Archive for the ‘diseases’ Category

Guillain-Barré syndrome

May 9, 2013

Yesterday I went to a talk by Hans-Peter Hartung about autoimmune diseases of the peripheral nervous system. To start with he gave a summary of similarities and differences between the peripheral and central nervous systems and their relations to the immune system. Of the diseases he later discussed one which played a central role was Guillain-Barré syndrome. In fact he emphasized that this ‘syndrome’ is phenomenologically defined and consists of several diseases with different underlying mechanisms. There is one form which is sporadic in its occurrence and predominant in the western world and another which can take an epidemic form and occurs in China. At a time when medical services in China were very poor this kind of epidemic had very grave consequences. Now, however, I want to return to the ‘classical’ form of Guillain-Barré.

GBS is a disease which is fascinating for the outside observer and no doubt terrifying for the person affected by it. I first learned about it in an account – I do not remember where I read it – of the case of a German doctor. He was on holiday in Tenerife when he fell ill. He recognized the characteristic pattern of symptoms, suspected GBS and got on the first plane home. He wanted to optimize the treatment he got by going to the best medical centre he knew to get treated. The treatment was successful. In GBS the immune system attacks peripheral nerves and this leads to a rapidly progressive paralysis over the course of a few days. In a significant proportion of patients this leads to the control of the muscles responsible for breathing failing and thus to death. For this reason it it is important for the patient to quickly reach a place where the disease will be recognized and they can be put on a ventilator when needed.The disease can then also be treated by plasmapheresis or immunoglobulins. In the talk it was mentioned that in the epidemics in China it was often necessary to put patients on a manual ventilator which was operated their relatives. If this acute phase can be overcome the patient usually recovers rather completely, although some people have lasting damage. It is typical that in a single patient the disease does not recur although there are a small number of cases where there are several relapses and disability accumulates.

It has been suggested that influenza infections, or influenza vaccinations, can lead to an increased risk of developing GBS. This has been an important element of controversies surrounding vaccinations, including those against H1N1. I wrote briefly about this in a previous post. In the talk the speaker mentioned a recent Canadian study indicating a slight risk of GBS due to vaccination against influenza. Nevertheless this risk was still a lot less than that due to actually becoming infected with influenza. There has also been a German study with similar results which, however, has not yet been published. There is another kind of infection which appears to carry a much higher risk, namely that with the bacterium Campylobacter jejuni. I actually mentioned this in my previous post but had completely forgotten about it. In the talk it was pointed out that this infection is quite common while GBS is very rare. So the question arises of why GBS is not more frequent. A possible explanation is that the bacterium is rather variable. The suggested mechanism is molecular mimicry (and it seems that GBS is the first case where molecular mimicry was precisely documented). In other words, certain molecules of the bacterium are similar to molecules belonging to the nervous system. Then it happens that antibodies against the bacterium cause damage to the nerves. Depending on the variant of the bacterium this similarity of the two types of molecules is more or less strong so that the effect is more or less pronounced. There is some idea in this case what exactly the molecules are which show this similarity. They are so-called gangliosides, a type of glycolipids.

This has reminded me of an issue which fascinated me before. Is there a simple explanation of why some autoimmune diseases show repeated relapses while others show a single episode (like typical GBS), a continuous progression or a combination of relapsing and progressive phases at different times? Has anyone collected data on these patterns over a variety of autoimmune diseases?

SMB annual meeting in Knoxville, part 2

July 27, 2012

The music did seem to have a positive effect on the synchronization of lectures. Unfortunately it was not always there – for instance it was not there before my talk – and it seems to have been getting less and less. One good thing is that the name tags, as well as showing the usual information have the first name (or nickname) printed in large letters at the top. I find that this can be very useful for recognizing people after only having met them fleetingly.

The plenary talk of Claire Tomlin yesterday was about the HER2 receptor which plays an important role in breast cancer. It is connected to transcription factors in the nucleus by a signalling network containing two main pathways. One of these includes the MAP kinase cascade while another passes through the substance Akt. Excessive activity of this type of signalling can be reduced by a drug called lapatinib, which is a tyrosine kinase inhibitor. There is, however, a problem that this beneficial effect can be neutralized after some time. The speaker described ideas for overcoming this effect based on a study of the signalling network. A result of this analysis is that, counterintuitively, combining the administration of lapatinib with another treatment which increases the concentration of Akt at a different time could lead to a more effective therapy. I did not get the details but this seems like a case where mathematical modelling could actually contribute effectively to cancer treatment by suggesting new strategies. Relations were mentioned to the pattern of hairs on the wings of Drosophila. In her research on biomedical themes she benefits from her background in control engineering and aerodynamics.

The talk of Becca Asquith which I mentioned in the last post was cancelled. Instead there was a lecture by Sandy Anderson who seems to like to cultivate the image of the hard-drinking Scotsman. He started his career in mathematical modelling and then moved a long way towards medical research, now heading a lab at the Moffit Cancer Center in Florida. The subject of his talk was the role of heterogeneity in cancer. He started by giving a view of the importance of cancer (in terms of the number of people it kills) and the trends in the numbers for the different forms. They have mostly been decreasing for many years with the notable exception of lung cancer (for well-known reasons) but the rate of decrease is not very large despite the huge amount of effort, and money, put into cancer research. He said that death in cancer usually does not result from a tumour which stays in its original site but as a result of metastasis. Thus that is the key phenomenon to be understood. This requires an understanding of many different scales and for the talk he concentrated on the cellular scale. He claimed that an important fact that cancer researchers had not taken into account sufficiently until very recently is how heterogeneous tumours are. There is a large variation in the phenotype of the individual cancer cells and the phenotypes are evolving. This evolution is strongly influenced by the environment of the tumour, for instance the structure of the surrounding extracellular matrix. Experiments done on cell cultures may give misleading results since the ‘happy’ cells in the Petri dish with all modern comforts are not under the same pressure as corresponding cells in the body. The more the external pressures are the more the dangerous cells which are going to metastasize dominate over the others. In some cases treatment can accelerate the growth of a tumour. This danger exists if the treatment is given too late. These ideas have arisen by the use of mathematical modelling. These are ‘hybrid models’ which combine discrete and continuous dynamical systems and this is a terms which I have met in several other talks at this conference. One of the conclusions of this research is that it may be a good idea to control cancer cells rather to destroy them. For the attempt to destroy cells may destroy the relatively harmless ones and unleash the dangerous one on their surroundings. Anderson’s talk conveyed the excitement of the application of mathematical modelling in cancer research at this moment and I wonder if some of the young people in the audience might have been recruited.

This afternoon I went to a session on wound healing. There was an introductory lecture by Rebecca Segal and this was helpful for me since I knew very little about the subject. Two of the things I found interesting – I was already primed for this by talking to Angela Reynolds at her poster yesterday – is that immunology (dynamics of neutrophils and macrophages) plays a big role and that ODE models can be useful. Useful means that they can help doctors make decisions how to treat wounds they are confronted with in practise.

IPEX and CD25

December 20, 2011

In a recent post I wrote about some ideas of Kendall Smith and his role in discovering the cytokine IL-2. On 8th December I heard him give a talk in which he presented various ideas about IL-2, its receptor and Tregs. I discussed some aspects of IL-2 in the last post. When mutant mice are engineered which cannot produce IL-2 they show a strange combination of symptoms which combine immunodeficiency (a reduced capability of the immune system to fight pathogens) and autoimmune disease (an inappropriate reaction of the immune system to host tissues). This probably has to do with the fact that IL-2 is important for the production of both effector T cells and Tregs, which act in opposite directions. Similar phenomena are seen in the disease of humans called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). It is often attributed to a lack of the transcription factor Foxp3 which is of central importance for the function of Tregs. The gene for Foxp3 is on the X chromosome and this explains the way IPEX is inherited and the term X-linked in its name. However, as pointed out by Smith in his talk, one third of patients diagnosed with IPEX have no mutation in the Foxp3 gene. In this context he referred to a paper of Caudy et al. (J. Allergy Clin. Immunol. 119, 482). What is shown in this paper is that there is a different possible cause of IPEX-like symptoms, namely mutations in the gene for CD25, a surface molecule associated to Tregs.

The paper concerns a patient (an eight year old boy) who had suffered a horrific combination of diseases. It was found that he had mutations in both copies of the CD25 gene. The mutation in one copy came from the mother and was a frame shift due to an insertion. In other words, there is a extra base in the DNA which makes the part of the gene after it look like nonsense when it is being transcribed. The mutation in the other copy came from the father and consisted of one base being exchanged. This happed to cause a stop codon so that reading stopped at that point. The combination of these circumstances meant that the boy could not produce CD25 and this was the presumed cause of his disease. His Foxp3 gene was normal. On the other hand other IPEX patients can produce CD25. Thus there appear to be two diseases with related symptoms. The gene coding for CD25 is on chromosome 10, not the X chromosome. This is why two mutations are necessary to produce CD25 deficiency.

What is the connection to IL-2? The IL-2 receptor, which was also discovered by Kendall Smith and his collaborators, consists of three chains called $\alpha$, $\beta$ and $\gamma$. The second and third are always present on the surface of T cells but the first is only present in variable amounts. In fact the $\alpha$ chain of the IL-2 receptor is nothing other than CD25. The $\beta$ and $\gamma$ chains together allow for some IL-2 signalling but strong signalling in response to normal concentrations of IL-2 is only possible with the help of the $\alpha$ chain. In this case it is not only the case that the receptor signals when IL-2 is bound to it. Binding also causes the receptor to be taken into the interior of the cell and destroyed. This process is an important part of the dynamics associated to IL-2. The $\gamma$ chain of the IL-2 receptor also forms part of the receptor for many other cytokines, for instance IL-4. The gene for this receptor is on the X chromosome. When it cannot be produced due to a mutation this leads to a disease called X-linked severe combined immunodeficiency (SCID). In this case the immune system does not function since so much of its signalling system has been disrupted. This is also known as the ‘bubble boy disease’ since children affected by it have to live in a sterile environment.

Shifting attention towards Tregs

December 3, 2011

Yesterday I heard a talk by Abul Abbas where two of the main themes were regulatory T cells (Tregs) and interleukin 2. Correctly functioning immunity is the result of a balance between effector cells and Tregs and he emphasized that in trying to develop therapies it might be more valuable to concentrate on influencing the regulatory side. He described a mouse model which he has developed for studying autoimmune disease. One criterion in developing this model was that it should concern the target tissue where an antigen is expressed and not the lymphoid tissue. Another is that the target tissue should be easily accessible for doing experiments in vivo. For this reason he chose the skin. In this transgenic model antigen expression can be turned on and off by feeding the mice with doxycyclin. When the antigen is turned on an autoimmune disease results. If it is turned off the mice recover. If it is turned on again the mice get sick again but much less than the first time. This is reminiscent of ordinary immunity which is due to memory effector cells. In this case it seems that there are memory Tregs. This suggests the idea that a possible cause of autoimmune disease in humans could be a lack of memory Tregs.

When IL-2 was first discovered it was known for causing T cells to proliferate and thus strengthening the immune response. More recently it has been found that eliminating IL-2 does not necessarily act in an immunosuppressive way. Apparently it can be replaced by something else in driving the proliferation of effector T cells. On the other hand it also drives the proliferation of Tregs and Abbas argued that this is its most essential function. In that case it cannot be replaced.

The lecturer made a number of interesting comments about themes such as immunology, therapies for immune disorders and cancer, clinical trials etc. I did not note them down and I cannot reproduce them here. Nevertheless I have the impression that a learned of lot of things which I might profit from in the future.

The variability of living organisms

September 8, 2011

Today I heard a talk by John McKinney where a central theme was the variability of genetically identical bacteria. This means on the one hand the differences between individuals and on the other hand the differences in the state of one individual at different times. The organism most prominent in the talk was Mycobacterium tuberculosis (cf. my previous post concerning a talk by McKinney). This bacterium can be treated using antibiotics (95% of patients who complete treatment are cured) but requires a combination of several drugs over a long period. If a cure is possible why is it so difficult? In his studies on this question McKinney has found that variability in the population of bacteria of the kinds already mentioned must be carefully taken into account.

McKinney is now based in Lausanne, having been at Rockefeller University until a few years ago. It is natural to ask why a biomedical researcher would leave such a prestigious institution. The speaker explained a feature of his present institution which was very attractive to him. This is the expertise available there in engineering and this has allowed him to develop new experimental techniques based on microfluidics. Bacteria are grown within a microfluidic channel which is observed under a microscope over long time scales. The microfluidic system allows the conditions to be controlled very precisely. Nutrients are provided and waste removed on a continuous basis. The fate of individual bacteria can be followed very closely. The processes taking inside the cells can be followed using fluorescent labelling. It can be seen exactly when the cell divides, when and where its DNA is replicated etc. Often the population is observed in a phase of exponential growth but this kind of system could also be used as a chemostat (cf. this post) to observe a steady state population.

One of the phenomena to be understood is that the population of M. tuberculosis treated with an antibiotic is biphasic. The population decreases at an exponential rate for a while and then suddenly at a different, much smaller, exponential rate. This is a phenomenon at a population level and the new techniques can help to understand what is happening on an individual level. For example, the antibiotic isoniazid (INH) is believed to work by preventing the bacterium producing mycolic acid, a substance it needs to build its cell wall. One popular theory, the “unbalanced growth model” suggests that the volume of the bacterium grows while there is no more material available for its cell wall. As a consequence the wall thins until the bacterium bursts. The new observations on the properties of individual bacteria are inconsistent with this model. Another observation which arose while trying to understand the interaction of bacteria with antibiotics is that there is a protein which is expressed in a way whose time dependence seems to be stochastic. On the films transcription of this protein is marked by a red colour and the bacteria are seen to flash on an off in a random-looking manner,

Another film showed cells caught in a microfluidic cage. There are small connections of the fluid in the cage with the outside of diameter about a micrometer which allow nutrients and waste products to be exchanged. These connections are too small for  eukaryotic cells but on the film the cells were seen trying to squeeze their way through with apparently great energy. The aim is to cultivate bacteria in eukaryotic cells in a situation where they can be observed effectively through the microscope. The necessity of tracking the cells is avoided by locking them into the cage. This would mean that the bacteria could be observed in surroundings closer to their natural habitat.

All these observations seem to have raised more questions than they have answered but what better motor can there be for scientific progress?

Conference on modelling the immune system in Dresden, part 3

April 8, 2011

In my second ever post on this blog I quoted a celebrated paper of Ho et. al. on HIV therapy. One of the other authors of that paper was Avidan Neumann and on Wednesday I had the opportunity to hear him giving a talk. His subjects were HIV, HBV and HCV, with the greatest emphasis on the last of these. He did briefly mention the case of the man who is apparently the only person ever to be cured of HIV. This took place in Berlin in 2006. The man had both HIV and leukemia and as therapies for both of these he was given radiation treatment and a bone marrow transplant. The transplant was a very special one since the donor was an HIV controller. Since then the patient has not had any treatment against HIV and despite very thorough tests it has been impossible to find any trace of HIV in his body.

Coming now to HCV, this virus causes hepatitis C, a liver disease which is often chronic. It often has few or no symptoms but the liver is progressively damaged, frequently resulting in cirrhosis or even liver cancer. In the worst case a liver transplant is required and after the transplant the virus always infects the new liver. This disease affects about 300 million people and no vaccine is available. The standard treatment is to give interferon $\alpha$ and an antiviral drug ribavirin over many months and this can be very hard on patients due to side effects. A new treatment, a protease called telaprevir, may soon be approved by the FDA. It is much more effective in getting rid of the virus than the standard treatment. The reasons why it is effective have been understood using mathematical modelling. Listening to this talk gave me the impression how close medicine and mathematics can be.

Arup Chakraborty gave a talk on targets for HIV vaccines which had an essential connection to HIV controllers. He has done statistical analysis of HIV viral genomes looking for a certain type of pattern. He explained the idea by an analogy with the fluctuations of share prices. If the share prices of different companies are examined for positive correlations then it is discovered that they can be grouped into certain sectors. These are the companies which are strongly related to certain activities, for instance those which have some close connection to car production. The genome of HIV virions can be analysed for correlations in an analogous way. This results in the identification of positively correlated groups which may again be called sectors. It is not a priori clear what these groups really mean. Interestingly the group with the strongest correlations (Sector 3 if I remember correctly) contains sequences related to HIV controllers. It turns out that these sequences have to do with the activity of building the viral capsid. A problem with vaccines against HIV is that if a vaccine targets a particular peptide a mutation may change that peptide and destroy the recognition without damaging the virus too much. Thus the virus can escape the immune attack. The special sequences in Sector 3 are such that mutations which affect them are likely to affect the stability of the capsid and hence compromise the reproduction of the virus. An important role is also played by those MHC molecules which can present the special peptides. The MHC molecules which do this optimally, and which occur in controllers are rare in the general population. They are, however, presented in a subleading way by more common MHC molecules. This may be enough to form an element of designing a good vaccine. In analysing this problem Chakraborty is using sophisticated mathematics, in particular the theory of random matrices.

To sum up my impressions of the conference, it has convinced me that mathematical immunology is an exciting and dynamic field which I want to be a part of.

Conference on modelling the immune system in Dresden, part 2

April 7, 2011

Here I continue with my presentation of themes from the conference. On Tuesday there was a talk by Thomas Höfer. One of the main themes was the stochastic variability of the behaviour of cells. For instance the production of IL-4 by Th2 cells is subject to considerable variation among cells. Modelling was used to try to understand if individual cells change their secretion rates with time. Might they cycle between states of higher and lower production? This appears not to be the case – they probably only change their behaviour once. I had a chance to talk about this subject in some more detail with Michael Flossdorf at the poster session on Monday. Another case is that of the production of interferon $\beta$ by cells infected by a virus. There is a large variability and it seems that this has little to do with the details of the behaviour of the virus. Instead it is intrinsic to the cells producing the interferon.

Rob de Boer talked about experiments to study the dynamics of lymphocyte populations by labelling. In one type of experiments volunteers were given deuterated water for a certain period and during and after that period the amount of deuterium in the DNA of lymphocytes was measured. The only way in deuterium can be built into the cells is by being incorporated into DNA during cell division. Thus it is a signature of division. Interpreting the results required quite a bit of mathematical modelling. A useful comparison is provided by labelling using BrdU (bromodeoxyuridine). Deuterium has the advantage that it is not toxic.

Ramit Mehr talked about natural killer cells. These have been studied a lot less than their relatives, the T and B cells. NK cells cannot specifically recognize antigens like the other cells and so the question immediately arises how they know which cells to kill. An answer to this question which was at first controversial but now seems to be generally accepted is the ‘missing self hypothesis’ of Klas Kärre. The idea is that the MHC type I molecules on the surface of host cells can repress the activity of NK cells. If the MHC molecules are not there, and thus ‘self’ is missing, the NK cell attacks. When a virus affects a cells it may be in its interest to suppress MHCI molecules to avoid attracting the attention of cytotoxic T cells. Then it may just get out of the CD8 frying pan into the NK fire. Not so much is known about where and how NK cells develop. It seems that although NK cells do not undergo selection like T cells they nevertheless need to go through a period of education in order to do their job optimally.

Gregoire Altan-Bonnet discussed the influence of Treg cells on effector T cells. IL-2 stimulates T cells to proliferate. Treg cells can rapidly bind IL-2 and internalize it. Under certain circumstances this can deplete the amount of IL-2 and thus limit the proliferation of effector T cells. A mathematical model of this process has been studied by a group of people including several participants of this conference. (See Busse et. al. PNAS 107, 3058). As explained by Altan-Bonnet, it has been argued due to experiments with cells kept in separate wells that cell contact was necessary for the action of Tregs but this argument is not conclusive. The wells can simply act as a hindrance to diffusion of the IL-2.

Conference on modelling the immune system in Dresden

April 5, 2011

On Sunday I travelled to the Max Planck Institute for the Physics of Complex Systems in Dresden to attend a conference on modelling the immune system. Before coming here I knew almost none of the participants personally although quite a few of them were known to me by name and by their papers. It seems to me that this conference is bringing together a lot of the leading figures in the area of mathematical immunology. I find the atmosphere at the conference very pleasant and friendly. There is a high percentage of the participants who have changed fields.

In what follows I will summarize some of the most interesting things I heard. There is so much information to absorb that many deserving topics will get left out. In his talk Antonio Freitas presented experimental evidence for how the number of B cells in a mouse is controlled by a quorum sensing mechanism. In particular this involved the technique of parabiosis which I mentioned in a previous post. In fact he went further than standard parabiosis and joined three mice together rather than just two. According to the picture he presented the number of B cells is not determined by production rate but by something else, a soluble substance. Through a series of experiments this substance was identified as IgG antibody. More specifically, there is more than one population of B cells present and it is a population of cells secreting IgM which is held in check by the concentration of IgG. The IgG binds to a receptor on the B cells causing a repression. Mice where this mechanism fails suffer from a lupus-like syndrome.

Robin Callard talked about T cell homeostasis. He works at the Institute of Child Health and in his presentation the development of the immune system in children played an important role. With age the thymic production of T cells decreases but the number of T cells remains relatively constant. Due to the volume change of the body it is not the same thing to look at the number of T cells as to look at their density.  He mentioned the concept of TRECs (T cell receptor excision circles) which may be used as an indicator that T cells have recently come from the thymus. The origin of these is as follows. During the development of the T cell receptor DNA rearrangement takes place and some pieces of DNA which have been excised survive as closed loops in the cell. Due to other processes going on it is rather hard to interpret the significance of measurements of TRECs for T cell dynamics. Callard and his collaborators have produced a mathematical model in order to provide better insights into this question (J. Immunology, 183, 4329). In the last part of his talk Callard explained some ideas (which he described as speculation) about the dynamics of the long asymptomatic phase in HIV infection. The main idea was that HIV slowly damages the lymph nodes (or other lymphatic tissues). This proposed process is irreversible, which means that interrupting therapy in HIV (for instance in children) could have lasting negative effects.

Andreas Radbruch gave a talk about the ways in which modelling and experiment can be combined to obtain a better understanding of the immune system. He discussed three examples. The cytokine IL2 is responsible for the proliferation of T cells. In situations where certain T cells should not proliferate their growth must be held in check by other factors. The first example in the talk concerned a system responsible for this control which was only recently discovered. Key players are the transcription factor Foxo1 and the microRNA miR-182. The original work is in Nature Immunology 11, 1057. The second example concerned work on the way in which a T cell which has differentiated in the direction of Th1 then becomes committed to that state. The underlying work has already been mentioned in a previous post and since I had already studied this paper in some detail this was rather familiar ground for me. The third example was about memory B cells. There is a class of cells of this type which reside in the bone marrow with each one being attached to its own stromal cell. I did not understand the details of this story and had the impression that it was not so easy to follow for even some of the expert members of the audience.

I have just finished writing about the talks from yesterday and I will stop here for now. I hope to continue with my extracts from the conference in the near future.

Systemic lupus erythematosus and NETs

March 4, 2011

In other posts I have written about autoimmune diseases. These can be divided into those which are specific for one type of tissue and those which are systemic. The latter can affect many tissues. One of the commonest and best-known systemic autoimmune diseases is systemic lupus erythematosus (SLE). It is estimated by the Lupus Foundation of America that there about three and a half million people with this disease worldwide, with ninety per cent of them being women. Caucasians are underrepresented. Yesterday I heard a talk about some aspects of this disease by Virginia Pascual from Texas and this is what stimulated me to write this. Apparently there are few therapeutic possibilites at the moment. She said that no drug has been approved for use against SLE in the last fifty years but that she hopes that this will soon change. At one time the lifespan after diagnosis with this disease was five years. Nowadays, although there is no cure, the disease can be managed so well that with suitable medical care it does not lead to a significant decrease in life expectancy. The severity of the symptoms oscillates in time, with flares and remissions. An important mechanism of pathology in this disease is the accumulation of immune complexes and this leads to a danger of kidney failure. The antibodies forming these complexes are directed against parts of the cell nucleus, in particular DNA.

In the talk the speaker explained a network of mechanisms which are at work in SLE. Some of the key players are interferon $\alpha$, plasmacytoid dendritic cells (pDC’s), the toll-like receptors TLR7 and TLR9 and neutrophils. SLE patients typically have high levels of IFN$\alpha$ in the blood and this is not changed by moderate doses of cortisone. It can be turned off by pulse therapy (e.g. 1 g prednisolone per day for 3 days) but it comes back. Under some circumstances it is found that in SLE patients less neutrophils die by apoptosis than in healthy controls. They are dying by another mechanism. This brings us to the NETs (neutrophil extracellular traps) of the title. This concept goes back to a paper of Brinkmann et. al. (Science 303, 1352). It was discovered that neutrophils can eject part of their contents including DNA to form a kind of net which traps bacteria. In fact, as mentioned in the talk yesterday this phenomenon was already observed in lupus patients by Rifkind and Godman in 1957 (J. Exp. Med. 106, 607) but at that time the possibilities of interpreting it were limited. A link between NETs and SLE was suggested in a paper by a group including Arturo Zychlinsky in PNAS in 2010. There it was proposed that in some SLE patients it may happen that NETs produced to combat an infection may be the cause of a flare.

Coming back to therapeutic prospects, it was noted that an inhibitor for TLR7 and TLR9 is under development as a drug against lupus by the company DYNAVAX.

More on the inflammasome

October 21, 2010

In a previous post I mentioned the inflammasome. Today I heard a talk about this by Jürg Tschopp from Lausanne who is the father of this subject in the sense that the concept and the name were invented in his lab in 2002. I learned that there are many different inflammasomes, i.e. many different protein complexes of this type. The one he concentrated on most in his talk involves a protein called NALP3. The inflammasome is involved with the occurrence or maintenance of inflammation. This may occur as a reaction to PAMPs (pathogen-associated molecular patterns) or DAMPs (danger-associated molecular patterns). The former are sensed by toll-like receptors while the others, less-well known, are associated with NOD-like receptors. He presented a very long list of diseases and other substances causing inflammation which are known or suspected to activate an inflammasome. The substances independent of pathogens mentioned included uric acid crystals, asbestos, alum (which is a constituent of some adjuvants) and nanoparticles. The typical outputs of the inflammasome are IL1$\beta$ and IL18. There is a disease (or rather a group of related diseases) called CAPS (cryopyrin-associated periodic syndromes) where the inflammasome is defective and this presents an opportunity to learn about its functions.

He went on to talk about three diseases where the inflammasome may play an important role: gout, type II diabetes and MS. Gout is a disease where crystals of uric acid accumulate in the joints, causing deformity (he had some pretty horrifying pictures) and intense pain. Gout patients have attacks which can be treated with medication e.g. corticosteroids. Several days of treatment are necessary and the improvement does not last very long. He reported on successes in treating gout with anti-IL1$\beta$. In that case the treatment is effective after one day and can last for a year. This means that the positive effects of one injection lasts a year! He reported similar results on anti-IL1$\beta$ as a treatment for type II diabetes. The prospect he was presenting was that one injection of this substance could replace the innumerable insulin injections of a diabetes patient in a whole year. This treatment is the subject of phase 2 clinical trials by Novartis. It could even be the case that the $\beta$-cells, which have been partially destroyed in this disease, start to regenerate.

In the case of MS Tschopp was linking the inflammasome with IFN$\beta$ therapy. Apparently this substance inhibits activation of the inflammasome. He mentioned experimantal data which show that MS patients being treated with IFN$\beta$ exhibit reduced inflammasome activity in response to certain antigen challenges in comparison to healthy controls. I must say that some of the things I heard in this lecture sounded almost too good to be true. The speaker himself said that he has found the success of some of the clinical trials very surprising. Maybe this is really the beginning of a major new development in medicine. Could anti-IL1$\beta$ overtake anti-TNF$\alpha$ some day?