[special post] correlating sleep depth and inflammation

this paper talks about the relation between proinflammatory cytokines (IL-6 and TNF-a in particular) and sleep. this paper does not suggest any causal relationship between the two, only highlighting that they are related to each other. this was also the first paper on sleep and inflammation that i read and i found it so intriguing. but we now know that sleep does affect cytokine levels, and cytokines levels also affect sleep, but there is one main question that i can’t answer: if inflammation makes a person get more NREM sleep, shouldn’t he or she be more energetic after it? but why do my friends complain about lethargy?

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Sleep depth and fatigue: role of cellular inflammatory activation
KaMala S. Thomas, PhD, MPH, S. Motivala, R. Olmstead, and M.R. Irwin

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In summary:
This paper examines the association between cellular expression of proinflammatory cytokines, alterations of sleep depth and daytime fatigue, and looks at interleukin-6 (IL-6) and tumor necrosis factor a (TNF-a) more specifically. 31 men and women were studied for 3 days in the sleep lap to get data on their sleep patterns. Blood sampling was conducted to measure the levels of inflammatory markers and they tried to correlate the two. It was found that an increase in IL-6 production was positively associated with rapid-eye movement sleep.

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Point 1_________________________________________________

Proinflammatory cytokines are associated with a cluster of behavioural symptoms known as sickness behaviours. These symptoms, which include fatigue, sleep disturbance, depression, loss of appetite, and inability to concentrate, are common in individuals with medical conditions involving underlying inflammation.

The first time I saw “sickness behaviour”, I thought a lot of the symptoms paralleled those I experienced (it’s elaborated a lot more in this entry about depression). I can’t really recall fatigue, since I was so low spirited back in those days. Sometimes I feel like it’s the depression that sucked away all of my energy. My sleep was definitely disturbed, and the inability to concentrate? I’m not sure if that’s arising from my constantly itchy skin or not. My appetite got much larger though. It’s a bottomless pit as I recalled. I’m just saying that I share the same symptoms, but whether or not it’s due to the surge of proinflammatory cytokines in my body, I do not know. And I probably never will. HOWEVER, I think it’s useful to use these deviations from the normal as a gauge to see where we stand, and where your friends and families who are NOT going through TSW stand in terms of their health. Afterall, a lot of underlying inflammation that leads to serious problems do not show itself early on in their developmental stages. We can only observe our state of the health from subtle things like these to make a guess about our health.

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Point 2_________________________________________________

Prior studies have found that increases in circulating levels of IL-6 correlate with decreases of slow wave sleep (SWS), as well as increase in the amount and percentage of rapid eye movement (REM) sleep and REM sleep density. In addition, stimulated production of IL-6 mixed cell cultures is associated with increases in REM sleep amounts and percentage.

IL-6 is a proinflammatory cytokine, and it’s increase has been associated with a decrease in slow wave sleep. Slow wave sleep is the deepest sleep stages, it’s also the stage that allows the brain to recover from its daily mental activities. Being deprived of SWS would mean your brain doesn’t get enough rest! In addition to the lesser SWS, IL-6 increases REM sleep amounts! So.. more dreams, less quality rest.

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Point 3_________________________________________________

Results:
1. Evening stimulated monocyte production of IL-6 was associated with less SWS and a longer REM duration. Production of IL-6 was unrelated to stages 1 or 2 sleep, total sleep time, sleep efficiency, time to sleep onset, REM sleep, REM latency or REM density.

2. … participants in the lowest quartile of IL-6 production spent 11.3% of total sleep time in SWS, compared to 2.5% of total sleep time among those in the highest quartile of IL-6 production.

3. … REM duration was 10.6 minutes amongst participants in the lowest quartile of IL-6 production, compared to 22.5 minutes among those in the highest quartile of IL-6 production.

4. … increased evening production of IL-6 was associated with fatigue, and this relationship was mediated by shorter SWS. … REM duration was unrelated to fatigue.

1. Evening stimulated IL-6 production only affected slow wave sleep, which is stage 3 of the NREM, as well as REM duration. All the other parameters were unaffected.

2. Comparing the amount of time spent in SWS between the upper and lower quartile, the upper quartile only spent a quarter of the time that the lower quartile spent. => IL-6 reduces SWS.

3. Comparing between the upper and lower quartile of IL-6 production, the time spent in REM sleep by the the upper quartile is almost twice that of the lower quartile. => IL-6 increases REM sleep.

4. One possible mechanism for the increased production of IL-6 being associated to fatigue is through the decreased SWS duration. REM duration does not affect fatigue.

So I can spend the entire night dreaming and that would not make me feel tired the next day as long as I get sufficient SWS.

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Point 4_________________________________________________

Given that the first sleep cycle is generally dominated by SWS in normal sleepers, our findings may reflect a shift away from SWS toward more REM sleep in participants who have high proinflammatory cytokine expression.

I think it’s quite cool that we can now draw some idea about our inflammation levels within our body by observing our sleep. Any deviation from the norm may suggest that there’s underlying inflammation that we’re not addressing.

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Point 5_________________________________________________

Psychological stress may be a key factor predicting increases in IL-6 production and alterations in sleep architecture. It has been well documented that chronic stress is associated with increased sympathetic nervous system (SNS) activity as well as a greater production of proinflammatory cytokines. … increased nocturnal SNS activity is associated with a reduction in SWS and an increase in REM sleep. Taken together, these findings suggest that heightened nocturnal SNS activity, possibly due to stress, may lead to increased production of proinflammatory cytokines, which may alter sleep stages.

I had to google what on earth is SNS. Well, it’s the fight or flight response in the body in response to stress. Acute stress increases our cortisol and plasmas cytokine levels. Chronic stress blunts our cortisol levels in the long run as our body adapts to the new state of affairs. As a result, the anti inflammatory cortisol levels are not high enough to bring down the counteract the cytokines. What we get is then a proinflammatory profile. It was found that the body’s response to stress at night is associated with a reduction in SWS and increase in REM sleep.

So long term stress may lead to a proinflammatory profile, which leads to lesser quality sleep, and eventually fatigue (and you feel worst from the bad sleep). Such a bad cycle!!! Gotta take care of stress at its root! And if not, tackle it with other methods like meditating and exercising, otherwise it’s a downward spiral to never ending stress.

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Point 6_________________________________________________

Our findings extend research on proinflammatory cytokines and sleep architecture beyond circulating cytokine levels to examine relationships between sleep architecture and cellular cytokine expression. Given that circulating cytokine levels can come from sources other than immune cells and may not necessarily be indicative of immune dysregulation, our findings provide further evidence that increased proinflammatory cytokine activity resulting from immune dysregulation plays an important role in regulated sleep stages.

Initially I only highlighted the second sentence which says circulating cytokines may original from other sources other than immune cells. In my mind, I was thinking “perhaps, just maybe, if it’s even possible, that our skin cells release so much proinflammatory cytokines into our blood stream that led to so much weird symptoms”.

But that’s all in my head. I have no way to prove it. It would be interesting if we can investigate the cytokine levels in our blood during TSW, because as far as I know, the cortisol level is pretty normal. Previously I was so hung up on the effects of cortisol on our state of the skin, but now I’m starting to divert my attention elsewhere.

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Point 7_________________________________________________

… circulating markers of inflammation (C-reactive protein) was linked to greater fatigue among healthy individuals who participated in the CARDIA population based study. Additional, the current findings suggest that a reduction in SWS may be one pathway through which inflammation leads to a reduction in general health and fatigue in healthy individuals. … Given that inflammation was associated with fatigue in both studies, these findings highlight the deleterious effects of immune dysregulation on general health and well being otherwise healthy individuals.

I really like this paper because it showed me how sleep architecture can be used as a way to gauge how inflamed I am. It’s not just about the inflammation on the skin, but rather, inflammation INSIDE the body. I’m not sure about you all, but I believe that all chronic sickness are all due to chronic inflammation. Cancer, heart problems, diabetes, EVERYTHING. It has to be noted that inflammation presents itself in many different forms. It’s not all about itching, swelling, and turning red. At the very heart of inflammation is cellular destruction. In the short term, it’s good because inflammation helps our body recover from any damage it received. But chronic inflammation is undesirable because it sets up the breeding ground for a lot of those diseases I just mentioned. You can read how cancer and inflammation is related here.

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Point 8_________________________________________________

This is the first published study to examine associations between stimulated IL-6 and sleep architecture. Additionally, given the correlational nature of this study, we cannot infer that a causal relationship exist between proinflammatory cytokines, sleep architecture, and fatigue.

While this study only studies the correlation between IL-6 and sleep architecture, correlation is NOT causal. It doesn’t mean that IL-6 causes the change in sleep architecture. For all we know, it could be the other way, which was discussed earlier on as well whereby deprivation of sleep will lead to an increase in proinflammatory cytokine production. I know it’s kind of pointless to mention this point right now because it feels like I’ve just wasted time reading this paper when it doesn’t tell me whether or not the inflammation causes the change in sleep architecture. However, I still find this paper to be interesting and useful because we now know that sleep and our state of inflammation is related. With a simple relation, I will then be able to link the state of sleep to the state of inflammation, regardless of the causal nature between the two factors.

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PUTTING IT ALL TOGETHER

Sleep is not created equal. We get our rest mainly from the (stage 3 of the) NREM sleep, and the deprivation of it will lead to fatigue, that’s why some people complain about tiredness even after sleeping for 8 hours or more – if it’s mostly REM instead of NREM, they’re hardly resting at all! Remember it’s quality over quantity!

During my worst TSW moments, I could hardly sleep. And when I do fall asleep, I know I’m in very light sleep because I wake very easily (which is not typical of NREM) and I have so many dreams during those times!!! Waking when I’m having my dreams allow me to remember my dreams easily, and that’s how I come to conclude that my sleep is usually in the lighter stages back then. I’m not sure if it’s the itching that kept me in the light sleep stages, or if it’s just my body’s state of inflammation.

I’ve also had a chance to try out some sleep monitoring apps with 2 other skin friends, I only tried it recently when I’m sleeping normally, but they’re still in the midst of it and their results are vastly different from mine. While I had a normal sleep cycle, they hardly reach the deep sleep stage. Also, they are sleeping much more than I do, but still feeling tired. Something is amiss here.

However, the sleep monitoring app correlates movements to the state of your sleep, so it may be less accurate for our case because I know we will scratch a lot during our sleep, and this doesn’t necessarily mean we’re NOT in the deep sleep stage.

Despite the possible inaccuracy, it gives us a possible view into our body by observing our sleep. Assume the app data to be valid, then this would very much explain for their crazy sleeping (and fatigue)!

If IL-6 decreases slow wave sleep, it doesn’t matter how much longer you spend in NREM due to the increase in IL-1, if you’re not in stage 3 of the NREM, you’re not getting quality rest. And the paper suggested that fatigue is brought about by the decrease in slow wave sleep, which may be why my friends sleep so endlessly because the body is making up for the lack of quality sleep by quantity!

So it’s reasonable to attribute fatigue to our withdrawals, not only are we using a lot of energy to regenerate skin cells and to maintain our body temperature (as we’re giving off so much heat to the surrounding), we’re not getting the rest that we need.

There was one question that popped up when I was reading all these papers. If increase in IL-1 increases NREM sleep time (which should mean you get more stage 3 rest assuming the percentage time spent in each stage doesn’t shift), and the increase in IL-6 decreases slow wave sleep, why is the overall effect of fatigue more prominent? Shouldn’t the shifts cancel each other out?

I think I found my answer when reading the first set of paper.


Image taken from the paper. A) IL-1 beta levels, B) IL-6 levels, D) IL-10 levels. The coloured lines are added by me to indication increments/reduction between the different groups. Pink/red is for normal mice, while blue/green is for psoriatic mice.

Recall this part of the paper, where sleep deprivation will increase the levels of proinflammatory cytokines. The increment of IL-6 is almost twice that of IL-1! I was too fixed on the idea that when they increase, they all increase equally. I was wrong. And the symptoms that I observe are in fact the net effect of the actions of the different cytokines! And who’s to say that each unit of the cytokines will exert the same effect on our system? Perhaps, they all illicit different magnitudes of response, which just makes things more complicated.

I can sleep in peace now. One more question off my mind. Now, I’m going to ponder about the mystery of the universe. (this question puts me to sleep everytime).

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[special post] how does inflammation affect sleep

this is part 2 of the sleep series. i’ve wrote about how sleep may possibly affect TSW symptoms a few weeks ago, today i share 2 papers that talk about how the immune system affects sleep.

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The Role of Cytokines in Sleep Regulation

James M. Krueger*

Sleep and Performance Research Center, College of Veterinary Medicine, Washington State

University, Pullman, WA 99164-6520, USA

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In summary:

this paper discusses the positive effects of interleukin-1 beta (IL1) and tumor necrosis factor alpha (TNF) (amongst the other sleep regulating substances) on non-rapid eye movement sleep during normal and inflammatory conditions. the mechanism of how they affect sleep is also proposed, but the author acknowledges that the entire mechanism responsible for sleep regulation may be beyond our current findings and understandings.

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Point 1______________________________

Many of the variables that affect sleep have been linked to hormonal and humoral mechanisms. These mechanisms are often linked to each other in biochemical cascades and feedback loops and link sleep to multiple other physiological and mental processes. … The regulatory output is an emergent property of the entire system. … Similarly, sleep disorders occurring during pathologies likely result from the disproportionate stimulation of one or more of the humoral/hormonal mechanisms.

I have always seen our body as a complex machine that contains thousands of processes within. Each output is not merely a result from one single process, but rather, a combination of many. The inputs might not be singular too, which makes it even harder to pin point a certain factor which may affect the end result, in this case, it’s sleep.

Because everything works in harmony to give rise to the symptoms that we may observe, it’s quite futile to state how one variable alone will affect the state of the health. The body is a system, and everything is in a fine balance. Once you tip the balance, you get a weird symptom. Perhaps that’s also the reason why it’s harder than you think to maintain good health, because it is not on the extreme ends of the scale – It’s in the centre. Too much or too little of something isn’t good for you. And the notion of “moderation” is not that clear and distinct, and differs from person to person. Before we discover our personal “sweet spot”, we’d always be hovering above or below the optimum level, and that means a deviation from good health.

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Point 2______________________________

However, it is not possible to isolate sleep as the independent variable because most, if not all, physiological parameters change with sleep. As a consequence, investigators have developed lists of criteria to be met before a substance is considered a sleep regulatory substance. Criteria common to these lists are:
a) The substance if injected should enhance sleep.
b) If inhibited, sleep should be reduced.
c) The level of the substance should vary in brain with sleep propensity.
d) The substance should act on sleep regulatory circuits.
e) The substance should be altered in pathological states associated with enhanced sleepiness.

All of these criteria have been met by IL1, TNF, growth hormone releasing hormone (GHRH), adenosine, and prostaglandin D2 for non-rapid eye movement sleep (NREMS) regulation.

For rapid eye movement sleep (REMS) regulation, prolactin, NO, and vasoactive intestinal polypeptide also meet these requirements.

The definition of a sleep regulatory substance (SRS) is mainly defined by the criteria set by investigators. I think it’s more than sufficient to understand just point a and b. The presence of SRS will enhance sleep, and the lack there of leads to reduced sleep.

Non-rapid eye movement sleep consist of 3 stages, and as the name suggest, there is no rapid eye movements. Stage 3 is the deepest of them all where your brain does most of the resting. rapid eye movement sleep is light sleep (where you have a lot of dreams). Remember that our body is a balance, so all the chemicals and cells named as SRS are in fact in a balance to give you a normal sleep cycle.

When they are not balanced, we get funky sleep. I know that there are some of you who gets insomnia (which is seemingly unrelated to today’s topic on sleep, but it’s still somewhat related to our body. Not sure if anyone is interested at all.), and there are some who sleeps too much and still feel tired, and it maybe just me who have too many dreams when I do fall asleep back then.

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Point 3______________________________

Conditions that enhance endogenous production of IL1 or TNF, e.g., excessive food intake or infectious disease, promote NREMS.

So it seems like food coma goes beyond the common belief of “the stomach drawing blood away from the brain”. And this also gives me a hint of idea why there may be a link between itching and eating. Excessive food intake increases the IL1 production! And IL1 is a pro inflammatory cytokine, which means.. pronounced inflammatory actions such as itching and swelling.

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Point 4______________________________

Both IL1 mRNA and TNF mRNA increase in the brain during sleep deprivation.

The messenger RNA (things that decrypt DNA into readable information by our cells to produce the respective proteins) of IL1 and TNF are increased during sleep deprivation. More messengers to pass the production notice, factory produces more inflammatory IL1 and TNF as a result. It points back to how lack of sleep will increase inflammatory responses.

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Point 5______________________________

TNF is elevated in patients with chronic fatigue syndrome, chronic insomniac patients…

Why am I not surprised. I’m not sure which is the cause and effect though, since they sleep and TNF affects each other both ways. Chronic fatigue probably means not getting good sleep, the lack of sleep will raise pro-inflammatory cytokines. Nothing new here. Same goes for people who has insomnia.

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Point 6______________________________

There are also several findings showing that cerebral blood flow during sleep is enhanced in those areas disproportionately stimulated during prior waking.

Totally unrelated to TSW and inflammation, but I find this interesting because there’s a phrase in Chinese that says 日有所思, 夜有所夢 (if you think about it in the day, you will dream about it at night), now it’s backed up by scientific evidence!

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How (and why) the immune system makes us sleep

Luca Imeri and Mark R. Opp

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In summary:

this paper investigates the possible mechanism that can explain for why the body makes us sleep more when it’s dealing with an infection. they attributed it to the immune signalling molecules are amplified during an infection.

DISCLAIMER: TSW is NOT an infection, but as i suspect that our body is highly inflammed during TSW, i thought it’s suitable to look at how the inflammation (irregardless of the cause) will affect sleep.

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Point 1______________________________

Historically, it was widely thought that the only consequence of night time sleep loss was daytime sleepiness resulting in cognitive impairment.
We now have compelling evidence that, in addition to cognitive impairment, sleep loss is associated with a wide range of detrimental consequences, with tremendous public-health ramifications. For example, short periods of sleep loss at the time of vaccination reduce the vaccine’s effectiveness. Sleep loss is associated with increased obesity and with reduced levels of leptin and increased levels of ghrelin, the combination of which increases appetite. Sleep loss is also associated with diabetes and impaired glucose tolerance in a dose-related manner: individuals that report sleeping less than 6 h per night are ~1.7 times as likely, and those that report sleeping less than 5 h per night are ~2.5 times as likely, to have diabetes than individuals that obtain 7 h of sleep. Cardiovascular disease and hypertension are also associated with sleep loss: the risk of a fatal heart attack increases 45% in individuals who chronically sleep 5 h per night or less. Collectively, these examples demonstrate wide-ranging consequences of sleep loss on physical health. Obesity, diabetes and cardiovascular disease are pathologies that are characterized, in part, by inflammatory processes.

In summary, loss of sleep leads to more problems than we ever thought of, beyond feeling sleepy the next day, which will impair cognitive abilities. Long term sleep loss will increase your risk in getting obesity, diabetes, and cardiovascular diseases, which pretty much mean your metabolism system is out of whack, and you’re screwed. All in all, not getting sufficient sleep is equivalent to committing suicide slowly.

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Point 2______________________________

IL-1 and TNF increase non-REM (NREM) sleep in several species (rat, mouse, monkey, cat, rabbit and sheep) irrespective of the route of administration. NREM sleep that follows the administration of IL-1 or TNF has some characteristics of physiological sleep in the sense that it remains episodic and is easily reversible when the animal is stimulated. However, IL-1 generally causes fragmentation of NREM sleep. The magnitude and duration of IL-1’s effects on NREM sleep depend on the dose and time of administration: very high doses are NREM-sleep suppressive and, in rodents, IL-1 is more effective in increasing NREM sleep when it is administered before the dark phase of the light-dark cycle.

There are two types of sleep, the lighter stages also called the REM sleep, and the deeper stages where most of our cell’s restorative work takes place, it’s generally categorized as non-REM sleep. REM sleep is categorized by the episodes of dreams that we usually get during that stage of sleep.

In the animals tested, it was found that administration of IL-1 and TNF, both pro-inflammatory substances will increases NREM sleep. However, IL-1 will break up the duration of NREM sleep, instead of an undisturbed cycle of NREM sleep, it is now fragmented.

The effects of IL-1 are dose and time dependent, high doses suppresses NREM sleep (meaning more REM sleep), and it is most effective in increasing NREM sleep when administered before the sun goes down.

So now we see, if we increase IL-1 slightly, it’ll induce more NREM sleep, but too much of it will end up suppressing it.

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Point 3______________________________

In humans, IL-1 plasma levels are the highest at the onset of sleep.

Why do I itch more when I sleep? Is it because there’s nothing to distract me? Apparently.. it may be due to a surge in the pro-inflammatory cytokine. The “aha” moment.

Makes sense?

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The rest of the second paper was rather irrelevant to my interest so I gave up trying to make notes for it.

I was interested in reading up on sleep and the immune system because I found some anomalies between me and a few of my skin friends.

While I know that everyone is different, but I still felt curious about what could possibly  be happening in their body that could explain for the discrepancies. Personally, I suffered from insomnia a hell lot during TSW, but this two skin friends of mine were the opposite. They slept around the clock whenever they flared. It’s something I didn’t experience even when I was flaring back then. I get very fragmented sleep, like 3 hours of sleep before waking up for 2 hours and diving back for a few more hours of sleep.

Honestly speaking, I still have no idea what accounted for the difference between me and them. It may be the gender, because another skin friend of mine (who’s female) had insomnia just like me.

These papers talked about how the cytokines will increase NREM sleep, but NREM sleep is different from total sleep time. I can sleep for 8 hours but spent 50% of my time in NREM, while a person undergoing severe inflammation spends 70% of the 8 hours in NREM. This is not equivalent to me sleeping for 8 hours and my friends sleeping for more than 10 hours.

Maybe.. there’s more to it. 😛 After all, IL-1 and TNF is NOT the only proinflammatory cytokines in our body, neither are they the ONLY substance that will affect our sleep. Whatever I just discussed right now only offers a slit for me to observe the bigger problem. And just as what the first point in the first paper said, the things that we can physically observe are the emergent property of the entire system. Clearly, I’m missing something.

[special post] a peek into TSW and depression (and other stuff)

ever since the previous post on some of my hypothesis about the state of my skin, i’ve wanted to make more of those entries that are backed with scientific research, because.. who doesn’t like research, especially since you and i are so skeptical about everything ever since the entire topical steroid and eczema saga?

here goes.
i’ll raise some of the interesting points i’ve read from the scientific journal (they’ll be in quotes), and i’ll add on the translation (in italics) as well as some of my personal thoughts and even more hypothesis on that point.

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Glucocorticoid Dysregulations and Their Clinical Correlates: From Receptors to Therapeutics

Andrea H. Marques, Marni N. Silverman, and Esther M. Sternberg
Section on Neuroendocrine Immunology and Behavior, Integrative Neural Immune Program,
National Institute of Mental Health, National Institutes of Health, Rockville, Maryland, USA

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In summary:
There is evidence to show that the regulation of glucocorticoid might have an effect on depression. Glucocorticoid regulation includes the HPA axis, glucocorticoid hormone levels, factors that regulate local glucocorticoid availability and the glucocorticoid receptor functions. It has also been found that immune molecules (cytokines and interleukins) activates the HPA axis and alter brain function, including memory, cognition, and mood. The effects of cytokines induces sickness behaviours, which resembles depressive symptoms.

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POINT 1 ____________________________________________________

Cushing’s syndrome can also be triggered by prolonged and topical application of high doses of corticosteroids that can lead to hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Conversely, major depressive disorder (MDD) itself is associated with dysregulation of the HPA axis, although it is not clear whether the altered HPA axis function is primary or secondary to depression. Both exogenous use of high-dose steroids and endogenous excess of these hormones are associated with mood disorders or depressive symptomatology in some individuals… indeed, successful antidepressant treatment with reduction of depressive symptomatology is associated with resolution of impaired HPA axis function.

By correcting impaired HPA axis function, the depressive symptoms have been reduced, hence, There is a link between HPA axis dysregulation and the state of the mood.

Previously, I have attributed the feeling of depression I experienced during TSW to the lack of self-esteem, overall sadness of feeling out of control of my skin, and the pain and sufferings I experienced both physically and mentally. But now, there might be an additional reason to add to the list!

What if, during TSW (at least in the very initial stages), my HPA axis is indeed dysregulated (most probably down regulated by the years of steroid use, and then rapidly upregulated due to the sudden cessation of topical steroids, which led to a stable oscillatory recovery to normalcy over time. I’ll talk more about system control next time :D), thus contributing to the depression? if that’s the case, then the state of the mind might be used to determine the state of the body! BUT, with that said, the HPA axis will normalize within a few months, which is way shorter than the entire duration of time when i felt depressed. so.. yeap, the depression that i felt is most probably a mixture of many reasons.

POINT 2 ____________________________________________________

At a molecular level, polymorphisms in the human glucocorticoid receptor gene may be associated either with receptor hypo- or hyperfunction, which could contribute to differential individual sensitivity to the effects of glucocorticoid treatment. … Morever, changes in expression and stability of different glucocorticoid isoforms can be triggered by inflammation and have also been associated with mutations or polymorphism in the receptor.

A glucocorticoid receptor in layman’s term is the light bulb socket. The lightbulb (glucocorticoid) will fit snugly into the socket and light up (glucocorticoid doing what it should, producing anti-inflammatory effects).

A polymorphism is like a foreign factory worker that creates these lamps based on a given set of instructions written in a language that he didn’t know better. there are three different correct interpretation to the gene if read in different ways. the optimal scenario is when he installs 2 sockets into the lamp. sometimes, he installs three sockets, sometimes just one. So one lamp is brighter (hyperfunction) while the other is dimmer (hypofunction). Get it? Some cells react better to glucocorticoids while some react less well.

Which got me thinking, what if the use of topical steroids
1) increased the cortisol level in my body so much, to counter it, the body try to blunts the sensitivity of the glucocorticoid receptors? To achieve that, they’ll have to change their protein structure by deliberate changing the expression of the DNA. i don’t think the DNA actually mutates, but the decryption of said DNA might have changed due to mutation, meaning, if the source code 123 will produce ABC initially, after mutation, 123 will now produce DEF.
2) changes it’s architecture by some salt/ionic influence (after all, it’s a protein, and the shape of protein will affect it’s affinity to its relevant molecule), therefore reducing its sensitivity towards glucocorticoids.
3) down regulates the gene that makes glucocorticoid receptor proteins by some unknown mechanism.
4) inflammation causing mutation to the glucocorticoid receptor!?

The direct implication of the modification of glucocorticoid receptor (in our case, it’s most probably the hypofunction, meaning it’s not binding to glucocorticoids correctly) is increased inflammation, resulting in a loss of effect of glucocorticoids because it’s not binding appropriately to inflamed areas. Makes sense?

It has been shown over in research that prolonged usage of topical steroids will lead to systemic absorption of said steroids. Only god knows if such excessive quantities will result in changes in the sensitivity of our glucocorticoid receptors. By which method do the steroids change the receptors? I do not know.

I’m not ready to join professor X and his school yet. My special power to shed skin like a snake is already gone.

POINT 3 ____________________________________________________

Immune molecules, such as interleukins and cytokines, activate the HPA axis, with the resultant release of glucocorticoids, which in turn modulates the immune response. In addition, cytokines can alter local glucocorticoid availability and glucocorticoid receptor function, therefore affecting an individual’s glucocorticoid sensitivity.

In order for glucocorticoids to exert their effects, they diffuse across the cell membrane and bind to cytosolic receptors. Only unbound glucocorticoids are capable of diffusing across the membrane. However, 90% of circulating glucocorticoids are bound to CBG. … reduced level of plasma CBG have also been found during various inflammatory conditions.

In addition, the enzyme 11β-HSD regulates glucocorticoid availability by acting as a shuttle in the conversion of glucocorticoids between its active and inactive forms. There are two isoforms of this enzyme. 11β-HSD-1 acts mainly as a reductase, converting inactive glucocorticoids (cortisone) to active glucocorticoids (cortisol), whereas 11β-HSD-2 acts as an oxidase/dehydrogenase to convert glucocorticoids from an active (cortisol) to inactive form (cortisone). Pro-inflammatory cytokines…have been shown to upregulate 11β-HSD-1 or downregulate 11β-HSD-2 expression/activity, favouring the formation of active glucocorticoids and counterbalancing inflammation. However, enhanced expression of 11β-HSD-2 or reduced expression of 11β-HSD-1 in immune cells would lead to reduced local levels of glucocorticoid, thereby favouring a pro-inflammatory cytokine profile. This condition has been demonstrated in autoimmune patients and could be another possible mechanism underlying glucocorticoid resistance in such diseases.

The body senses inflammation -> hypothalamus in the brain sends a signal to the pituitary gland that sends another signal to the adrenal gland to produce some cortisol to tame inflammation. This is the gist of the HPA axis.

Cortisol up regulates anti-inflammatory cytokines and/or inhibits  pro-inflammatory cytokines.

Moving on to the availability of glucocorticoids, what is produced does not equate to the amount of cortisol that reaches the target cell. For the glucocorticoids to have an effect, it must first pass through the cell membrane, and only single cortisol can pass through. It’s as though the bouncer of a club will screen the cortisol for a partner before he allows it into the area to bind with the receptor. HAHAHAHA what an analogy.

If the cortisol is already bound to something else, it can’t reach the target cell! During inflammation, CBG levels are lowered -> lesser cortisol is bound -> more cortisol is able to enter target cell.

So, if inflammatory conditions promote the entrance of corticorticoids into the cell, why is it not having the expected anti-inflammatory effect?

I can only say .. One does not simply walk to Mordor.

It appears there are enzymes that will devour the glucocorticoids. If you read the above excerpt from the paper and got confused (like I did), I’ll make your life easier by just calling them 1 and 2. 1 activates cortisone to cortisol, while 2 deactivates cortisol to cortisone. Under normal circumstances, inflammation markers will increase the amount of 1 (mostly residing in the liver, lung, adipose tissue and brain), while decreasing the amount of 2 (expressed in kidney, colon, and sweat glands) to favour the formation of cortisol to reduce inflammation.

But due to some strange event, the expression of 2 seems to be enhanced in immune patients (and most likely in us too, if you were to read this entry written by dr Fukaya, explaining a possible mechanism of such tendencies). When enzyme 2 is at work, it converts cortisol to its inactive form, leading to a lower LOCAL level of active cortisol, which favours the production of pro inflammatory cytokines (since cortisol inhibits them, the lack of cortisol would mean there is nothing to stop its increase). This is the only logical reason that I could use to explain why does the skin continues to be inflamed despite a normal serum cortisol level.

I have always wondered the relationship between adrenal functions and the state of the skin. Many people have reported about adrenal fatigue, but I remember reading somewhere that blood cortisol levels and adrenal readings of TSW patients are normal (did I see someone report his test result in the ITSAN forum? I really can’t remember. If you happen to know, do correct me, for my memory is faulty, and this piece of memory went against my hypothesis that we’re all having too low a cortisol level, that’s why our skin is constantly inflamed).

However, I believe I can now construct a new hypothesis. The action of glucocorticoid have on a cell is determined by 2 factors – whether or not it reaches the final destination, and whether it is able to fit into the socket appropriately. For all I know, our adrenal gland is diligently producing enough cortisol, but some of the cortisol could not resist CBG, so they can’t enter the cell. While those who managed to remain single gets devoured by enzyme 2. If there are still any remaining cortisol left by that, it will realize that the socket no longer fits perfectly, or the number of sockets are way lesser than usual.

This is such a sad story.

POINT 4 ____________________________________________________

Cytokines have been shown to induce a constellation of symptoms referred to as the “sickness behaviour”, which has many overlapping features with depression (lethargy, somnolence, fatigue, anhedonia, decreased appetite and locomotion, and cognitive deficits). … Conversely, cytokine antagonists or knockout mice have been found to block these behavioural changes in rodents and reduce depression and fatigue in patients with autoimmune or inflammatory disorders.

… only a percentage of patients with depression exhibit increased levels of pro-inflammatory cytokines. The presence of inflammation and elevated cytokines could be a risk factor contributing to the development of depressive symptomatology in patients treated with high doses of glucocorticoids.

Continuing from the sad story of the cortisol not being able to fit into the socket to exert its power to inhibit pro-inflammatory cytokines and promote the production of anti-inflammatory cytokines, the result is obvious: INFLAMMATION.

The excessive cytokines that are present will then induce some behaviours that you and I are all very familiar with.

Lethargy, excessive sleeping, tiredness despite sleeping excessively (or normally), inability to enjoy activities that used to be pleasurable, decreased appetite and movement.. and.. retardation in the mental processes.

I guess I can blame my bad results on TSW. And you guys can blame your lethargy and crazy sleeping on TSW too. OK, if not TSW, just blame it on the inflammation, that’s a more general statement that will apply to more people. ;P

The last bullet point is saying, if one is already treated with high doses of glucocorticoids, there is a higher possibility that the cytokines levels are elevated (due to factors mentioned earlier), and it may lead to the development of depressive behaviours.

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as this paper is talking most about the relationship between HPA axis dysregulation and clinical depression, it appears to me that the paper try to make it sound like inflammation will cause depression. i’m not in any stand to refute that, but i just want to inform you guys that i’m merely drawing the points that are relevant to our skin condition and presenting them to you. there are a lot more information in the paper, you can read it by clicking on the link!

my original plan was to digest all 20 papers (i admit i bloated that figure up :X) that i’ve downloaded before coming up with something coherent, but i realize that by the time i went on to the second paper, i already forgot what i noted down for the first paper and could hardly follow that train of thought. plus, that would have taken me a few more months before i can present to you my findings, which would have felt like another final year project to me.

instead, presenting these papers in bite size chunks seems more beneficial for everyone! i wouldn’t want you to get indigestion like i did 😛

as i share more papers with you all, you’ll see how everything ties in together to show you the complexity of our immune system and our skin. it is seriously so difficult to try to pin point specific causes or factors because everything is so inter-related. the cause of a problem might be the result of another problem, it’s almost never-ending.

the best thing to do is to actually.. stop thinking.
but for those of you who would like to have an answer to help explain certain things, i hope this helped in some way or another.