allergies 101

Allergies 101: Part the Third

kbonham — Mon, 19 Dec 2011 18:00:00 +0000

Allergies 101: Part the Third

I know this post has been a long time coming. In the first part of this series, I told you that allergies are the result of an immune response against an external, but normally not harmful substance. In part 2, I told you that allergies are the result of a specific type of immune response called "Th2," which leads to the production of IgE antibodies, and that this immune response is thought to have evolved to combat infections caused by worms. But what makes your immune system think it's supposed to be battling a worm?

The short answer to the questions is: we don't know. For other types of immune responses, the past 15 years has given us a great deal of insight into the ways that the immune system recognizes the infections. Toll-like receptors (which I study) and other so-called "pattern recognition receptors" are able to recognize molecules that are unique to bacteria, or unique to viruses and respond accordingly. If there is such a molecular pattern for worms, we don't know what it is, and we don't know what receptor (if any) can recognize it.

But there might be a clue in the nature of the proteins that tend to become allergens. Dust mites, cat dander, birch tree pollen and papayas may not seem to share much in common, either with each other or with the worms the immune system thinks it's fighting, but rather than sharing a particular molecular shape, perhaps they share a particular chemical activity. It turns out, many allergens are proteases - enzymes that cut up proteins.

Normally, cells see their exterior environment through receptors, proteins on the surface of cells that bind onto a specific molecule called its ligand. When the ligand binds to a specific groove in the receptor, it activates a series of events inside the cell that lead to a change in behavior.

In the case of most pattern recognition receptors, the ligand is some microbial product - for instance, many bacteria (gram negative) have a molecule called lipopolysaccharide (LPS) in their cell wall, and we have a receptor (TLR4) that recognizes LPS. But the sensors of worms (and allergens) may behave a bit differently. Worms are much more closely related to us than bacteria and viruses, and finding differences are essential for this system to work (you wouldn't want your macrophages freaking out over your own cells). Since there might not be a molecular shape that works, what about an enzymatic activity?

Many worms secrete cysteine proteases - enzymes that cleave proteins ~~at cysteine residues~~ and have cysteines in their active site- during their life cycle in the gut, and it may be possible for the immune system to detect this and know to start a Th2 response. In fact, one of the best models for this sort of an immune response is papain, a cysteine protease from papaya and a potent allergen. Knocking out all of the known pathogen sensors has absolutely no effect on papain's ability to activate the immune system, so there's something going on that we don't quite understand.

There are a couple of ways this could work. Their might be a substrate for cysteine proteases that, when cleaved, becomes a ligand for a receptor.

Another possibility is that the receptor itself is cut, and this cut is required for the signaling activity to occur.

There are other known examples of these sorts of mechanisms, but as yet, no one has been able to find a receptor that is responsible for this activity in the immune system, so the jury is still out. In addition, there are many allergens that are not thought to be cysteine proteases, so there may be multiple pathways, or this idea might be completely wrong. But considering allergies are on the rise, and considering how little we know about this aspect of immunity, it might be a good thing for us to figure out.

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Allergies 101: Part 1
Allergies 101: Part 2

kbonham Mon, 12/19/2011 - 13:00

Allergies 101 - Part deux

kbonham — Thu, 17 Nov 2011 13:30:00 +0000

Allergies 101 - Part deux

Earlier this week, I wrote a little bit about what causes allergic symptoms - your immune system confuses pollen (or some other allergen) for a worm, and then arms your granulocytic grenades to explode every time you come into contact with it. But why does this confusion happen? This is a bit more complicated.

As I mentioned in the first post, the immune system broadly speaking is geared for 3 types of infections:

1) Intracellular - these pathogens (all viruses and some bacteria like Listeria) live most or all of their life inside our own cells. In order to deal with them, the immune system needs to be able to identify and kill infected cells, while preventing new cells from becoming infected.

2) Small extracellular - These pathogens (mostly bacteria, some fungi) live outside of cells. They are small enough to be eaten by phagocytes, but often reproduce very quickly and produce toxins that can kill or manipulate healthy cells.

3) Large extracellular - Pathogens like worms can't be eaten by our own cells, and they can't be neutralized with antibodies. They only way to deal with them is to make their living environment terrible and try to flush them from the body.

The control over these different programs is mediated by a range of signaling molecules called "cytokines," which are secreted by different types of immune cells. Say you're riding the subway and some jerk doesn't cover their mouth when they cough - you now have viruses in your airways. Infected cells will recognize they are infected and release cytokine cocktail A_i (infected). At the same time, professional phagocytes like dendritic cells and macrophages will recognize the presence of virus even if they themselves aren't infected (largely through Toll-like Receptors), and release cytokine cocktail A_p (phagocyte). Some of those dendritic cells will scurry off to neighboring lymph nodes and call in the big guns - helper T-cells will get activated and run the show from then on, releasing boatloads of cytokine cocktail A_t, directing B-cell development and so on.

The details of what's in each of these cytokine cocktails isn't super important, and there's a lot of overlap, but the key thing to understand is that the specific cytokine cocktail A (for viruses and other intracellular pathogens) is different from cocktail B (for worms) and cocktail C (for small extracellular pathogens). The T helper cells that develop in response to these different cytokine cocktails have been extensively studied, and are called Th1 (for , Th2 and Th17 respectively (don't ask what happened to Th3-16). Immunology aficionados will know that this is grossly simplified, but bear with me.

We know a lot about how these T cells choose their fate. For Th1 cells, for instance, we know that a cytokine called IL-12 is particularly important for inducing Th1's, and that Th1 cells then produce a lot of a cytokine called interferon gamma (IFNÎ³). IL-12 is made by macrophages and especially dendritic cells in response to various TLR ligands, so the connection is pretty clear. For Th2's, the trouble T-cells in allergies, it's a little less clear.

We know that the cytokine IL-4 is really important for Th2's. Th2's themselves produce a lot of IL-4, but for a long time it was thought that IL-4 was also needed to induce Th2 development (if you put naÃ¯ve T-cells in a dish with IL-4, they will become Th2). But this lead to a bit of a chicken-egg question. Macrophages and dendritic cells don't make IL-4, and it was thought that whatever the source of the cytokine, it would have to be a professional antigen presenting cell. For a long time, immunologists thought that Th2 was sort of a default pathway, that T-cells would develop into in the absence of other signals. Recently, a number of groups published some evidence that a particular type of granulocyte called a basophil could make IL-4, could present antigen to T-cells and were necessary for Th2 development, but several labs are disputing this finding.

My classmate and former roommate is actually working on a project that addresses this question much more directly, and he's got some awesome data that unfortunately I can't share with you because I can't risk his competitors finding out what he's discovered. I promise to blog the crap out of his paper when it's published.

But an even more basic question is how the immune system recognizes what types of pathogens (and by mistake, what type of allergens) should induce a Th2 response. For viruses and bacteria, the last 15 years have seen the discovery of a plethora of innate receptors that specifically recognize bacterial and viral patterns, and cause the release of various cytokine cocktails, but no one has ever convincingly shown a receptor that can recognize worms.

The key to understanding this recognition may actually come from understanding what sorts of things make potent allergens. That similarity, and the importance of papayas in studying allergies, coming up.

kbonham Thu, 11/17/2011 - 08:30

Allergies 101

kbonham — Tue, 15 Nov 2011 15:00:00 +0000

Allergies 101

One of my favorite places on the internet is r/askscience, a place on reddit where people come and ask questions, and a panel of scientists answer. People can ask follow-up questions, and there is often some great back-and forth (to be honest, part of the reason I haven't been writing as much here is because I'm using up all my time over there). Recently, an number of people have been asking questions about allergies - Can people grow out of allergies? Why is the incidence of allergies increasing? Can eating honey cure allergies?

You can check out those threads if you want answers to those specific questions (I'm commenting as "KeScoBo"), but I decided I wasn't done after my semen allergy posts, and thought it would be a good idea to go back to basics. From the perspective of the immune system, what are allergies, and how do they arise?

At its most basic level, an allergy is an inappropriate immune response to a non-harmful substance. But there are many ways the immune system can respond that wouldn't cause problems - they key to allergies is that your immune system thinks that pollen is a worm.

To back up a sec - as soon as a pathogen breaches the barriers of our skin or epithelial tissue, the immune system kicks into gear. Receptors on the surface of specialized immune cells or on the inside of normal cells fire off, indicating the presence of an infectious agent. Macrophages do their best to clear out the invades, dendritic cells run off and sound the alarm in nearby lymph nodes, and signaling molecules called cytokines and chemokines activate and recruit a massive influx of immune cells from the blood.

But not all infections are created equal. Depending on the type of pathogen, different receptors will be triggered, and the immune system will tailor its response appropriately. Broadly speaking, there are three major types of pathogens that the immune system needs to respond to:

1) Intracellular - these pathogens (all viruses and some bacteria like Listeria) live most or all of their life inside our own cells. In order to deal with them, the immune system needs to be able to identify and kill infected cells, while preventing new cells from becoming infected.

2) Small extracellular - These pathogens (mostly bacteria, some fungi) live outside of cells. They are small enough to be eaten by phagocytes, but often reproduce very quickly and produce toxins that can kill or manipulate healthy cells.

3) Large extracellular - Pathogens like worms can't be eaten by our own cells, and they can't be neutralized with antibodies. They only way to deal with them is to make their living environment terrible and try to flush them from the body.

One of the differences between these different immune responses is the selection of antibody isotypes. The binding sites of all antibodies are generated in the same way, but during an immune response, the B-cells that are participating are instructed to choose a particular butt depending on what type of pathogen their attacking. IgG is good at binding and neutralizing viruses and toxins, IgA can be shuttled across mucosal barriers, and IgE is good at making your life miserable.

Actually, IgE is the antibody isotype (butt) most associated with allergic reactions, and its "natural" job is to fight worms. Worms are mutlicellular, and often WAAAAAY bigger than our own immune cells. Because of this, the combat strategies that work well for viruses and bacteria are useless against worms - it'd be like trying to fight off a grizzly bear with a fly swatter. Instead, IgE arms the hand grenades - immune cells called granulocytes are filled with noxious chemicals, and chemical messengers like histamines. When the IgE coating the surface of these cells bind to something, the cell explodes - flinging poison and death at anything in the area.

Allergens trick your immune system into thinking they're a worm. Your immune system freaks out, and starts flinging hand grenades every time you inhale. As you might imagine, damage and misery result.

Up next: what makes your immune system think "worm."

kbonham Tue, 11/15/2011 - 10:00

Tags

Allergies/autoimmunity

allergies

allergies 101

Immune system

Another great thing about r/askscience and other science blogs: it's easy to forget that when most people look for information about a science topic they can't get past the journals' firewalls. Most journal articles aren't acessible unless you are attached to a university (or still have accommodating friends at one). If you need a pdf, ask nicely at reddit and someone will help you out.

It's been a long time ... ... ...on a personal note, when I was in lab school in the Navy, this is the sort of thing that really fired me up to want to learn more about hematology, immunology...I can't really be specific, but it was things like electrolyte balance in blood, clotting factors and clotting factor cascades, antigen-antibody response... ... ... at any rate, this is great to read and see again. I really find this stuff interesting and have never been able to find anything in libraries or on the internet that really delve into it like I would find in a good college/university education.

Hi Kevin, cool post - have you thought about uploading some of your stuff to December's MolBio carnival? I'm hosting it over at my blog, Ruleof6ix and thought this allergy stuff would be pretty interesting! Check out the link: http://molbiocarnival.blogspot.com/

"it's" does not equal "it is'; PLEEEASe use 'its'.

If IgE invokes more of an inflammatory response than other antibodies, is this possibly why an allergic condition can in some cases develop into an autoimmune response?

Thanks!

@ hibob - Yup. Paywalls are retarded. In fact, I think the entire science publishing model is broken, but that's a subject for another post.

@ Mike - Yeah, I've been kicking around the idea of writing a book that would explain the immune system for precisely that purpose.

@ Connor - No, I rarely think about carnivals. I'm thinking about it now though :-)

@ Snooty - Fixed, but I believe you mistyped: "It's" actually DOES equal "it is." You also used apostrophes when you meant to use quotes, and periods and semicolons go on the inside of quotation marks. But somehow I knew what you meant...

@ Megan - I'm not aware of allergies that turn into autoimmune disorders, though people who are prone to allergies are statistically more prone to autoimmune disorders. If the regulatory mechanisms that keep the immune system in check are weak, your immune will attack things that it's not supposed to, whether that's pollen or your beta islets.

So I take allergy shots, Xolair, Allegra, and whatnot because my stupid body thinks it's fighting worms??? Curse you, body!

@ Karen - Yup. And the irony is, if you were actually fighting worms, you probably wouldn't have allergies (more on that later).

Reminds me of case of autism and colitis that improved by taking pig whip worm eggs several times a week.

This is a great post that really exemplifies all the great sources on the web available that bolster's the public's understanding of immunology and disease! Also,as a fellow Immunology PhD student who has taught many immunology courses, I appreciate your spot-on easy-to-understand explanation of the inflammatory nature of IgE involved in allergy.

I've really enjoyed We Beasties since I stumbled across it months ago and I hope you (and your awesome readers) can help support a fellow science research blogger. I'm a finalist for a $10K scholarship for full-time students who blog, but I need the support of the online community to win! If you're interested to learn about the latest published research in the fields of immunology, human health and disease, I encourage you to checkout Escaping Anergy:The Immunology Research Blog!
Thanks in advance and keep on advocating science communication!!

@ http://www.collegescholarships.org/blog/2011/11/15/vote-for-the-winner-…

Just today saw this:

http://onlinelibrary.wiley.com/doi/10.1111/j.1399-5448.2011.00758.x/abs…

Wahlberg, J et al (2011)
Asthma and allergic symptoms and type 1 diabetes-related autoantibodies in 2.5-yr-old children
Pediatric Diabetes
DOI: 10.1111/j.1399-5448.2011.00758.

Does that make the link any closer?

@ Megan - I know the study on colitis, but I've never seen a link between worms and autism, and a quick pubmed search didn't turn anything up. Do you have a reference by any chance? I know there was some (now discredited I believe) thought that colitis was associated with autism - it's possible that the two were conflated without any scientific study.

@ Neil - Thanks for the link! It looks like there's a pretty good statistical correlation, but again, I don't think that argues that having an allergy would directly lead to autoimmunity. Though honestly, I don't know how you could tease out the difference, at least in humans.

Evidence is now coming out of Africa where in some area,s they have been running a de worming program that for the first time allergy has reard it's ugly head.