Tag: inflammation

Glimpse of an elusive diagnostic biomarker for Chronic Fatigue Syndrome

April 23, 2013 / / 1 Comment

The clinical entity of Chronic Fatigue Syndrome1 (CFS) has so long eluded explanation. Patients of CFS complain of extreme and prolonged fatigue that is disproportionate to their physical and mental activity, and is not alleviated by any amount of rest. The condition may well last for more than 6 months at a time, and may be accompanied by a variety of other symptoms, such as pain in the muscles and/or joints without swelling, memory impairment, significant lapse of concentration, headaches, painful lymph nodes in the neck or armpit, and so forth. Physicians currently employ the 1994 case definition in which persistent (>6 months) fatigue is to be present along with at least 4 of 8 known associated symptoms, for the condition to qualify as CFS; if these criteria aren’t fully met, the condition is referred to as ‘idiopathic’ (without known cause) fatigue. Management of both conditions are practically identical.

For patients of CFS, the bouts can be debilitating, perhaps made worse by the fact that scientific research has not yet identified the root cause of the condition, and can, therefore, offer no solution beyond symptomatic relief.

Many theories as to the cause of CFS abound, such as:

  • Direct effect of viral infections;
  • Specific induction of host immunity as a result of invasion by some pathogenic microbe, et cetera.
  • Non-specific activation of the patients’ immune systems, a subset of which may be expressed as allergies;
  • Direct involvement of the central nervous system, resulting in abnormal, neurally-mediated lowering of blood pressure, which may cause light-headedness and compensatory tachycardia (i.e. increase in heart rate);
  • Indirect action of the brain, via the HPA (‘Hypothalamic-Pituitary-Adrenal’) axis, which may disturb the release of various stress-associated hormones.

In addition, symptoms in CFS may resemble those seen in many physiological, neurological, as well as psychological illnesses.

This, understandably, poses a diagnostic challenge; the problem is that all these phenomena in the human body are processed through physiological pathways that are highly inter-related, a fact which underscores the difficulty in arriving at a single factor responsible for CFS. Current thinking is, therefore, that CFS may be multi-factorial, i.e. triggered by a combination of an unknown number of factors.

In part, this is also the reason why there is no diagnostic test or ‘biomarker’ (an observable phenomenon that can be specifically attributed to the condition) for CFS, and why the diagnosis must be exclusionary, via a process of elimination of other possible conditions that may explain the symptoms. What makes diagnosis even more difficult – not to mention, controversial – is that the number, types and even severity of these symptoms are highly variable amongst patients, and the condition periodically goes into remission and relapses.

When symptoms arise, management – in absence of a cure – focuses on treating primarily those symptoms that disrupt life and activities most, such as pain, lack of sleep, memory problems, depression, anxiety, et cetera. Long term care involves specially-developed activity programs, behavioral therapy and other interventions that aim to mitigate the physiological and psychological effects of this chronic illness.

Given that many CFS symptoms mimic those of certain immune dysfunctions involving unregulated inflammation, a lot of research has focused on understanding the inflammatory pathophysiology of CFS patients. One recent study from the Stanford University medical school, published in the Journal of Translational Medicine2, investigated the role of cytokines in this condition. Cytokines are a group of small protein molecules produced and released by various types of cells in the body, including cells which comprise the immune system. Cytokines take part in cell-to-cell signaling; released by one type of cells, cytokines affect other cells, either in their immediate environment or elsewhere in the body, by binding to receptor molecules present on the surface of these cells. These receptors recognize specific cytokines, and the binding at the cell surface initiates cascades of sub-cellular (inside the cell) biochemical reactions which lead to a specific effect. For example, some cytokines are active in regulation of developmental processes3 during the implantation of the embryo and maintenance of pregnancy. Again, ‘pro-inflammatory’ cytokines, released by certain leukocytes of the innate immune system, can recruit other leukocytes and bring them to the site of infection or injury, in order to mediate various effects4.

The Stanford group, led by Elizabeth Stringer, hypothesized that the daily variability of the levels of various cytokines in the serum may correlate with the observed variations in the severity of CFS symptoms. In a pilot study they had monitored the daily levels of 51 different cytokines in 3 women with fibromyalgia (another chronic painful condition) and CFS, and discovered that one adipokine (cytokine released by fat cells, ‘adipocytes’), called Leptin, stood out. Leptin, which regulates appetite, metabolism and behavior5, and has profound inflammatory effects, as well as a protective role in mucosal immunity6, was found to correlate significantly with the self-reported fatigue severity.

In the current study, participants (CFS patients and healthy controls, all female) were chosen carefully to account for or exclude other existing conditions that may confound (i.e. not allow proper interpretation of) the observations. Twice a day, 20 participants answered questions about the severity of fatigue, muscle/joint pain and sleep quality that they experienced during the study period, which included blood draws for 25 consecutive days. In the CFS patients, serum Leptin levels correlated strongly with daily levels of fatigue; although Leptin levels were associated with a plethora of pro-inflammatory cytokines, no other direct correlation was found, indicating that Leptin may be the central player in the CFS-associated inflammatory process mediated by a network of cytokines. None of these associations were observed in healthy controls. Leptin levels were predictive of daily fatigue levels in women with CFS, and using cytokine predictors, the authors were able to distinguish between high fatigue and low fatigue days with 78% accuracy.

Leptin Fatigue Correlation
Illustrative image composite made from parts of Fig. 2 & 3 of Stringer et al. (Ref. 2)

Interestingly, absolute Leptin levels, as well as the range of daily fluctuations, were not abnormal in CFS patients, which suggests that Leptin alone may not be responsible for causing the inflammation in CFS. As the authors indicate, larger and more detailed studies are necessary to explore a causal role of Leptin and/or its cytokine network in driving CFS severity, and uncover hitherto elusive diagnostic biomarker(s) and therapeutic targets.

Further reading:

  1. CDC information website on Chronic Fatigue Syndrome.
  2. Stringer, EA, et al. Journal of Translational Medicine 2013, 11:93; doi:10.1186/1479-5876-11-93.
  3. Saito, S. Journal of Reproductive Immunology 2001, 52:15-33; PMID: 11600175
  4. Whitney, NP, et al. Journal of Neurochemistry 2009, 108:1343-59; PMCID: 2707502.
  5. Gautron L, Elmquist JK. Journal of Clinical Investigation 2011, 121:2087-93; PMCID: 3104762.
  6. Mackey-Lawrence NM, Petri WA Jr. Mucosal Immunology 2012, 5:472-9; PMCID: 3425733.

Diabetes and Chronic Inflammation – connecting the dots, Part Deux

September 13, 2012 / / 2 Comments

ResearchBlogging.org

In the FIRST POST of this two part series, I laid out some facts about Type 2 diabetes which results from insulin resistance, and indicated how non-esterified (‘Free’) Fatty Acids (FFAs) induce chronic inflammation via engagement of TLR4 and the NF-κB pathway, eventually leading to Insulin resistance – and yet, since FFA doesn’t bind TLR4, it’s not known how the twain meets. The elegant set of studies described in the Pal at al. paper in the July 29, 2012 issue of Nature Medicine [1] provides evidence for a mechanism hypothesized to be active in lipid-induced insulin resistance, i.e., one that can connect the dots.

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Diabetes and Chronic Inflammation – connecting the dots, Part Un

September 13, 2012 / / 4 Comments

Nature Medicine has recently featured studies dealing with obesity-related insulin resistance which leads to a type of diabetes, called Type 2 diabetes. Of these papers, one by Pal et al. (Nature Medicine, 18(8):1284, August 2012) highlights some specific aspects of the disease, including prospects for future therapeutics. I found it interesting – for various reasons* – enough to spur me to write about diabetes in the context of their observations. I shall make it a 2-part series; in the first post, I would talk a bit about diabetes in general, and follow it up with a review of the main findings of their elegant studies. (Full disclosure: I have parents and grandparents who are/were diabetic.)

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Part 2 of 2: Inflammation and Exercise: friend or foe?

August 25, 2011 / / 1 Comment

ResearchBlogging.org
As I mentioned in Part 1 of this two-part post, inflammation is a two-edged sword, requiring a fine balance between initiation and termination, in order to promote health and not disease.

With this idea in mind, I came across a recent review article by Gleeson et al. in Nature Reviews Immunology, which focuses on the anti-inflammatory effects of exercise and its implications in health and disease.1

The authors observed that pathogenesis of various conditions associated with many metabolic and other diseases (such as diabetes, cardiovascular disease, certain cancers, dementia and so forth) have been shown to be dependent on the interplay of metabolic and immune processes, and appear to be associated with inflammation. Exercise, or high physical activity, is known to protect against the development of many of these conditions, and therefore, may have anti-inflammatory properties. The authors reviewed the existing literature to seek the evidence for that hypothesis.

The authors compiled a list of several possible mechanisms by which exercise exerts its anti-inflammatory effect. This includes:

  1. A reduction in visceral fat mass – this exerts an indirect effect to decrease inflammation, since accumulation of fat in the omentum, liver and muscles, as well as the expansion of adipose tissue, results in enhanced production of certain inflammatory mediators (such as TNF, Leptin, IL6, CCL2/MCP1, CCL5/RANTES etc.) and consequent reduction of anti-inflammatory cytokines (such as Adiponectin). An obese body lives in a persistent state of low-grade systemic inflammation, and therefore, fat-loss through exercise has an anti-inflammatory effect.
     

  2. Release of IL6 from working muscles – A fall in muscle glycogen content with exercise signals the muscles to secrete IL6, keeping the concentration of this pro-inflammatory cytokine high for the duration of the exercise. This rise in circulating IL6 appears to start off a cascade in which certain anti-inflammatory cytokines (IL10, IL-1RA) are elevated and exert their direct and indirect effects to minimize inflammation induced tissue damage. However, elevation of IL6 is dependent upon the duration of activity, and a significant increase requires 2 and a half hour of more of strenuous exercise.
     

  3. Increased levels of circulating cortisol and adrenaline – IL6 stimulates the release of the stress hormone, cortisol, from adrenal glands. Besides, exercise itself activates the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, thereby signaling the production of more cortisol and adrenaline from the adrenal gland, as well as adrenaline/noradrenaline from the adrenal medulla, for the duration of the exercise. Cortisol and the catecholamines (adrenaline and noradrenaline) are both known to have potent anti-inflammatory effects.
     

The authors also discussed a few other possibilities that don’t have enough evidence yet – such as exercise may (a) reduce the influx of macrophages (histiocytic inflammation) into adipose tissue, (b) prevent the adhesion of inflammatory cell to the inner wall (endothelium) of blood vessels, by reducing the expression of a surface molecule called ICAM-1, © attenuate the number of pro-inflammatory mononuclear leukocytes (monocytes) in the total blood pool; and so forth.

What first caught my attention was the authors’ surmise that exercise could reduce (downregulate) the surface expression of a set of receptor molecules (the TLRs) that are very important in the detection of and host response to microbial pathogens. Blood monocytes from physically active individuals had decreased TLR4 expression, and following an acute, prolonged bout of strenuous exercise, the expression of TLR1, TLR2 and TLR4 on monocytes was decreased for at least several hours. The reduction in TLR expression has been associated with decreased inflammatory cytokine production.
But this doesn’t augur well, since TLR1, TLR2 and TLR4 represent major mechanisms by which immune cells detect bacterial and fungal pathogens. Indeed, towards the end of the review, the authors comment on the repeated observation that “the long hours of hard training that elite athletes undertake appear to make them more susceptible to upper respiratory tract infections”. In addition, the anti-inflammatory cytokine IL10, produced copiously during extensive exercise, limits the effectiveness of pathogen-specific innate and adaptive immune responses.

Therefore, at the conclusion of the article, I was left unsure as to the benefits of exercise as propounded by the authors, especially from an anti-inflammatory mechanistic viewpoint. However, it must be said that much of the above-mentioned evidence of the anti-inflammatory (and thereby, beneficial) effect of exercise is circumstantial, judging by the indirect nature of many of the effects, as well as the dependence of the said effects on intensity and duration of the exercise. Neither the interplay between pro- and anti-inflammatory cytokines, nor their relative dynamics, appear to be well-understood in the context of exercise.

For example, in this review, the authors have not touched upon the conflicting evidence that during exercise, contracting muscles give rise to localized inflammatory responses through synthesis of pro-inflammatory cytokines IL1β, TNF and IL6, whose levels are not transitory but remain high for days. There is also evidence that the pro-inflammatory cytokines may mediate muscle growth, as well as muscle repair following injury; in fact, IL6 has been identified as an essential regulator of hypertropic muscle growth2 via satellite cells (muscle stem cells) which are also involved in skeletal and cardiac muscle repair.3 Therefore, suppression of IL6 in the long term (as hypothesized in the anti-inflammatory model) cannot be beneficial to the host as a whole. The hypothesis of omental and muscle fat leading to a beneficial reduction of Adiponectin1 is also suspect, since the absence of Adiponectin expression causes contractile dysfunction and phenotypical changes in skeletal muscle.4 There also appears to be a strong relationship between exhaustive exercise, such as marathon running, and chronic low-grade inflammation induced by the massive systemic release of several pro-inflammatory cytokines and chemokines, such as IL6, IL8, G-CSF, M-CSF and MCP1 (which mediate recruitment and activation of inflammatory effector cells, neutrophils and monocytes), although host tissue damage may be restricted by compensatory mechanisms.5

In conclusion, benefits of regular exercise and physical activity are well observed. But perhaps it is best not to draw, yet, all-encompassing mechanistic conclusions involving inflammatory processes, because inflammation is a highly complex process fine-regulated by many factors; it may indeed not be possible to consider all those factors properly in context. Different types and intensities of physical exercise may well stimulate or suppress certain inflammatory processes, but their exact nature and consequences seem far from understood.

References:

1. Gleeson, M., Bishop, N., Stensel, D., Lindley, M., Mastana, S., & Nimmo, M. (2011). The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease Nature Reviews Immunology, 11 (9), 607-615 DOI: 10.1038/nri3041

2. Serrano AL, Baeza-Raja B, Perdiguero E, Jardí M, & Muñoz-Cánoves P (2008). Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell metabolism, 7 (1), 33-44 PMID: 18177723

3. Grounds MD, White JD, Rosenthal N, & Bogoyevitch MA (2002). The role of stem cells in skeletal and cardiac muscle repair. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society, 50 (5), 589-610 PMID: 11967271

4. Krause MP, Liu Y, Vu V, Chan L, Xu A, Riddell MC, Sweeney G, & Hawke TJ (2008). Adiponectin is expressed by skeletal muscle fibers and influences muscle phenotype and function. American journal of physiology. Cell physiology, 295 (1) PMID: 18463233

5. Suzuki K, Nakaji S, Yamada M, Liu Q, Kurakake S, Okamura N, Kumae T, Umeda T, & Sugawara K (2003). Impact of a competitive marathon race on systemic cytokine and neutrophil responses. Medicine and science in sports and exercise, 35 (2), 348-55 PMID: 12569227

Part 1 of 2: Inflammation: A two edged sword

August 25, 2011 / / 0 Comments

ResearchBlogging.org
Inflammatory mechanisms are very important for the innate defence system of the body. When the host body encounters stimuli it perceives as harmful, such as pathogens and/or products thereof, injured cells or tissue, or any foreign object that irritates the surrounding tissue, the host often responds with a complex generalized response. A part of this response involves vascular tissues, leading to increased translocation of circulating white blood cells (WBC or leukocytes), especially the granule-containing cells (such as neutrophils) and mononuclear cells (such as monocytes), as well as plasma (containing necessary proteins, such as fibrin, complements, and immunoglobulins, a.k.a. antibodies), from blood to the area of injury. This process is known as inflammation.

There are many players in this, including immune defense cells already resident in the tissue; they secrete certain biochemical mediators (e.g. ‘cytokines’, ‘chemokines’, ‘prostaglandins’ and so forth), that initiate various biochemical events and act as beacons for the migrating leukocytes to home in on. The first batch of leukocytes would themselves secrete more of such mediators, in order to call in reinforcements. This is how the inflammatory response matures, involving the local vascular system, the immune system, and various cells at the site of injury.

What do these inflammatory immune cells do? These cells, now called ‘Effectors’, are able to kill the offending pathogens, destroy the remnants of injured cells or tissue, break down or bury the foreign object, so that the healing process can begin. Several non-cellular processes, associated with the plasma proteins, help inititate and propagate this inflammatory process, also taking part in healing.

Inflammation can be classified temporally as (a) acute – a short term process that often initiates within minutes or hours following injury and subsides upon resolution of the injury, or (b) chronic – a prolonged process in which inflammatory cells may progressively shift to the site of injury even after the deleterious stimulus is gone, causing persistent destruction of tissue.

Superficial acute inflammation, such as on the skin, may be observed as a zone of redness, hot to touch, prone to swelling, and often, tender. This is what happens after, say, an insect bite, frostbite, skin contact with plants such as Poison Ivy, or immune reactions due to hypersensitivity to certain medicines (e.g. metronidazole, an antibiotic, causes me to break out in hives; some allergic responses can cause inflammation of the airways, leading to respiratory distress). However, inflammation can equally occur in internal organs, and may cause a pain sensation when it reaches those areas that contain nociceptors (pain-sensitive nerve endings). This is how various non-steroidal anti-inflammatory drugs work; they reduce pain by inhibiting various molecules that are responsible for inflammation.

Chronic inflammation, on the other hand, is considered responsible for a large variety of unrelated human diseases, ranging from immune system disorders that cause unmitigated, exuberant inflammation – such as observed in allergic reactions; inflammatory injury to muscles (myopathies) or to various organ systems (e.g. inflammatory bowel diseases, pelvic inflammatory disease, and glomerulonephritis); various autoimmune disorders, and so forth; to non-immune diseases, such as certain cancers, atherosclerosis and ischemic heart disease.

As a student of host-pathogen interaction, I encounter inflammation from that specific context, but the principle remains generalizable. This concept has been nicely laid out in the Damage Response Framework of Microbial Pathogenesis proposed by Casadevall and Pirofski in 2003.1 One of the mechanisms by which microbe-induced damage is caused to the host tissue is inflammation, i.e. immune-mediated damage. Virulence (i.e. the ability to cause disease) of various bacterial, fungal and parasitic pathogens is often paralleled by their ability to incite various profiles of inflammation. For example (all from Ref. 1),

  • The etiological agent of tuberculosis, Mycobacterium tuberculosis, is a pathogen that causes disease in two ways: in immunocompromised individuals (such as HIV+ people), the host doesn’t mount an adequate response. Interestingly, in immune-sufficient individuals, the damage is mediated by a robust inflammatory response that the host generates against the bug.
     
  • A mutant of everyone’s beloved yeast, Saccharomyces cerevisiae, that has altered surface properties capable of eliciting a strong inflammatory response, is virulent in mice.
     
  • Lung damage in AIDS patients from pneuomonia induced by Pneumocystis carinii is mediated largely by the residual immune system, which is likely why corticosteroid-induced specific suppression of inflammation leads to better outcomes in patients.
     
  • The mold pathogen, Aspergillus fumigatus, causes disease in individuals with weak or strong immunity, and in the latter, the disease takes the form of exuberant inflammatory response and hypersensitivity reactions to Aspergillus antigens.
     
  • Neurocysticercosis, a debilitating neurological disorder, occurs when the host mounts a strong inflammatory response to the worm parasite Taenia solium, even if the worm is dead.

Therefore, evidently, inflammation is a two-edged sword, requiring a fine balance between initiation and termination, in order to promote health and not disease.

Click here to continue to Part 2.

References:

1. Casadevall, A., & Pirofski, L. (2003). The damage-response framework of microbial pathogenesis Nature Reviews Microbiology, 1 (1), 17-24 DOI: 10.1038/nrmicro732

Additional Reading: The Wikipedia article on Inflammation is quite extensive and well-referenced.

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