I'm Too Sexy for Your... Virus? Or, Immunity as it Relates to Peacocks

I know something's amiss when my google news alert returns headlines like these:

Why women who lust after Brad Pitt may just fancy his immune system

It's His Immune System That You Actually Want to Sleep With

The key to male sexiness: A powerful immune system?

and my personal favorite

Antibodies, Not Hard Bodies: The Real Reason Women Drool Over Brad Pitt

These snazy headlines are all pointing to a recent paper in Nature Communications. The paper's methodology is pretty simple: They took 74 Latvian men and immunized them against Hepatitis B. Later, they measured the participants' blood for levels of HepB antibody, as well as levels of testosterone. Finally, they showed photographs of each of the participants to a panel of ladies, asking them to rate the subjects' attractiveness. As far as I can tell, Brad Pitt was not involved in this study.

After some analysis they determine a few things - a) Men with higher levels of testosterone have statistically higher levels of anti-HepB antibodies after vaccination. b) Men that were rated as more attractive by the female judges had statistically higher levels of testosterone. c) Men that were rated more attractive had statistically higher levels of anti-HepB antibodies.

This is reported in all the stories above as "Higher testosterone makes your immune system better! Higher testosterone is sexy! Women are attracted to a better immune system!" As you might suspect, it's a good deal more complicated than that. How is immunity like a peacock's tail?

The most interesting thing about this study (in my humble opinion) is precisely what all those news reports didn't talk about. The whole reason the authors cite for doing this study has to do something called the "immunocompetance handicap hypothesis." The idea goes like this: individuals can provide visual proof of fitness (ability to make strong babies), by ostentatiously displaying something that puts them at a competitive disadvantage. For instance, a male peacock with a huge, colorful tail should have a much harder time hiding from and escaping from predators. If a peacock with such a tail manages to survive despite such a handicap, he must be super fit in other ways, and that fitness is irresistible to peahens.

The immunocompetence handicap hypothesis posits that testosterone works like the peacock's tail. In addition to regulating secondary sex characteristics (broad shoulders, big muscles... you know, sexy things), testosterone is also thought to suppress the immune system. So if a testosterone-filled manly man isn't riddled with illness, he must be super fit in other ways, and that chiseled jaw is just a visual cue to his internal perfection. The reasoning here may seem backwards, but it's on solid theoretical footing.

The trouble is, it doesn't seem like this hypothesis is supported by the data. In this study, men with higher testosterone had stronger immune responses to the vaccine, but I just got through telling you that testosterone is supposed to be a handicap. There's one final wrinkle that I haven't mentioned yet - the stress hormone cortisol. That cortisol suppresses the immune system is well known, and several studies have shown that artificial elevation of testosterone leads to higher levels of cortisol. It seems that the belief that testosterone suppressed the immune system may have been based on an artifact (an effect of the experimental design rather than a true biological phenomenon). In fact, in this new study, the men with the lowest levels of cortisol showed the strongest correlation between antibody response to the vaccine and high testosterone levels.

The authors say that their data shows "support for the stress-linked immunocompetence handicap model of sexual selection," but it seems like they're trying too hard to shoehorn their data into the handicap framework. If high testosterone is related to better immune response, and high testosterone is attractive, you don't need a handicap model at all. To the extent that there is any causal link between attractiveness and immune response (and I don't think the data is that great - see below), it seems that attractiveness is a visual cue of a good immune system, not of some handicap.

I've read the discussion section of this paper a number of times, and I still don't really understand exactly what they're trying to say. Maybe I'm missing something, but while the title of the paper is "Evidence for the stress-linked immunocompetence handicap hypothesis in humans," it seems like the simplistic headlines more accurately describe the data. Carl Zimmer hates it when people write "more research is needed" (because when is more research not needed?), but in this case I think it's valid. There is some (vaguely) suggestive data, and some (maybe) interesting correlations, but nothing like a complete story. I think more research is needed, if only to clarify the point and actually address what the role of this hormone in immune function actually is.

And I still don't know how strong Brad Pitt's immune system is :-(

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If you liked this piece, consider submitting it to Open Laboratory 2013 (you can read about Open Lab here). If you didn't like it, let me know why in the comments.

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The Data

Because this paper has only one figure and it's pretty self-explanatory, I thought I would show you the data for So you can judge it for yourself. I put it here at the end because I'm not sure how much people care about primary data, but I'd like to include it for those of you that do.

Facial attractiveness is plotted on the vertical axis against a measure of anti-HepB antibodies on the horizontal axis.

Male attractiveness vs Immune response

I'll be honest, I photoshopped out the trend line that was included in the original graph, but seriously, would you conclude from this data that immune response is correlated with attractiveness? There are plenty of unattractive people that showed a great immune response (lower right) and people rated as attractive with low immune response (upper left). It's a bit interesting that the two people with the best immune response were also rated the most attractive (upper right), and all of the people that showed no response to the vaccine were rated unattractive (those are the dots hugging the vertical axis on the left), but even when you see the graph with the trend line, the link doesn't seem that strong (a perfectly horizontal line would indicate no correlation, the steeper the slope, the higher the correlation).

Attractiveness vs immune response (with trendline)

Maybe you're not used to looking at this sort of data, but I think it's especially unconvincing when you compare it to the correlation between testosterone and antibody response:

Testosterone vs Immune response

In my opinion, the best you can conclude from this is that there's something that should be followed up on. There's certainly no causal link, and the correlation isn't even particularly strong.

A Vaccine for Drug Addiction

Cool:

During the tests, mice were given access to deposits of heroin over an extended period of time. Those given the vaccine showed a huge drop in heroin consumption, giving the institute hope that it could also work on people[...]

Using the immune system's ability to make an immune response against any molecule is awesome, but there are a number of potential problems with this sort of approach. In the article, a scientist is quoted as saying that this might block other opioids that are used as theraputics (like Vicodin), but I don't think it's a good idea to use opioids as pain relievers in addicts anyway. It seems to me that the real danger is that drugs like heroine work because they mimic neurotransmitters our bodies naturally make, and activating an immune response against a molecule so similar to our own might predispose people to autoimmunity. Still, it's a neat idea, and I suppose that a small increase in risk for autoimmunity might be worth it to stop a crippling addiction.

Vaccinating Against Semen - Immunity as Contraceptive

I promise, this will be my last semen post for a while. I've talked about allergy to semen. I've talked about allergens in semen. And I've talked about autoimmunity to semen.

All of these are problems, leading to discomfort or infertility. But what if those problems could be leveraged for our benefit? i-124bd5cd88cf3b85607cdd350df44eda-Sperm_Anton_van_Leeuwenhoek_Rabbit_dog-thumb-500x380-72031.jpg

[Source: These drawings were made by Antonie von Leeuwenhoek - the first man to view sperm cells under a microscope]

Using the immune system as a contraceptive is not a new idea. In 1899, Karl Landsteiner and Elie Metchnikoff (both of whom would later win Nobel Prizes) independently demonstrated that injection of sperm into animals could produce an antibody response, and others later demonstrated that this could lead to infertility. The first study in humans was in 1929, and a patent for a "spermatoxic" vaccine was filed in 1937.

Since then, there have been a number of advances in the using the immune system to intentionally induce infertility. But you may be asking yourself, "Why bother?" After all, hormonal birth control is safe and highly effective. But there are a number of problems associated with hormonal birth control that could be addressed by a vaccine. And I'm not even talking about side effects:

An estimated 80 million women have unintended/unwanted pregnancies worldwide annually, and 45 million of these end in abortion. In the United States, each year, half of all pregnancies are unintended, which results in over 1 million elective abortions. In over half of these unintended pregnancies, the women were using some type of contraceptive.

Another major problem is access. In the developing world, where one might argue family planning is most needed, medical services are not always readily available. Since hormonal birth control requires consistant use, and access to a daily pill or monthly shot just won't cut it.

This calls for a better method of contraception that is acceptable, effective, and available both in the developed and developing nations. It should be non-steroidal, non-barrier, non-surgical, intercourse independent, and reversible. Contraceptive vaccines (CV) have been proposed as valuable alternatives that can fulfill most, if not all, of the properties of an ideal contraceptive. Because of their high target specificity, long-term action, low cost, and without any side-effect, the development of CV is indeed an advancement in the field of contraception. As the developed and most of the developing nations have an infrastructure for mass immunization, constructing vaccines for contraception is an exciting proposition.

There are several approaches to a contraceptive vaccine*, all involving different targets. Some target certain hormones, which would prevent the production or development of sperm/eggs. However, as many of these hormones are required for non-reproductive processes, these vaccines can have unwanted side effects. As an example, a protein called GnRH triggers the release of other hormones necessary for the development of sperm and eggs, and can be effectively targeted by a vaccine. However, loss of these hormones also leads to impotence, and so is essentially off the table for human use (though it is currently being used as a non-surgical way to sterilize pets and feral animals).

Another target of vaccines is HcG, which is expressed on fertilized embryos. The selectivity of this protein is its strength - since there are no targets except those associated with pregnancy, the side effects should be minimal. However, scientists have had trouble achieving an effective immune response against this protein**. Plus, it leaves the burden of birth control on women (since an immune response against an embryo wouldn't mean much in a man).

By contrast, a vaccine against sperm could solve many of these problems; it could be effective in both men and women (blocking production in men or stopping fertilization in women). And the inheritant immunogenicity of sperm that I've mentioned earlier means that it shouldn't be hard to generate an effective immune response. Indeed, several groups are currently working on making this a reality.

The main drawback of this approach that I see is lack of intentional reversibility. So far, in all of the human trials dating back to 1929, the effect of the vaccine was not permanent - antibody titers against the sperm waned over time, and fertility returned - but turning the immune system off should the patient want to have a baby is not controllable. In principal, it should be possible to target only the B-cells making anti-sperm antibodies for destruction, but until such a process is validated, this method will not be a tenable option for anyone that may want to get pregnant at a later time.

In any case, it seems we're stuck with hormonal and barrier methods for now, but I think this is a great example of leveraging the power of the immune system in ways nature never intended.

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*It should be noted here that in many parts of the developing world, anti-vaccineconspiracy theories, which postulate that polio vaccination campaigns are really a secret plot to sterilize the population, have taken root. Should and actual contraceptive vaccine campaign ever occur in the developing world, folks had better make damn sure the intentions are out in the open.

**Since the date of the review that I'm reading, there have been some advances on this front, but still no effective vaccine in humans.

Possible explanations for Tumor Vaccine study

Abbie over at ERV has a really great summary of a new Nature Medicine paper, in which the authors managed to turn a mouse's immune system against prostate tumors by infecting them with viruses engineered to express prostate proteins. Some of the results struck her as a bit counterintuitive, but I thought of some possible explanations. I was going to leave this as a comment on her blog, but the more I read the paper, the more stuff bubbled up, and I though it deserved a full post. Go read Abbie's post first though, or this probably won't make much sense. Admittedly speculative explanations to follow:

This vaccine is not causing autoimmunity when it is injected intravenously. But it does induce autoimmunity if you inject the vaccine directly into the prostate.

I dont know how that works.

I think there are two explanations here (not mutually exclusive). The first is that the dose of virus used for the direct injection into the prostate is effectively MUCH higher. They use the same number of viruses (1 x 10^7 PFU) for both treatments, but in the intravenous injections, those viruses are going everywhere in the body. That means there will be lots of small infections, many of which will be effectively dealt with by the innate immune system. And the T-cells that do get activated will have to clear that local infection before wandering into the prostate and realizing there's something interesting there too. This will make space for other regulatory systems to kick in, and since most of the infections will be far from the prostate, you won't run as much risk of epitope spreading

But I think the better explanation is that what they're seeing isn't actually "autoimmunity." Rather, it's probably due to the destruction virus-infected non-tumor cells. Putting 10 million infectious virions in one small tissue area means that A LOT of non-tumor cells are going to be infected and potentially targeted by T-cells. They try to control for that with a virus that encodes GFP (a protein from jellyfish), but that's a single protein with a limited number of potential T-cell epitopes. A better control would have been using a viral library from a different tissue (they already have one for B-cells! why didn't they use it?).

One possible detraction from this point is that say that immune cells from the locally injected mice respond to normal prostate tissue in vitro. But they don't show the data. They also don't mention what happens after 60 days out with the locally injected mice, but DO say that the intravenously injected mice were fine after 60 days (they don't show that data either). Once the mice clear the VSV infection, what happens? If it's really autoimmunity, the prostate should continue to be attacked. Plus, they should be able to transfer autoimmunity by transferring immune cells into healthy (uninfected) mice, but they didn't do that experiment.

But how the heck is a vaccine with a normal prostate clearing prostate tumors and not killing the normal prostate tissue???

Normally, T-cells that are reactive against your normal proteins are deleted before they can get out and do damage. Even though cancer cells are technically "self," they usually have tons of mutations, and the hope with cancer vaccines has been to direct the immune system against these so-called "altered self" proteins. So Abbie's question is legit, but I think she answers it herself later on.

[...]they used human prostate cDNA in mice, which worked better than mouse prostate cDNA in mice

The human prostate proteins are not "self" to the mouse. Our proteins are very similar to mouse proteins, but there are definitely differences. And those differences might look like the differences in the cancer cells - differences T-cells can exploit.

And theyre doing this via a prostate-specific Th17 response (whiiiiich is usually indicative of autoimmunity) and CD4 T-cell response (think antibodies) instead of CD8 (cytotoxic T-cells) or Natural Killer cells, the cells who normally clear tumors.

CD4 cells have a lot of jobs. There are a bunch of different types, and we don't need to go into everything here, but basically, they tell other cells what to do and help them do it better (for instance, As Abbie mentioned, they can activate B-cells to make the right type of antibodies). Th17 cells are a type of CD4 cell that is usually seen in infections with extracellular pathogens, and in some types of autoimmune diseases. These cells are very inflammatory and have a bunch of effects on non-immune cells, and they can recruit really destructive immune cells called neutrophils. But all of these effects are non-specific.

It's the CD8 T-cells that are able to zero in on specific cells and destroy them without touching their neighbors, but in the text of the paper, they say that CD8 cells are not involved:

therapy was dependent upon CD4+ T cells but not CD8+ T cells or natural killer (NK) cells (Fig. 3h).

However, the data they present seems to directly contradict this statement. To do the experiment, they repeated the viral treatment, but depleted different cell types, and plotted how many mice stayed alive.

i-0947fa84ade694d9f025e271e1d7391b-Screen shot 2011-06-21 at 6.18.11 PM.png

The top (ASEL) line shows just the viral treatment - after 50 days, 100% of the mice survived - sweet. If they depleted NK cells (orange), a couple of the mice died around day 30, but it didn't seem to have a huge effect. When they got rid of CD4 cells, all of the mice were dead by 20 days - clearly indicating that CD4 cells are important. But they get the exact same survival curve (black) when they deplete CD8 cells. I've read this section like 10 times trying to figure out what I'm missing, but at least based on the data, it looks pretty CD8 dependent to me.

In fact, since the survival curves overlap so perfectly, I wonder if the Th17 cells are important at all. They claim that there's a Th17 response and not a Th1 response (again - "data not shown"), but they don't actually show that the Th17 response is required. But CD4+ T helper cells ARE required to "license" (activate) CD8+ killer cells.

It's a cool paper, but the more I read it, the more dodgy the immunological explanations seem. The weird thing is, none of their kooky immunology is required to make this a cool paper - even if everything I wrote above is right, the results are still awesome. But honestly, after re-reading this a number of times, I'm kinda surprised some of these glaring errors made it past reviewers.

Bacterial ROS to the malaria rescue!

You've all heard of Malaria. It's bad. It infects hundreds of millions of people, mostly in developing nations. It rarely leads directly to death*, but the resulting illness can lay people out for days or weeks, increasing an already heavy economic burden on many of the poorest countries in the world. Folks from affluent regions can get medication to prevent or treat the illness, but treatments can be expensive and have nasty side effects, so it's not practical for most of the population. The good news is that Plasmodium, the parasite that causes the disease, can only be transmitted by mosquitoes, and relatively simple measures like insecticide-treated nets (or more complicated solutions like targeted lasers** to zap mosquitoes out of the sky) can stop the spread.

These solutions reflect an obvious bias that we have: when it comes to malaria, mosquitoes are the enemy. They carry the parasite from an infected person to another victim. What doesn't occur to most people is that mosquitoes get infected too, and they might have evolved ways to slow the parasite down. Part of the parasites' life cycle occurs in the insect, and it undergoes critical developmental processes as it travels from the mosquitoes gut to its salivary glands. But Mosquitoes don't only play host to Plasmodium, and like us, they harbor many friendly strains of bacteria that can play a role in mosquito immunity against the malaria parasite. It turns out that at least one of the denizens of the mosquito gut can help keep the parasite at bay.

ResearchBlogging.orgNatural Microbe-Mediated Refractoriness to Plasmodium Infection in Anopheles gambiae

It's a title only a scientist could love, but the translation is fairly simple: bacteria can prevent malaria from infecting mosquitos. Other groups had previously shown that the gut bacteria in mosquitoes could affect the parasites, but no one had shown how. First, these guys isolated wild populations of mosquito gut bacteria and discovered that one particular strain of Enterobacter (they call Esp_Z) almost completely prevented malaria growth inside the insect.

i-6355710b869b02d92864e90bb1ac38de-Screen shot 2011-05-31 at 5.33.10 PM.png

The graph on the left shows how many live parasites could be isolated from the guts of mosquitoes fed with different strains of bacteria (or left alone - that's the PBS column). On the right you see what they pulled from the salivary glands, which is the most important from an infection perspective (since that's the point of transmission). The dots all represent individual mosquitoes, and it's pretty clear: Esp_Z seems to kill off all of the parasite. As I mentioned before, this is in keeping with a lot of previous research. But now they have a specific strain, and they can start trying to uncover the mechanism - the "how" behind this phenomenon.

The first thought the researchers had was that maybe Esp_Z was boosting the mosquitoes' own immune response. We know that insects have an immune system, and we know that it is important for a mosquito's response to malaria. This immune system does respond to bugs in the gut, so maybe this bacterial strain is just triggering the immune system to make a hostile environment that killed plasmodium as collateral damage. But when they knocked out the mosquito's own immune system, Esp_Z was still able to completely block growth of the parasite.

Next, they turned their attention to reactive oxygen species (ROS). A couple of weeks ago, I wrote about how our own cells use the killing power of ROS, but it turns out that some bacteria may use the same strategy. The researchers noticed that the flasks containing the parasite-killing bacteria had much higher levels of ROS than the benign strains. They also saw that just using the culture medium alone from these bacteria was almost as effective at killing Plasmodium as cultures that actually contained Esp_Z. If they neutralized the ROS with vitamin C, however, the killing effect completely vanished.

Unfortunately, it's probably impractical to go around trying to feed every mosquito in Africa this strain of bacteria, but this research hints at new potential ways of combating this epidemic. And considering shooting mosquitoes out of the sky with lasers is considered a viable option, I'd say we need all the help we can get.

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*I say rare because out of 2-300 million cases/year, there are "only" about 1 million deaths (mostly children). That's still unacceptably high.

**This video also has a great explanation of the problem of malaria, and some of the ways people are already trying to combat it.

Cirimotich, C., Dong, Y., Clayton, A., Sandiford, S., Souza-Neto, J., Mulenga, M., & Dimopoulos, G. (2011). Natural Microbe-Mediated Refractoriness to Plasmodium Infection in Anopheles gambiae Science, 332 (6031), 855-858 DOI: 10.1126/science.1201618

Using the immune system to fight cancer

Cancer sucks. I'm sure I don't have to tell you that - it's one of the leading causes of death in developed countries, and our treatment options are pretty thin. Basically, it amounts to cutting out the tumors that can be seen, and then giving a controlled administration of poison in the hopes that the cancer cells die before you do. Don't get me wrong - advances in oncology have saved many lives, but it's no surprise that there's a lot of research happening to find better options. One promising avenue of study is augmenting the immune system to fight cancer directly. It's known that the immune system already plays a role in protecting us from tumors (immunodeficient mice and humans are more prone to cancer), and we already know it's great at targeted destruction, so it seems like a no-brainer. Indeed, my weekly "immunology research" google news alert almost always has at least one article about a new study curing cancer with the immune system. Case in point:

The answer to curing cancer may lie in the capabilities of the human immune system as opposed to current chemical treatments, according to a new study published by researchers at Dartmouth-Hitchcock Medical Center. The study, published Nov. 15 in Clinical Cancer Research, used tumors found in cancer patients to develop individualized vaccines that induce immune responses to cancers.

This study is pretty great, but there's a caveat. ResearchBlogging.orgA lot of scientists have tried using antibodies to target everything from traditional chemotherapeutics to bee venom directly to tumors, but this strategy has a lot of drawbacks. First of all, the tumors need to have a particular antigen - something that's different on the tumor than on normal cells - and that antigen has to be present on the surface of the tumor cells, AND we have to know what the antigen is.

The strategy taken by this group is a bit different. Instead of deriving antibodies and attaching something deadly to them, they took dendritic cells from the patients and pulsed them with mushed-up tumor cells along with some adjuvant to activate them. These dendritic cells were then given back to the patient, where they homed to lymph nodes and kick-started an immune response. In order for this treatment to work, the tumor still needs to have unique protein antigens (otherwise the immune response would be non-specific), but we don't actually need to know what the antigen is - we can just let the immune system decide for itself. Plus, the antigen doesn't have to be on the surface; in contrast to antibodies, T-cells can actually "see" what's going on on the inside.

The patients in this study were followed for 5 years, and of the ones that generated a good immune response, 63% had survived with no recurrence (compared to 18% for the controls). Still, only about 60% of the patients treated actually generated an immune response in the first place. And this isn't the first study to try dendritic cell based autologous tumor vaccine (autologous just means using the patients' own cells), it's just that most of the attempts thus far have been unsuccessful.

There are a lot of reasons this might be the case. First off, any tumor that actually starts growing has by definition already figured out some ways to subvert the immune system. We know that some tumors directly suppress the immune system by activating regulatory T-cells or generating wound-healing macrophages, some just hide from the immune system by down-regulating certain markers, and there are probably numerous other methods that we know nothing about. Giving the immune system a boost may be able to overcome this limitation, but it's also possible that a tumor doesn't actually have any antigens for the immune system to target. Tumors started out as your own cells, and the immune system is trained not to see self. If tumor cells have just deleted or over-expressed normal proteins, there would be nothing to target.

Finally, it's possible that the immune system will target the tumor, but that the tumor will learn to escape. Every individual's cancer is unique, but within a particular tumor, there can also be a lot of variation. If the vaccine finds a particular antigen, it's quite possible that individual cells within the tumor will not be expressing that antigen (or express it at low levels), and those cells will then be selected for as the T-cells rush in and lay waste to their brethren.

Despite these caveats, it's still exciting to see this strategy working. As we learn more about the way that cancer develops, and how the immune system reacts to it, we will hopefully be able to augment this treatment to be even more effective.

Barth RJ Jr, Fisher DA, Wallace PK, Channon JY, Noelle RJ, Gui J, & Ernstoff MS (2010). A Randomized Trial of Ex vivo CD40L Activation of a Dendritic Cell Vaccine in Colorectal Cancer Patients: Tumor-Specific Immune Responses Are Associated with Improved Survival. Clinical cancer research : an official journal of the American Association for Cancer Research, 16 (22), 5548-56 PMID: 20884622

Weight loss and macrophages

Macrophages are really good at gobbling stuff up. It's all right there in the name - they are big (macro) eaters (phage). I study them in the context of the immune system - one of the things they do really well is eat up bacteria and other pathogens that have found their way into your tissues. As a front line sentinel, they also are capable of kick-starting inflammation and recruiting the rest of the cells necessary to clear an infection. But that's not all, there's more. ResearchBlogging.orgWeight loss and lipolysis promote a dynamic immune response in murine adipose tissue

Here we characterized the response of adipose tissue macrophages (ATMs) to weight loss and fasting in mice and identified a role for lipolysis in ATM recruitment and accumulation. We found that the immune response to weight loss was dynamic; caloric restriction of high-fat diet-fed mice led to an initial increase in ATM recruitment, whereas ATM content decreased following an extended period of weight loss.

So why is there an immune response when you lose weight? Well... there isn't really.

When lipolysis is activated and FFA [free fatty acid -KB] concentrations increase acutely, macrophages accumulate rapidly in adipose tissue, without a significant initial increase in inflammation

Let's back up.

It's been known for a while that the adipose (fat-storing) tissue of obese mice and humans accumulate macrophages. These macrophages have also been linked to inflammation, and immune reactions to insulin, leading to diabetes. The thought is, when your adipocytes (the cells that store fat) get overloaded, sometimes they die and spill out all of those fatty molecules. Macrophages need to come and clean up the mess, but the large amounts lipid are tough to breakdown, and they can get a bit overwhelmed. Their inability to deal with the situation (it's actually called "frustrated phagocytosis") can stress them out and cause them to secrete cytokines that get the inflammatory cascade rolling. And when inflammation occurs chronically, you run into problems.

These researchers wanted to figure out what would happen on the other side if the weight was lost, so the fed the mice a high-fat diet, which caused them to get obese. i-14741891983d42763ee1a96360e9b789-3335023599_10a26e44dd-thumb-500x340-57944.jpgThen they put them on a calorie-restricted diet. This caused the fat in the adipose tissue, which is stored as triglycerides, to get broken down into smaller free fatty acids (FFA) - a process called lipolysis. It turns out that the release of FFA serves as a signal to recruit even more macrophages.

ATM figure

These macrophages end up accumulating triglycerides and slowing down the release of FFA, preventing a huge spike in local concentrations of free fat. But what about the immune reaction? As I said above, the immune system doesn't really come into play. These macrophages don't induce inflammation, and once they've mopped up the roaming lipids and the mice get back down to a normal weight, the macrophages bail and leave the tissue happy and healthy. It's only when the work never stops, and the fat stores don't deplete that these cells get stressed and act out.

Macrophages are often thought of in the context of an immune response, but they're really our bodies' blue collar workers. From wound healing to cleaning up messes to being the first responders during a dangerous situation, macs just do what needs doing. I guess the moral of this story is don't overwork them, or their intricate connection to many of the most important parts of our physiology will come back to bite us.

Kosteli A, Sugaru E, Haemmerle G, Martin JF, Lei J, Zechner R, & Ferrante AW Jr (2010). Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. The Journal of clinical investigation, 120 (10), 3466-79 PMID: 20877011

It itches! The immune system turns up in the strangest places

ResearchBlogging.orgNormally, I would feel woefully unqualified to analyze a Nature Neuroscience paper, but I'm going to do it anyway. How could I pass it up? It features a Toll-like receptor!

Toll-like receptors are typically expressed in immune cells to regulate innate immunity. We found that functional Toll-like receptor 7 (TLR7) was expressed in C-fiber primary sensory neurons and was important for inducing itch (pruritus), but was not necessary for eliciting mechanical, thermal, inflammatory and neuropathic pain in mice.

TLR's are on the front lines of immune defense. They are present on many cells types, especially immune cells, and alert the cell that something foreign is in the area. Evolution has selected them to recognize things that are found on bacteria, viruses and fungi, but not on our own cells. If a cell expresses a TLR, and that TLR binds to its ligand, that usually tells the cell that something is wrong, and an immune response should be triggered.

But a TLR is just a receptor, and there's no reason, in principal, that it couldn't be co-opted for other uses. And that seems to be what these authors found For a long time, TLR7 has kinda been the unwanted stepchild of the innate immunity field. Some folks had discovered a couple of ligands that induced anti-viral immunity in immune cells, but those ligands don't follow the typical mold of being associated with pathogens. Mice that lack TLR7 don't have a profound defect in combating viruses, and most people tend to ignore TLR7 entirely.

It made sense to look for immune functions, since other members of that receptor family have immune functions, but there's no reason why TLR7 must be an immune receptor, and these authors found something altogether different. When imiquimod - one of the ligands originally described for TLR7 - is injected into mice, the mice get itchy. Mice that don't have TLR7 don't get as itchy.

i-89dc3f71dd6f0621e871f1b4fab4a4a0-Screen shot 2010-11-08 at 4.59.47 PM.png

Based only on what I've told you, this might not seem that surprising, but this is a completely novel role for a TLR. If you inject the ligands for other TLRs (like lipopolysaccharide for TLR4), you get massive inflammation, not itching. Further, they showed that TLR7 was required for several other (though not all) "pruritic" (itch-inducing) agents.

i-e2b7458a6e89242f67fd3dbf96bc6e3f-Screen shot 2010-11-08 at 4.59.32 PM.png

The thing that I found most surprising is that TLR7 is actually expressed on the sensory neurons of mice, and that the TLR7 seems to be necessary to generate an action potential in response to imiquimod. There's a lot to follow up on here, but these guys are neuroscientists, and so the things I'd love to see as an immunologist are not necessarily on their list of priorities. Still - I've always been fascinated by neuroscience - maybe now I'll have an excuse to move in that direction as a post-doc.

Liu T, Xu ZZ, Park CK, Berta T, & Ji RR (2010). Toll-like receptor 7 mediates pruritus. Nature neuroscience PMID: 21037581

Why every "OMG we've cured cancer!!" article is about melanoma

[This article was originally posted at webeasties.wordpress.com] About 4 years ago, I went to a seminar at TSRI that convinced me that cancer would be over in relatively short order. The man speaking (I wish I could remember who it was) showed that his group had been able to target radioactive heavy metals directly to melanoma solid tumors to destroy them. The data were striking; enormous, football-sized tumors shrank to nothing in a matter of weeks, and the therapy worked more than 90% of the time. I couldn't understand why this wasn't a bigger deal, why wasn't this front-page news?

As it turns out, this wasn't a novel concept - targeting chemotheraputics directly to tumors has been happening for a long time. Since that seminar, I've seen news articles talking about numerous studies showing targeted delivery of various drugs and even bee venom to tumor cells, leading to their elimination. Recently, a group at CalTech published a paper in Nature showing nano-particle delivered siRNA can destroy melanoma tumors in a very successful human clinical trial. Is this the future of the fight against cancer? he trouble with eliminating cancer is that it's your own cells causing the problem. Anything that can kill a tumor cell can also potentially kill a normal cell. The trick for scientists and clinicians is to focus treatments to the few ways that tumors are different. The most obvious difference is that tumor cells are dividing rapidly (that's what causes tumors to be dangerous in the first place), so the first (and still most successful) chemotherapies are lethal to dividing cells (this is the same reason that radiation works). The trouble of course, is that tumor cells are not the only cells dividing in the body. Side effects of these traditional treatments include hair loss (hair-follicles need to rapidly divide), nausea (the cells lining the stomach and intestine need to be replenished all the time) and immunodeficiency (most cells of the immune system need to divide to fight infection), and these side-effects are not mild. The drugs are essentially poison, and the goal is to poison the body just enough to kill the cancer without killing the patient.

But division isn't the only way that tumors are different. Tumor cells are ravenous, and must be constantly supplied with more nutrients, so drugs targeting angiogenesis (the formation of new blood vessels) are useful in slowing or stopping tumor progression. Cancer cells are riddled with mutations and genomic instability, so drugs that inhibit parts of the DNA repair pathways are being researched (this is a bit more complicated, so I'll save further explanation for another post). But you can probably imagine why interfering with these processes can also be dangerous to the rest of the body, not just the cancer.

One of the best hopes for truly specific cancer treatment is the existence of tumor antigens. These are proteins that are expressed or presented on the surface of tumor cells, but are absent or present at much lower levels on normal cells. There are many reasons this might happen (that wikipedia article explains it pretty well, and feel free to ask if you're curious), but the key here is specificity. We can use antibodies (and other proteins that bind with high specificity) to send drugs and other therapies directly to the tumors. This is how the researchers I heard at TSRI targeted radiation, it's how bee-venom was targeted in nano-particles, and it's how the group at CalTech targeted siRNA. So why melanoma?

Melanoma is one of the easiest cancers to study. Taking a biopsy of the tumor doesn't require invasive surgery (it's on the skin), and the originating cells can often be studied well before they've actually crossed the line into cancer. So we know a lot about what tumor antigens melanoma expresses. Some other types of cancer also have well-known tumor antigens, but many don't. In addition, even the well-known tumor antigens of melanoma aren't expressed on every tumor of this type. Every type of cancer is different, and every individual's cancer is different. Translating these targeted therapies to be more widely used in the clinic is still a long way off.