Friday, August 3, 2012

Sunshine, Pathogen Genocide, Vitamin D, Happiness, and Cognition

Immunology has long fascinated me. Somewhere, sometime I read how the immune system was so sensitive it could identify a self from non-self protein in as little as 10 amino acids. "Crap!" I internally exclaimed even though completely ignorant of immunology at that time. As it turns out ...

Sort of true. That is a class of molecular structures known as PAMPS: pathogen associated molecular patterns.  Charles Janeway is the poster boy on that front. Our innate immune system is sensitized to these patterns. When you crunch numbers in a crude off the top sort of way, the immune system does a remarkably good job at fending off pathogens that have certain mathematical advantages. The challenge is so great that evolution came up with(remarkably!) the heavy and light chains which allow a tremendous ongoing creation of antibody types until there is one that "fits". It is a numbers game and while there are good odds with microbes the odds are bad with viruses because their replication and mutation rates are, relatively speaking, much higher. Two modern viruses are excellent examples of this. Hepatitis C and HIV exist in a variety of variants that will keep expanding. So when you think of mass extinctions remember one viable cause is a tiny molecular structure of only two key components which can wipe out a species very quickly and leave no trace. It dies with the species. That is an unsuccessful virus and not our concern. We are concerned with all the bugs that manage to live on and in us.

The immune system appears to be particularly tuned to the microscopic world. Recent studies have raised new questions about our pathogen genocidal imperatives. The Hygiene Hypothesis continues to gain support. For purely intuitive reasons, which in this instance simply means what I already believe, I don't believe in the Hygiene Hypothesis which goes like this: the outbreak of increasing rates of immunological related disorders is arising because, particularly during our developmental years, our immune systems need exposure to various potential "danger signals"(all hail Polly Mattzinger, former Playboy Bunny) in order to develop an appropriately balanced immunological response to future exposures.

It is true that there are remarkable rises in some immunological related disorders, and if you include conditions like autism, and even some subgroups of schizophrenia and depression, the increase could be much higher. My reference to neuropathological conditions may seem counter-intuitive but I'll get to that latter.

One way to think about The Hygiene Hypothesis is to consider the impact of hormonal signals like vitamin D. Perhaps the lack of pathogen exposure, and vitamin D production because let's face it if you really want to avoid pathogens stay indoors and breathe those chemicals instead,  results in a lack of regulatory T cells because typically with an immune response you will see activation of both inflammatory and anti-inflammatory pathways, with some sort of feedback set up finally resolving the issue. However, in the same way that the adaptive immune system will develop a set of cells expressed for the purpose of addressing any future equivalent pathogen exposure, it may also be the case that each pathogen exposure creates a subset of regulatory T cells.

T cells have a preferred body location, if they don't find their way to tissues that express MHC 1 relevant proteins for that particular T cell the T cell may well die. But with MHC 1 occupancy it is maintained in a "ready state" within a particular tissue type. It isn't just T cells though, dendritic cells can take up permanent residence in tissue sites long after injury. The first time I came across this was in relation to cerebral infection where it was found longstanding dendritic cells being maintained in the CNS, the last place you would expect to find such a cell type. (However it is now known that microglia under stimulation via a CSF will ramify into a dendritic cell like morphology). The skin has a specific type of dendritic cell, Langerhans. One amazing property of dendritic cells is upon exposure to a previous antigen the cell will enter the bloodstream, migrate to the thymus, and rapidly "instruct" a whole bunch of T cells to go on a killing spree. A bit like a radio shock jock only much more intelligent. Hence dendritic cells are sometimes referred to as "sentinels".

So there we have two distinct cell types that gravitate towards a specific tissue type and are forearmed for any future equivalent attack. The same might be true of regulatory T cells.

Where are most of these immunological disorders arising? Respiration and food allergies, the two key entry points for new proteins. Our gut is where a great deal of immunological activity is regulated. By sanitising what we eat and the air we breathe we may be creating epidemics of immunological disorders.

Just today I read a news item which touched on a similiar idea. Ward off Type 1 diabetes via short term gut worm infection? Other studies in gut inflammatory disorders have made the same claims. So this "non-self" pathogen is actually helping us prevent getting sick? I don't understand this finding, it reminds me of an email I received some weeks ago from a friend of mine which had a study indicating that exposure to gram negative bacteria at low concentration reduced inflammation.

We have a number of studies demonstrating that exposure to certain pathogens actually reduces the risk for future pathology or mitigates pre-existing pathologies. The type 1 Diabetes result is fascinating because the worms induced the expression of interleukin-4 and 10. Both of these cytokines are distinctly anti-inflammatory and activated by vitamin D. That makes sense, what doesn't make sense is why a pathogen induces an anti-inflammatory response. So then ...

Pathogens that could live long lives in our gut without causing too much damage would still be subject to immunological attack at various time points. The pathogens that engender an anti-inflammatory response would be enhancing gut health, reduce attack incidence, and hence have a selection advantage against pathogens that made you like really sick. In relation the gram negative bacteria study this explanation is not relevant because those bacteria are very nasty. As a trend though the successful(persistent) pathogens, be they viral or microbial, do not so much kill as stress or even become symbiotic. Even molecules have learned not to destroy that which sustains them. Way ahead of  us.

So we come to Polly. Forget the self - non-self stuff. What Polly and others taught us is that the immune system is attuned to "danger signals": indicators that something bad might happen. The previously mentioned PAMPs are an example of regular danger signals(read here: long and complex with a good historical overview of the maturation of Danger Theory, with the aforementioned Charles Janeway playing another leading role). A great many proteins, including abundant numbers of "self" proteins, are potential danger signals to the immune system. We even regularly produce auto-antibodies to a wide range of self proteins. This can be counter intuitive but that it does make sense when you keep the Danger Theory model in mind.

There is another  point here - for a T cell to be activated, to go ahunting, it needs co-stimulation. So with MHC-1 occupancy keeping the cells in a 'ready state' the cell then needs a "danger signal" before it ramps up the attack. Pathogens that reduce inflammation by reducing danger signal production or a direct anti-inflammatory signalling or a combination of the two, will still be subject to occasional attack but only when their numbers become so great the danger signals become sufficient to induce local T cell activation which in turn induces a localised inflammatory response allowing more immunological agents into the tissue. Hence our bodies are in a constant balancing state with respect to "non-self" entities that reside with us.

Now this is where we run into a more subtle problem. It is often stated that of all the cells in our body perhaps only 1/5 are "our" cells. Multi-cellular organisms are the perennial feast of the microbial world? That is one way of looking at it. The wrong way. We always presume we are the cells made by our body. But if you stripped away all those other cells you will be very quickly dead. So which is "self" and "non-self" here? Our pathogen holocaust of recent decades may well have killed off some of those "non-self" cells that were actually fundamental to balancing our immune response. I buy this disinfectant which claims to kill 99.99% of germs and think to myself: "of which 99.99% are freakin' harmless and a few at least are beneficial!". I think I've almost written myself into believing The Hygiene Hypothesis.

If the greater majority of cells that exist on our body are not made by our body then what do we mean by "our body" and "self" from "non-self"(oh shit this is getting ridiculous!). Anyways, enough of Wittie, let us go then you and I, while the concepts are spread out across the screen, to face the overwhelming question, should I wash or should I play? (Can you imagine T.S. Eliot performing with The Clash?)

We have already fundamentally restructured the microbial world. The weird thing is that simultaneously there has been a striking rise in immunological and inflammatory related disorders. I have long been puzzled as to why we rely so heavily on anti-inflammatory drugs and steroids, as if somehow the immune response is persistently excessive in modern populations.

We've made a mistake. Given that the greater majority of cells on our bodies, and by default in the general environment because that's where they are coming from, have been co-existent with us for yonks, they must be the types of cells that either do not induce "danger signals" or generate anti-inflammatory signals or a combination of the two. That is, our pathogen genocide has eliminated pathogens which are important players in our immunological balance. As the above type 1 diabetes study and a number of others indicate, some pathogens clearly are inducing an anti-inflammatory response, we might be on the tip of an iceberg here and only beginning to appreciate that the incredibly complex regulatory networks involved in physiology.

There is no going back home. We have irrevocably altered the microbial world and the prevailing view is that  had some unintended consequences. It appears to be the case that modern human physiology is a little too prepared to move into an inflammatory state and this is arising because because of the loss of a multitude of very tiny immunomodulators, if my above argument is correct the net result of their combined input was anti-inflammatory, which would have the added benefit of providing much stronger signal contrast for pathogens that can be really damaging. Those bugs that were on us were not not free riders, they were paying their way. We threw them off the bus.

There are still some big problems with my above thinking but I'll leave that line of thought there and if anyone can help please do.

Vitamin D as a Counter Strategy to the Consequences of our Pathogen Genocide.

My original impetus for writing this post was this news item. As you can see, I've gone somewhat astray.

Sunlight and vitamin D findings may help understanding of autoimmune diseases

Fortunately, vitamin D is a great way to regulate our inflammatory state. It works both at the cell population level and response level(Stat3?). It promotes the production of interleukins 4 and 10, both key anti-inflammatory interleukins, and, most importantly with respect to the above argument, it promotes the production of regulatory T cells. So maintaining good vitamin D status is not just about preventing autoimmunity, it may now be a fundamental requirement to maintain high vitamin D status because our pathogen genocide has perturbed our immunological balance resulting in an explosion of immunological and inflammatory disorders.

Exposure to sunlight isn't just about vitamin D exposure though, and the problem with relying on the sun for vitamin D is that vitamin D production is UVB dependent which means exposure at specific times of day relative to latitude, and the sun damage risk. With care, however, the latter can be managed, and a news report today highlights how sunlight, through a very different process, can play a vital role in modulating inflammation.

Researchers discover molecular link between circadian clock disturbances and inflammatory diseases
Note this statement from the news item:
Cryptochrome serves as a break to slow the circadian clock's activity, signaling our biological systems to wind down each evening. In the morning, CRY stops inhibiting the clock's activity, helping our physiology ramp up for the coming day.
A number of studies support their claim below:
"Our results strongly indicate that an arrhythmic clock system, induced by the absence of CRY proteins, alone is sufficient to increase the stress level of cells, leading to the constant expression of inflammatory proteins and causing low-grade, chronic inflammation."
It isn't enough to get enough sleep, the ideal to maintain a stable sleeping pattern because our circadian rhythms, with appropriate environmental cues, will be remarkably stable, though for poor sods like myself phase delay is a constant problem. The morning exposure to sunlight seems to be particularly important, as the news item states it promotes a physiologic signal to lower inflammation. So it does seem like in those old movies where the star would get up in the morning and first thing swing the windows open to greet the day is a good idea. No vitamin D to be produced at that time of day or sun damage but as that news article reveals the reduction in inflammatory mediators is important. This is where we come to happiness.

Happiness: The Sun Can Provide

Being out in the sun is fun. It makes  people feel better. The reduction in inflammation, and subsequent increase in serotonin, are two important components here. So we need to look quickly at some issues regarding Depression. It has long been acknowledged that depression is often associated with increased inflammatory mediator expression. Apart from from the neuro-endocrine changes that occur, an important immunological component of this inflammation is the induction of an enzyme, indoleamine deoxygenase(IDO).

The amino acid tryptophan is essential for serotonin production but IDO degrades it into toxic compounds. Microbes often need serotonin and by stripping out tryptophan this early immune response mounts one form of attack. That is why when we get sick we often feel like crap: our serotonin levels have been crashed by IDO. Over the long term this is not only bad for the brain because of serotonin loss but also because these toxic compounds can be damaging, not only to brains but I imagine many other tissues as well. There is a clear linkage between chronic inflammation and cancer incidence. IDO provides one very example of why this is so. Tumours will express high levels of IDO and this inactivates T cells, hence some therapies aim at inhibitors of IDO. This goes some way to explaining the increased rates of cancers observed in shift workers, who experience a persistent circadian disruption which is inherently inflammatory. There's an irony, our pathogen genocide might be promoting cancers.

Tryptophan should be for serotonin should be for melatonin and steady maintenance of both of these molecules is fundamental to health. For if IDO is preventing serotonin production it must be preventing melatonin because melatonin is produced from serotonin and melatonin has consistently demonstrated anti-tumoral properties and most importantly can potently stimulate Natural Killer cells, first line defenders against rogue cells. It is also a remarkable antioxidant, in a sense "self regenerating", whereas many antioxidants requires other agents to regenerate their antioxidant capacity. For a comprehensive look at melatonin this page is worth a look.

So we see a compounding effect here, where the induction of systemic inflammation can induce toxic compounds of various types which increase DNA damage, promote tumour cell survival through T cell inactivation via IDO, and lower melatonin production which is not only has important anti-tumoural properties but is also a key regulator of our circadian rhythms. The stage is set, bring on  that rogue cell ... .

Or send in the clowns, preferably on an open air set on a sunny day. Laughing is good too. Exposure to sunlight does increase serotonin levels and while I don't think that is the full explanation for the hormetic and mood enhancing effects of sunshine it is an important one. Especially if you consider that with out sterilised world and reduced sunlight exposure with subsequent widespread vitamin D insufficiency  we have compounded our potential for inflammation. I am not convinced that the reduction in IDO is a sufficient explanation for the increased serotonin levels seen with sunlight exposure. Important, not sufficient.

So think very seriously about your vitamin D status. Get it checked, get it on the high side. Overdose is very difficult if not impossible but there are some very important issues to consider here:

The typical recommendation is for vitamin D and calcium. Wrong. You must have vitamin Ks in your diet because even with vitamin D tissue calcium deposition will occur. Maintaining good levels of vitamin K is fundamental to health and surprise surprise we come all the way back to our friendly bugs because it is some species of gut bacteria that produce vitamin K. Home is where one starts from, as we grow older the pattern becomes more complicated .... .


There is some evidence to suggest that it may be more than just sunshine that is at play here. For example, some studies suggest the behavior and cognition of ADD children improves in natural environments. This study highlights how depressed patients perform better on cognitive tests when receiving sunlight exposure. Perhaps it is the case that our behavior is also much more strongly modulated by seemingly neutral environmental contingencies than we currently believe? This paper might be the one I read long ago. It addresses the benefits of natural environments, the restorative power these have on our being. Our modern world is incredibly stimulus rich, I sometimes wonder if we are pumping out important neuro modulators such as serotonin, dopamine, norepinephrine, and acetylcholine at unusually high rates, all of which are produced by relatively small nuclei in the brain, and so exhausting our physiological potential to maintain these modulators at appropriate levels. This might also throw some light on why meditation is proving so beneficial. It appears to reduce our "startle response" thereby making us in a sense resistant to this modern stimulus bombardment.

We all need time out. Mine is now. It is 3.00 am and I'm done. I trust you have enjoyed the exploration.

1 comment:

click here said...

The day experience sunshine seems to be particularly essential, as the information product declares it encourages a physiologic indication to lower swelling. So it does seem like in those old films where the celebrity would get up in the day and first thing move the windows open to introducing the day is a wise decision. No vitamin D to be created at that time of day or sun damage but as that information article shows the decrease in inflamation related mediators is essential. This is where we come to pleasure.