Michael Behe lecture

Intelligent design proponent Michael Behe is giving a talk in London on Monday 22nd November as part of his tour of the UK. From the ad:

200 bones. 600 muscles. Millions of nerves. Billions of cells. Trillions of organisms all working together to make one body - you. But how? An accident of evolution?

Book now for the 'Darwin or Design?' tour featuring US scientist Prof. Michael Behe and hear why he claims to have discovered evidence that life is really designed - findings that have rocked the scientific world.

The 'Darwin or Design?' national tour starts Sat 20th November. See and hear the scientific case for Intelligent Design from its leading voice - Prof Michael Behe.

Ask your questions live from the floor - engage personally with Mike Behe.

I'll be there. I would like to hear his comments on the following:


1) Behe claims that intelligent design is falsifiable, in that if someone can show how an 'irreducibly complex' system evolved in a stepwise fashion, then intelligent design would be proved incorrect. But this seems unlikely to me. If someone showed how the flagellum evolved step-by-step, Behe could simply say 'OK, the flagellum wasn't intelligently designed, but the immune system was'. In other words, he can always move around and point to another supposedly irreducibly complex system to support his argument. I think this refutes the notion that intelligent design is falsifiable.


2) If we base our knowledge of design on human design, as ID proponents do, then we must base our knowledge of intelligent designers on humans. So if ID is true, this means that intelligent designers (humans) are themselves designed by a intelligent designer. But crucially this 'earlier' intelligent designer is subject to the same criteria and so must also have been designed. This inevitably leads to an infinite regress of designers and a continual begging of the same question. I expand on this point here.


3) Behe claims that a system is irreducibly complex by the following:

By irreducible complexity I mean a single system composed of several well-matched, interacting parts that contribute to the basic function, wherein the removal of any one of the parts causes the system to effectively cease functioning

The problem is that this isn't evidence of intelligent design. It is actually predicted to happen by evolutionary theory. These ‘irreducibly complex’ systems CAN evolve through step-by-step neo-Darwinian evolution. Herman Muller described the process back in 1918. For example, take a relatively complex system that performs a function. Next, gradually make that system more efficient and sophisticated by step-by-step addition of new “parts”. Then, remove some of the earlier redundant “parts” (as happens in evolution) thus increasing efficiency. You now have a more complex system than the previous one, however, if you were to artificially remove a “part” of this new system, it would cease to function. As you should be able to see, this does not mean that it couldn’t have evolved.

Here is an analogy...

Imagine a river with three stepping stones forming a rudimentary bridge. The stones constitute a system with a function. If you add a long piece of wood across all three stones it is now a slightly more complex system, still with the same function. The middle stone can now be removed without loss of function, and this newer (slightly) more complex system is more efficient in that you can walk across it rather than hopping from stone to stone. If you now remove any of the other parts of this system, ie the wood or the two outer stones, it will lose its function, and thus the bridge can be termed irreducibly complex. However, it came about in a step-by-step fashion (which includes removal of redundant parts) without loss of function.


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Edit 01/12/10

I was unable to attend the talk but PaulJ has provided a report.

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AIDS vaccine: progress in the face of ignorance

I think most would agree that there are a lot of ignorant people in the world. Luckily, most of these individuals aren't a threat to the general public, just to themselves. But unfortunately, some are. Among the most dangerous are those who crusade on behalf of the anti-vaccine groups. They are quite literally encouraging the spread of disease (and sometimes death) by discouraging the use of vaccines.

The poster child for this movement is Jenny McCarthy (you know, the girl who gets paid to take her clothes off) who, despite a complete lack of scientific and medical training, reckons she is well-placed to comment on and dissuade the use of the MMR vaccine. Together with her supporters, including her husband Jim Carrey (you know, the guy who gets paid to make funny faces), she insists that this medically-validated vaccine causes autism.

It doesn't.

In fact, the original research that apparently 'proved' this has recently been retracted by the Lancet, and the author who was largely responsible for the unethical behaviour has been widely discredited. The fact is, the MMR vaccine saves lives, and so by influencing parents to forego this important step in a child's health results in deaths (and many more illnesses).



McCarthy and co are actively causing death and disease. A website called www.jennymccarthybodycount.com is keeping tabs on this. At the time of writing the numbers were:

Number of preventable illnesses: 54,907
Number of preventable deaths: 501
Number of autism diagnoses scientifically linked to vaccination: 0


Anyway, this post wasn't meant to be about McCarthy or autism. Instead, I want to discuss a recent publication in Nature by Herbert W. Virgin and Bruce D. Walker, which discusses efforts to develop a HIV vaccine.

Here's the abstract:

"Developing a human immunodeficiency virus (HIV) vaccine is critical to end the global acquired immunodeficiency syndrome (AIDS) epidemic, but many question whether this goal is achievable. Natural immunity is not protective, and despite immunogenicity of HIV vaccine candidates, human trials have exclusively yielded disappointing results. Nevertheless, there is an indication that success may be possible, but this will be dependent on understanding the antiviral immune response in unprecedented depth to identify and engineer the types of immunity required. Here we outline fundamental immunological questions that need to be answered to develop a protective HIV vaccine, and the immediate need to harness a much broader scientific community to achieve this goal."

The authors first remind the readers of the scale of the problem; in some regions, HIV infection rates in young women can increase from 1% at the age of 15 to over 50% by their early 20s - an incredible difference within a few years.

Here is the problem.... Vaccines work by stimulating the natural immune response.

This is usually an effective method as the body is somewhat adept at clearing vaccines. The main setback in developing a HIV vaccine is that the natural immune response isn't very effective against HIV and, accordingly, attempts to promote a vaccine-induced response to HIV have been equally as ineffective. Despite this alarming obstacle, the authors remain confident that a vaccine can and will be developed, although they admit that whether this vaccine will prevent infection, or instead prevent disease progression, is hard to predict. They mostly base this on studies in monkeys infected with simian immunodeficiency virus (SIV), which is very similar to HIV and indeed, is thought to be a candidate for its origins.

However, the fact that not all HIV infection lead to AIDS is encouraging, because this means that natural immunity capable of preventing disease progression does exist. Some individuals can harbour HIV for 30 years, and live relatively normal lives without developing AIDS. It is the, as yet unidentified, immune factors behind this remarkable resistance that must be harnessed in order to develop a robust HIV vaccine.



The authors go on to discuss different potential strategies, including eliciting both T cell and B cell responses. Another interesting aspect of current HIV vaccine research is the area of vaccine evolution, as HIV sequences have tremendous diversity and mutation rates. This 'strength' of HIV can also be exploited as a 'weakness', because if we can better understand the constraints on HIV evolution, we can potentially force the virus down a particular evolutionary pathway, and thus back it into a corner - a corner in which we have the upper-hand. This 'evolutionary trap' vaccine is an exciting idea.

A final observation the authors make is that it is difficult for scientists outside the HIV field to get involved in HIV/AIDS-related research. Funding issues discourage many researchers from straying from their own areas of expertise. This causes a bottleneck to emerge, where it becomes progressively more difficult for 'fresh' labs to break into this area.

The authors conclude "We must finally apply the full power of modern science to the AIDS vaccine efforts, and by defining the knowable unknowns translate this knowledge to vaccine-mediated protection against a pathogen that has already caused over 30 million deaths and shows no sign of relenting."

Of course, if and when a HIV vaccine is developed, are we likely to encounter the same type of resistance espoused by McCarthy and her type towards the MMR vaccine?

Inevitably, the answer is yes.

Individuals are transient in the long-term, but ignorance is permanent.

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Evolution of the Immune System

One of the major arguments of Michael Behe in the Dover trial, in which intelligent design creationism was shown up to be the vacuous nonsense that it is, was that the immune system is too complex to have evolved through purely natural processes. I think its reasonable to assume that for someone to make such a wide, sweeping claim they must be up to date with the literature...

Not Behe.

In fact, when presented with a stack of thick textbooks, all of which included chapters on the evolution of the immune system, Behe had to admit that he hadn't read any of them. Not one!

Let's just say that his honour, Judge Jones, was not amused. And, of course, the rest is history.

Well in the January edition of Nature Reviews Immunology, there is an interesting commentary on the very subject that Behe knows nothing about, and yet feels qualified enough to dismiss - evolution of the immune system.

How did our complex immune system evolve?

Max Cooper and Brantley Herrin discuss the evolution of innate and alternative adaptive immune systems for defence purposes and conclude that successful vaccines and other therapeutic manipulations of the immune system will require a composite strategy.

The immune system basically consists of two arms, innate and adaptive immunity (although, as ever, this is an oversimplified account).

Innate immunity works tirelessly to keep you free from infection every second of every day. If you need any evidence of this, think of how quickly an unrefridgerated body can decompose following death. And innate immunity isn't picky; it will protect you against anything it recognises as foreign. If you've heard of interluekin, interferon, TNF, macrophages, neutrophils, Toll-like receptors or complement, you've heard of innate immunity.

In comparison, the adaptive immune system is only called upon when innate immunity fails to eliminate a microscopic invader. But let me tell you, that little bug is in for a whole lot of trouble, because the adaptive immune system will target it specifically and mount a massive immune response to attack it. If innate immunity is like low level police constantly patrolling the streets, adaptive immunity is more like an elite squad of detectives and sharpshooters out to get their man. Common players in adaptive immunity include T cells, B cells and antibodies.

However, the benefits of adaptive immunity are only enjoyed by higher eukaryotes, including me, you and anything with a backbone. Organisms 'below' this in the evolutionary tree make do with innate immunity alone - indicative of the power and efficiency of the innate immune system. We share many innate immune components with mice, chickens, fish, fruit flies and even plants (in fact, in the same issue of Nature Reviews Immunology there is a whole review dedicated to a comparison of our innate immune system with that of the worm). And as one would expect if the immune system evolved, the closer we are to another species in the evolutionary tree, the more sequence similarity we find in the genes encoding these common proteins.

How does Behe explain this?... Well who knows, but my guess would be that he'd trolley out the usual creationist line that similar sequence could simply mean similar designer. Of course, the existence of endogenous retroviruses easily refutes this argument, but that is something for another day (but if you want to know more right now, click here).

As mentioned, the adaptive immune system is found exclusively in vertebrates. Cooper and Herrin discuss recent work that has cast new light on the evolution of adaptive immunity. It turns out that jawless vertebrates (hagfish and lamprey) have an adaptive immune system that functions slightly differently - in fact, the preliminary work on this was published in 2004, you know, before Dover. Specifically, hagfish and lamprey use entirely different types of antigen recognition receptor, meaning they use different proteins than we do to identify foreign pathogens. However, despite this difference, following recognition we all use similar mechanisms to direct our immune response to eliminate the invader.

Now the exact step-by-step evolutionary pathway that created these two different adaptive immune systems isn't known. Of course it isn't. It's completely unreasonable to expect that level of detail to be discovered, and Behe knows this. That's the reason he uses this type of argument - it's classic God-of-the-gaps drivel. However, based on current knowledge the authors sum up the probable evolutionary mechanisms involved:

The evolution of alternative adaptive immune systems was facilitated by two rounds of whole genome duplication, which enabled the original function of a gene to be maintained while allowing evolutionary selection of modifications of additional gene copies for new purposes. The common ancestor of lamprey and hagfish probably emerged between the first and second rounds of genome duplication, as amphioxus and tunicates have single gene copies, lamprey have two gene copies and jawed vertebrates typically have four copies of retained genes.

And of course, as usual with real science, this work leads to more questions:

Such convergent evolution of mechanisms for the generation of diverse antigen receptors after the split in jawless and jawed vertebrate ancestry raises the question of whether the two pathways of lymphocyte differentiation arose in a common vertebrate ancestor.

It's nice to know that people are working on this stuff, as opposed to others who try to stifle science with fanciful stories about mousetraps and magic.

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Swine Flu Vaccine - Priorities Wrong?

In the current edition of Nature (30 July 2009) there is a short correspondence from Italian immunologists on the subject of a swine flu vaccine.

I think it conveys an important message.

In the piece entitled "Flu: vaccinate to cut risk of chimaeric virus emerging", Ilaria Capua & Giovanni Cattoli from the Istituto Zooprofilattico Sperimentale delle Venezie in Italy, make the suggestion that any decisions on priority distribution of swine flu vaccine should take into account areas at higher risk of the emergence of a reassortment virus. This is a virus containing an assortment of genes from various different viruses and can occur in geographic locations where different human and animal viruses are simultaneously present

There is a risk of generating novel influenza A viruses through reassortment of the eight genes that result in antigenic shift, which would give rise to strains to which the human population has no immunity. For example, reassortment occurred between avian and human influenza viruses to create the human pandemic viruses of 1957 and 1968

Developing countries are breeding grounds for these types of reassortment viruses due to inadequate security and safety measures. Based on this, the authors indicate that along with the vaccination of risk patients and healthcare workers, emphasis should be placed on vaccinating populations in developing countries.

Fast-tracking vaccination of humans against pandemic influenza in developing countries where zoonotic flu in poultry is endemic would help prevent reassortment between naoH1N1 or other novel pandemic influenza strains and avian influenza viruses. That would deflect the unpredictable and serious consequences of viral reassortment to humankind worldwide.

So it is vital that we think on a bigger scale here. Undoubtedly each government has prioritised the vaccination of it's own citizens (here in Ireland they are apparently buying two doses per person), however the global community needs to think outside the box and firstly prevent the emergence of reassortment viruses. This constitutes a far greater risk to the human race and must be addressed immediately.

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The Impact of Immunology on Human Welfare

As part of our daily lives we are constantly exposed to an extensive array of pathogens, such as bacteria, viruses and parasites. These microscopic invaders tirelessly attempt to gain entry into the cells, tissues and organs of our bodies – and yet despite this relentless barrage of germs, symptomatic disease is relatively uncommon. Key to this defence is the immune system. Over the years the combined efforts of immunologists, in understanding how the immune system functions, have impacted significantly on human welfare.

Vaccination, for example, is commonplace today; we can safely immunise both children and adults against a variety of viruses. For this, we owe a debt of gratitude to early immunologists, such as Edward Jenner and Louis Pasteur, who pioneered the development of vaccines, consequently leading to the eradication of smallpox. Whilst the number of lives that have been saved through vaccination is surely beyond comprehension, the annual influenza vaccine alone is estimated to be 70-90% effective at preventing hospitalisations from influenza complications according to the US Centers for Disease Control and Prevention.

Increased understanding of the causes of organ rejection was another significant impact of immunological research on human life, as it paved the way for successful transplantation medicine thus prolonging the lives of countless otherwise condemned patients. Specifically, the realisation that cell, tissue or organ rejection is due to a host versus graft immune response proved critical.

On a broader scale, the generation of monoclonal antibodies (MAbs), usually produced by immune cells to detect pathogens, has assisted researchers to study protein function, impacting on a diverse range of biological sciences. MAb techniques are still widely used today and their contribution to biological research, not to mention their extensive use in medical intervention, cannot be underestimated.

However, despite the continuing success stories, one area of research in need of a significant breakthrough is autoimmunity. This topic covers a number of disorders in which the body fails to discriminate ‘self’ from ‘non-self’ and consequently attacks host cells in the absence of pathogenic signals. Whilst a lot of progress has been made in several autoimmune disorders, such as rheumatoid arthritis and systemic lupus erythematosus, the underlying mechanisms causing these diseases are still unknown. As such, treatment invariably involves symptomatic relief rather than preventing disease pathogenesis.

One of the major problems in preventing autoimmunity is the inevitable unwanted side effects of potential treatments. Current strategies involve dampening the immune response in affected individuals, which treats the symptoms of autoimmunity but also leaves the patient severely immunocompromised and at risk of infection. This conundrum leads to a patient also being prescribed antibiotics and antivirals, along with their side-effects, to counteract the diminished immunity. Researchers are currently trying to bypass this problem by specifically targeting immune cells involved in autoimmune disorders, namely activated Th1 and Th17 cells, whilst sparing other uninvolved immune cells, allowing patients to maintain an adequate defence against infection. Further work is required, but it seems there may be light at the end of the autoimmune tunnel.

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Highlights from Nature (Jul 16th 09)

In the current edition of Nature:

-The Schistosoma japonicum genome reveals features of host–parasite interplay

-The genome of the blood fluke Schistosoma mansoni

-The active form of DNA polymerase V is UmuD′2C–RecA–ATP

-Contamination of the asteroid belt by primordial trans-Neptunian objects

-Manipulation of photons at the surface of three-dimensional photonic crystals

-Photoconductance and inverse photoconductance in films of functionalized metal nanoparticles

-Evidence for middle Eocene Arctic sea ice from diatoms and ice-rafted debris

-Migration of the subtropical front as a modulator of glacial climate

-Global patterns of speciation and diversity

-Evolution of a malaria resistance gene in wild primates

-Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

-A conserved ubiquitination pathway determines longevity in response to diet restriction

-A reevaluation of X-irradiation-induced phocomelia and proximodistal limb patterning

-The AP-1 transcription factor Batf controls TH17 differentiation

-Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus

I've briefly commented on the highlighted studies below the fold

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The study on Global patterns of speciation and diversity by de Aguiar et al employs a computational model to measure speciation.

We simulated the evolution of a population whose members, at the beginning, are uniformly distributed in space and have identical genomes. The population evolves under the combined influences of sexual reproduction, mutations and dispersal. During reproduction, potential mates are identified from among those in a spatial region around an individual (specified by a spatial mating distance, S) whose genomes are sufficiently similar to that of the individual (specified by a genetic mating distance, G). This is a minimal form of sexual selection, essential (necessary but not sufficient) for speciation, called assortative mating (postzygotic genetic incompatibilities may have a role but are not essential). A mate is chosen from this set at random. Reproduction with crossover and mutation occurs. An offspring is then dispersed within a region around the originating and expiring parent. Genetic variation grows over time, due to mutation and recombination. We identify a species as a group of organisms reproductively separated from all others by the genetic restriction on mating and connected among themselves by the same condition...

Here is a figure showing the speciation of a 2000-strong homogeneous population into several distinct 'species' (colours) without any geographical boundaries:



What is interesting about this result is that it correlates well with what is known to occur in nature, as explained here:

Examples of such patterns are the constant rate of speciation observed in the fossil record; the higher diversity of freshwater ray-finned fishes than of their marine counterparts; the species–area relationships of birds, flowering plants and tropical-forest trees; and the relative species abundance of birds and forest trees.

This is clearly just one step in the marathon that is understanding biodiversity, but it's informative, nicely presented and has lots of pretty colours!



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Next, the study by Schraml et al entitled The AP-1 transcription factor Batf controls TH17 differentiation investigates the role of Batf in TH17 cell maturation and hence how this transcription factor contributes to autoimmunity, my specific area of interest.

I've desribed the role of TH17 cells in autoimmunity in an earlier post. They are a subset of T helper cells, the others being TH1 and TH2 cells, which direct the immune response following pathogenic assault. However, overactivation or a lack of appropriate suppression of this response can result in autoimmunity as these cells will drive the response towards host cells in the absence of pathogens.

In this paper, the authors have generated Batf^-/- mice in order to study the effects of Batf on their experimental model, namely experimental autoimmune encephalomyelitis (EAE), an autoimmune disease in mice. They found that Batf^-/- mice produced less IL-17 than wildtype mice (figure below, b), suggesting that Batf is involved in TH17 cell development. The same mice showed normal IL2, IFN- and IL10 levels, indicative of normal TH1 cell function.

Interestingly, the Batf^-/- mice were resistent to EAE, as shown in the figure below (a, open triangles). This result adds further evidence to the role of TH17 cells in autoimmunity, and points to Batf as a critical transcription factor regulating its pathogenesis. To further prove this point, the authors gave the Batf^-/- mice functional naive T cells (CD4+) from wildtype mice and this resulted in the mice becoming susceptible once again to EAE (c, open triangles).



This adds to the TH17 story which is becoming a very hot area in immunology. If we can understand what is driving the differentiation of these cells, we will theoretically be able to suppress this to combat autoimmunity.

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First Article Published!!

Well folks, as I mentioned in my first post, I have been trying to break into science communication. Good news! I was commisioned to write an article for The Scientist, which is now published, on an immunology exhibition in Trinity College Dublin called Infectious: Stay Away. It's a great exhibition where the visitors get to participate in many of the exhibits, including one where they extract their own DNA for use in an on-going population genetics study. A subscription is required to read the article, but the good news is it's free to sign up! Here is a taster:

At the entrance, I'm greeted by a team in outbreak gear -- full overalls and face masks -- who insist that I proceed into the decontamination zone. Here, I'm screened and electronically tagged to monitor my infection status throughout my visit. This jarring introduction is perhaps one of the most innovative ideas in Infectious -- the world's first simulation of a live epidemic. The electronic sensor around my neck can communicate and infect other sensors when in close proximity, and by periodically infecting a random visitor with an "electronic virus", the exhibition curators can monitor the spread of that virus as it infects the influx of visitors.

As I navigate through Infectious, I find a lab bench with several microscopes inviting me to get up close and personal with parasites, bacteria and the bioterrorist's favourite, anthrax. Nearby, a mosaic of Petri dishes lines the wall, each having being kissed by a visitor over the weeks since Infectious opened. A multitude of microorganisms grow in the dishes, some conforming to the outline of lips. I admit, this particular part of the exhibition makes me think twice about being amorous ever again.

Suddenly the red light on my electronic tag begins flashing. I have become infected. I give a suspicious glance to the person next to me and make my way to the disinfection station, where an animation representing each visitor and their role in the spread of the virus plays. I stare at this real-time visualisation of the infection kinetics as the ease with which viruses can spread through a crowd hits home.

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Nature review: Type I interferons and AIDS

Viruses have evolved highly effective mechanisms to manipulate the host immune response and facilitate replication. Following HIV infection in humans or simian immunodeficiency virus (SIV) infection in rhesus macaques, a chronic activation of the innate immune system is observed. This immune response is triggered by the recognition of viral RNA and DNA by members of the Toll-like receptor (TLR) family, specifically TLR7 and TLR9 on plasmacytoid dendritic cells (pDCs). These cells are also known as interferon (IFN)-producing cells due to the massive quantities of IFNa secreted following stimulation. One outcome of this chronic inflammation is a reduction in the regenerative ability of CD4+ T cells. This effect results in significant T cell depletion and is a major contributor to immunodeficiency associated with AIDS.

However, it now appears that divergent host immune responses can also result in different outcomes to the same virus. For example, in contrast to rhesus macaques, sooty mangabeys do not progress to AIDS following SIV infection, but instead act as a reservoir host for the virus. A recent paper in Nature Medicine by Mandl et al (1) examined the differences in the immune response to SIV in both sooty mangabeys and rhesus macaques in order to understand the mechanisms contributing to AIDS progression. Although viral replication was comparable in both species, minimal T cell and NK cell proliferation was observed in the sooty mangabeys following SIV infection, as opposed to high cell proliferation and expansion in the rhesus macaques. In addition, pDC activation was increased in the rhesus macaques but not in the sooty mangabeys, as measured by expression of the chemokine receptor CCR7, a reliable marker of pDC migration to lymph nodes (1). These results show a significant attenuation of the immune response to SIV infection in the sooty mangabeys, suggesting that the lack of AIDS progression in this species is a result of specific immune response mechanisms, as opposed to properties inherent to the virus itself.

Figure from O'Connell and Siliciano (2).

The authors next investigated TLR7 and TLR9 responses to SIV in peripheral blood mononuclear cells (PBMCs) from humans, rhesus macaques and sooty mangabeys. Despite high IFNa production in humans and rhesus macaques, they found much lower secretion of IFNa from sooty mangabeys (1). However, this effect was not limited to SIV infection, as reduced IFNa production was also observed when PBMCs from sooty mangabeys were stimulated with a panel of TLR7 and TLR9 ligands. Interestingly, the ability of sooty mangabey PBMCs to produce the proinflammatory cytokines TNFa and IL-12 was not diminished, implying that TLR7 and TLR9 recognition of SIV is normal in these cells, but that there is a deficiency in the downstream pathways leading to type I IFN production (1). The researchers suggest that this deficiency may lie at the level of interferon regulatory factor 7 (IRF7), the critical transcription factor for type I IFN production. They come to this conclusion following sequence analysis of genes encoding prominent members (including TLR7, TLR9, MyD88, IRF7 and several type I IFN promoters) of the TLR7 and TLR9 pathways in humans, rhesus macaques and sooty mangabeys. Whilst most genes were highly conserved, several polymorphisms were found in the sooty mangabey IRF7 coding sequence. The authors speculate that these polymorphisms, which cause amino acid substitutions in the transactivation domain of IRF7, may be responsible for the deficiency in type I IFN signaling, and consequently the protection against AIDS.

This study has provided an interesting new insight into the immune mechanisms contributing to the progression of AIDS. Specifically, it appears that IRF7 polymorphisms resulting in the attenuation of the type I IFN response in sooty mangabeys protects against the development of AIDS. These mutations have been preserved in sooty mangabeys as they offer an evolutionary advantage, namely a reduced susceptibility to immunodeficiency disease. This implies that the pathogenesis of AIDS in susceptible species may be a combination of both viral replication and prolonged immune activation. Based on this research, a potential therapeutic strategy to combat AIDS would involve inhibiting virus binding to CD4 on pDCs, thus attenuating cell proliferation. In addition, the inhibition of excessive type I IFN release by pDCs may prove to be beneficial, either through the use neutralising IFNa antibodies or by specifically targeting IRF7. However, these potential strategies are not without limitations, as an inhibition of type I IFN production would leave a patient dangerously immunocompromised. Instead, more research into the contribution of innate immune mechanisms to AIDS progression may result in the use of specific inhibitors as part of a combinatorial therapeutic approach.

(1) Mandl et al. Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med. 2008 Oct;14(10):1077-87.

(2) O'Connell and Siliciano. Immune alteration fends off AIDS. Nat Med. 2008 Oct;14(10):1016-8.

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Nature review: IL-23 and autoimmunity

Cytokines are the chemical messengers of the immune system. They are secreted by a wide range of celltypes and bind to receptors on neighbouring cells, usually resulting in cellular activation or differentiation. This seemingly simple process is vital to the complex cellular machinery of the immune system, as it facilitates rapid communication between different immune cells, thus enabling the host to mount a fast and effective immune response to an invading pathogen. Specifically, the release of cytokines by cells in an infected area sends a chemical signal which activates and recruits other immune cells to the site of infection.

In recent years, the interleukin-17 (IL-17) family of cytokines have been of great interest to immunologists. This is because Th17 cells (T helper cells that produce IL-17) have been shown to be critical in the pathogenesis of autoimmunity. However, the actions of another cytokine, IL-23, are known to be necessary in order for Th17 cells to exert this pathogenic effect, although the precise mechanisms are not clear. A recent publication in Nature Immunology by McGeachy et al (1) has now shown that IL-23 is not simply maintaining the effects of Th17 cells, a commonly held hypothesis, but instead that the cytokine is necessary for the complete differentiation or 'fine-tuning' of activated T cells into effector Th17 cells. The authors accomplished these results by generating an IL-23-receptor (IL-23R) knockout mouse in which they observed a reduced susceptibility to experimental autoimmune encephalomyelitis (EAE).

They found that IL-23R-/- mice had similar levels of CD4+ T cells when compared to wildtype mice, but crucially there was far less infiltration of these cells into the CNS following the onset of EAE. In addition to the lack of infiltration, the cells in the IL-23R-/- mice produced less IL-17 than the same cells in the wildtypes (1). Thus, in the absence of the effects of IL-23 signaling, CD4+ T cells are impaired in their ability to both move to the necessary site of damage and secrete IL-17. This strongly suggested that the CD4+ T cells were not completely differentiating into Th17 cells in the IL-23R-/- mice.

Picture: IL-23-mediated differentiation of CD4+ T cells into Th17 cells

In addition, the authors show that IL-23-mediated differentiation of T cells into Th17 cells is time-dependent by measuring induction of Th17 cells in the draining lymph nodes in an adoptive cell transfer model. They found no difference between IL-23R-/- knockout and wildtype mice until day 6, when a significant lack of Th17 cells were observed in the draining lymph nodes in the knockout mice (1). Together these results suggest that in the absence of IL-23 signaling there are fewer Th17 cells in the circulation, and hence less infiltration into the CNS resulting in a decrease in the Th17-mediated pathogenic effects that contribute to the pathogenesis of EAE. The authors go on to show that IL-23 induces Th17 terminal differentiation by a mechanism which includes the phosphorylation of the transcription factor STAT3 (1).

This work is important as it reveals the importance of the role of IL-23 in Th17 cell development. This will open up new areas of research towards targeting IL-23 or possibly blocking the IL-23 receptor in an effort to inhibit the pathogenic effects of Th17 cells in autoimmunity. Indeed, an antibody directed towards the p40 subunit of IL-23 has already been shown to decrease inflammation in psoriatic patients, thus confirming the possible benefits of this novel approach.

(1) McGeachy et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol. 2009 Mar;10(3):314-24.

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Nature review: The AIM2 inflammasome

Sensing and destroying foreign microorganisms is essential for the survival of multicellular organisms. The last decade has seen great advances in our understanding of how the body detects and eliminates invading pathogens. Central to this progress was the discovery of the Toll-like receptors (TLRs), a family of germline-encoded membrane receptors that are responsible for detecting microbes. Crucially, these receptors allow the innate immune system to discriminate between 'self' and 'non-self', an ability long known to be utilised by memory T and B cells of the adaptive immune system. The TLRs function by recognising bacterial or viral motifs, called pathogen associated molecular patterns (PAMPs). These PAMPS are essential for the structural integrity of the microbes and so are highly conserved in bacteria, viruses and other microbes. Different TLRs have evolved to detect specific PAMPs, enabling a wide range of directed immune responses to be induced.

Complementing the membrane bound TLRs are several cytoplasmic pathogen recognition receptors which have evolved to recognise intracellular microbes. For example, viral RNA can be detected by TLR3, TLR7, TLR8 and the cytoplasmic receptors RIG-I and MDA-5. Until recently, TLR9 was the sole receptor for viral DNA, however Fernandes-Alnemri et al (1) and Hornung et al (2) have independently published evidence in Nature (Vol 458, March 2009) that the cytoplasmic receptor AIM2 (absent in melanoma 2) also recognises viral DNA, leading to activation of a multi-protein complex called the inflammasome. The inflammasome is responsible for cleaving the proinflammatory cytokines pro-IL1β and pro-IL18 to their active forms, resulting in the recruitment of inflammatory cells to the site of infection. Cleavage of these pro-inflammatory precursors is achieved through the inflammasome-mediated activation of caspase-1, an enzyme that has been extensively studied in both immunology and cancer research.

Figure from Schroder et al (3).

An inflammasome-activating DNA receptor had previously been implicated in the DNA-induced interferon pathway, thus both studies initially searched databases for pyrin domain-containing receptors. The rationale for this was that the hypothetical DNA receptor would require a pyrin domain to bind the inflammasome protein ASC (apoptosis-associated speck-like protein containing a CARD), such as is the case for a family of cytoplasmic pathogen recognition receptors called the Nod-like receptors (Nods). Using this starting point, both groups of researchers identified AIM2, a member of the interferon-inducible HIN-200 family, and showed the ability of the receptor to activate the inflammasome and caspase-1 following synthetic dsDNA stimulation (1,2). Furthermore, Hornung et al also observed a role for AIM2 in innate immunity to dsDNA vaccinia virus (2). These results were corroborated in cells with decreased expression of AIM2, achieved through siRNA or shRNA. Following stimulation of AIM2-deficient cells with dsDNA, decreased caspase-1 activation and IL-1β processing were observed in comparison to AIM2-expressing cells (1,2). AIM2 was also discovered as a cytoplasmic dsDNA receptor independently in a third study by Bürckstümmer et al (4) published in Nature Immunology, in which a combination of genomic and proteomic screens were used to identify the receptor.

This combined work shows that cytoplasmic DNA binds directly to AIM2 resulting in a strong proinflammatory response. This novel mechanism by which our immune system can sense viral or bacterial infection may have therapeutic applications. For example, targeted activation of AIM2 could assist in the elimination of invading pathogens. However, this finding also has implications for autoimmunity, as AIM2 will presumably also sense 'self-DNA' released by apoptotic cells. Thus, inappropriate activation of AIM2 could lead to the overproduction of inflammatory cytokines and type I interferons known to be associated with autoimmune disorders. This makes AIM2 a potential therapeutic target, as blocking the receptor may inhibit the onset of inflammation. It will also be interesting to scan autoimmune patients for single nucleotide polymorphisms or SNPs in the AIM2 mRNA, as it has been shown that mutations in the NLRP3 inflammasome result in constitutive activation, resulting in enhanced and prolonged activation of caspase-1 and secretion of IL-1β.

1. Fernandes-Alnemri et al. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 2009 Mar 26;458(7237):509-13.
2. Hornung et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 2009 Mar 26;458(7237):514-8.
3. Schroder et al. Innate immunity: cytoplasmic DNA sensing by the AIM2 inflammasome. Curr Biol. 2009 Mar 24;19(6):R262-5
4. Bürckstümmer et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol 2009 Mar;10(3):266-72.

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