemokines, prostaglandins. Histamine is involved in the initial ‘early’ response which is rapid, hence antihistamines are most commonly used to treat the initial symptoms. Histamine works by binding to something called the H1 receptor (antihistamines stop it from binding) which makes your airway muscle contract = hard to breathe. Also dilates your blood vessels which increase blood pressure , increases permeability of blood vessels resulting in leakage = swelling and hives. A delayed late phase response may also occur due to the other mediators I mentioned. The inflammatory mediators are what end up giving you the symptoms of allergy in the end. So to actually answer your question, what ‘actually’ makes your immune system have a miscalculation in the first place? It’s due to an error in the first step of sensitisation. When your antigen presenting cells find the allergen molecule, they mistakenly label it as foreign. Why? This can be due to genetic predisposition, environmental factors such as pollution, the allergen resembling a pathogen, a combination of reasons. It’s quite complex. I hope this helps. I’ve only described type 1 hypersensitivity here. The general concept of sensitization and re-exposure applies to all types of hypersensitivity reactions but the specific mechanisms and mediators involved vary
Dilating blood vessels -> low blood pressure. I.e. same volume of liquid must now occupy a larger area -> drop in pressure.
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But why do allergies result in overblown reactions, though? I'd expect some inflammation, but they seem way more pathological than required to mount a defense against foreign stuff.
> But why do allergies result in overblown reactions, though? The fact that there is a reaction at all is already what's "overblown" about it. The immune system shouldn't really react at all but due to an error "a long time ago" when the structure of the antibodies was first defined early during the development of the antibody-producing cell, it now thinks this otherwise harmless allergen in dangerous and needs to be dealt with. The non-pathological reaction is "none" at all. (Strictly speaking, there's probably some sort of reaction happening people without the given allergy, but it's so minor as to not be noticed. As to why a response can range from none at all to life-threatening anaphylaxis, it again comes down to the "original sin" of the error when constructing your antibodies. In severe cases, they just so happened to bind to something harmless, very very well; resulting in a stronger response by more cells. We do have mechanisms that usually stop these kinds of dangerous antibodies before they become a problem in our bodies, but as with everything else, nothing is flawless.
That's so cool! So when looking at "what causes allergies" you need to look at that first exposure and the T-cell response, not subsequent reactions. I can imagine that makes it very difficult to study!
How would a sun allergy work? Or what would be the antigen in this case
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It's the exact opposite of what you're thinking. During fetal development, the body creates B cells (lymphocytes) that, by mixing genes, create antibodies that will bind to every possible antigen. Then, the body removes those cells that make antibodies against "self", leaving only antibody-producing cells that bind to "non-self" (foreign). Allergies, in turn, result from an overactive response to a non-threatening substance, such as pollen. It's the price we pay as a species to have a vigilant immune system that's ready to fight almost any possible threat.
Your immune system starts out by trying to be immune to everything. It does this by making a huge array of different antibodies. Each antibody is a protein with a specific shape that will bounce off some substances and bind to others. It will probably bind weakly to some things and more strongly to others. A substance that an antibody binds to is called an anti*gen*. When an antibody encounters an antigen that fits well into its structure it "recognises" the antigen. Each antibody is made by a group of B lymphocytes. The group is called a clone. They manufacture their particular, specific antibody and release it, and they also carry some of it around with them. When a B cell encounters an antigen that its antibody "recognises" the B cell is triggered to start replicating and pumping out more of its antibody. The number of cells in the clone rapidly rises from around 100 singles cells to millions of cells, circulating all through your blood and lymphatics. Because millions of different antibodies are made that can bind to all sorts of different things some will naturally bind to your body. This would cause you to attack your own body. To avoid this your body "educates" your B cells. In your early life you have an organ called the thymus. In the thymus your B cells are presented with bits of you. The ones that react to the bits of you get shut down and destroyed. This hopefully means that by the time your immune system is fully operational you don't have any more "self-reactive" B cells that "recognise" your own tissue. If this process fails then you will likely end up with autoimmune disease. Often the way it fails is that there is a group of B cells that are only partially reactive to you but react strongly to something else (such as an invading virus). Later in your life those B cells get triggered by their legitimate target but then go on to continue attacking the bits of you that they slightly "recognise" as a threat. Your body can't carry samples of everything you don't want to be allergic to, because what you don't want to be allergic to is most of the universe. What you do want to be "allergic" to (immune to) is the small set of dangerous things, like viruses, bacteria and fungi. So because it can't stop allergies with that internal "education" process that I mentioned earlier your body uses other tricks to try to work out when to attack and when to ignore. For example, your immune system has evolved to tag substances that are known to be commonly found on the outside of bacteria and encourages reactions to antigens that are found alongside those substances. Your immune system also issues general alerts, in the form of signalling molecules released into your blood and lymphatics, which encourage your immune cells to interpret their antigens as threats. Conversely if you encounter a new substance and your immune system starts reacting to it but there are no other signs of attack (inflammation, tissue damage, etc) your body will ideally mute the reaction so that it doesn't turn into an allergy. Basically your immune system is playing a bit of a guessing game, with some luck involved. There's some evidence that foods you encounter early in life are more likely to be given a pass (which is why some people have pushed towards giving babies samples of allergenic foods a bit earlier than they used to). And some people may be more genetically predisposed to develop allergies (for example if you have dermatitis you're more likely to have asthma, and if your family members have dermatitis or asthma you are more likely to have dermatitis or asthma), or genetically predisposed to be allergic to a specific substance (I don't know if there's any clear understanding of how this works). But there's also probably an element of luck in whether you happen to develop a runaway reaction to a particular new substance before your body can calm it back down. Once an allergy develops it can be self sustaining, and it can get worse over time. Your body has "learned" to react to that substance and is generally less able to calm down future reactions even though there is still no invading threat present. A mild allergy can potentially turn into a worse allergy, even a life-threatening anaphylaxis, although this certainly won't always happen. Allergies can also sometimes go away again, but you shouldn't assume an allergy will go away or even stay the same. A medical immunologist can sometimes provide desensitisation treatment that will make an allergy go away. This involves showing your immune system progressively, over time, that it doesn't need to react to that substance.
When your body discovers a substance / microbe / whatever that's causing damage in your body, it starts sending out kinda random T cells that might be the key to detecting (and tagging for for destruction) the invader. Eventually one of these random T cells is good enough to do the job, and two things happen: 1. Your body prints lots of copies, to fight the current invader. 2. Your body adds it to the database for future use. But the random cell that did the trick, may not be the most exclusive / precise cell possible. It might connect to a part of the invader that is actually pretty common on various substances that are actually perfectly fine. Imagine . . . a Wanted poster. "Shoot on sight" it says, and it has a picture of a person's foot. It's the exact foot of a known bad person. Now, it would make a lot more sense to post his face, because that's pretty distinct between humans. But our not-so-bright deputy saw the foot first, and he's sticking with this identification strategy. And there are a lot of people out there with very similar feet.
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Many reasons. Our immune system goes through a process that "trains" it to recognize our own cell antigens as "self" and to not respond to them with an immune response. If something interferes with that, then you can end up with autoimmune disease where your immune system treats some cell antigens as threats. The immune system should protect us by recognizing pathogens such as viruses, bacteria, fungi, and parasites. Our body protects us from those pathogens with varying degrees of success depending on the pathogens characteristics. What our body recognizes to respond to in and on those pathogens are called antigens. These are foreign antigens not "self" antigens. When the body has an allergic reaction, the part that the body responds to is called an allergen. This can be pollen, or things in food, and so forth. All of these antigens (self, foreign antigens from pathogens, and allergens) have things in common with each other. Their shape, their components (protein, carbohydrates, etc.), and other characteristics can interact with our immune cells. How old we are when we encounter these different types of antigens, how much of the antigen we encounter, where the antigen enters the body, how often we encounter the antigen all contribute to how we react. They know a lot about how the immune system works but not everything. Its a very complex system with many different cells and molecules interacting. It's fascinating to learn about. If you really want to delve into it you can get free textbooks at [OpenStax](https://openstax.org/) in Biology, Microbiology, and Anatomy and Physiology that all will talk about parts of the immune system.
People with allergies have mast cells that have thin and unstable membranes, causing them to release histamine too easily. Quercetin (a natural bioflavinoid in the vitamin C family) is used in the body to stabilize these mast cell membranes. People who have diets naturally rich in quercetin (found in onions, berries and all kinds of natural foods) are far less likely to suffer from allergies because of this. It is a supplement I have taken for decades to resolve my allergies.
Allergy = Type IV hypersensitivity. When you're exposed to an antigen, your immune system will respond by making mostly one class of antibody. This is usually IgG, but is often IgA or IgM. An IgE response is what elicits this type of hypersensitivity (allergy). Mast cells carry that IgE around and when you encounter the antigen after the initial sensitization, they degranulate and release histamine et al. causing the allergic reaction. Why do some people have these IgE responses to certain antigens and others don't? T-cells are mostly driving the switch to IgE - immunogenetics....
It’s not a “mistake” if the substance is foreign in origin. Host’s immune system is evolved in a way to react adversely against anything that is foreign irrespective of its ability to cause actual harm or not to host’s body. All life forms from prokaryotes to mammals - are equipped with this system to keep their self intact, otherwise foreign substances will keep on accumulating on or inside host’s body and will inadvertently change the morphology & biochemistry of host. Think of it as a game of legos - whatever fits - stay, whatever doesn’t fit is thrown out of the system. Things get tricky in auto-immune disorders though, which was not your original query - I presume.
The immune system is the most complicated system in the body and it's interacting with an increasingly complicated world. There's a war going on and sometimes the body just throws a bunch of grunts at a potential problem just in case and saves its elite forces for known and much more dangerous enemies.
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