All Posts tagged infection

Thirty years ago Maria de Sousa, then at the beginning of her career, noticed that lymphocytes were attracted to places with surplus of iron. This, together with

1- the fact that the vertebrate immune system (IS) was incredibly more complex that those of its ancestors (and evolution rarely increases complexity, which is energetically costly, unless something is gained)

2- the IS unique capacity to reach everywhere in the body

led her to a revolutionary new idea – could this new complexity be evolutionary sound, because it allowed the IS to perform some important new function, maybe protecting the body against iron toxicity?

In fact iron, although an essential element for most life forms, can also be toxic to these same organisms when free (not attached to proteins). This means that in this form it needs to be “watched” and regulated around the clock. In vertebrates, this is done through hepcidin, a liver protein that “moves” iron between cells and plasma according to the body needs (or potential dangers). The problem is that the hepcidin liver cells have limited mobility so a complementary far reaching iron control system was needed. Lymphocytes, with their unique capacity to move throughout the body were the perfect candidates and since 1978, de Sousa and her group have been chasing this idea.

Much of their work has been done on hemochromatosis – a disease where there are problems in the absorption of iron through the digestive track leading to too much iron in the organism and to its toxic accumulation in the organs.

From this work we know now that hemochromatosis patients also have a defective IS, and more, that their iron overload levels correlate with their lymphocyte deficiency – the less lymphocytes they have the more severe the disease. Work in animal models with iron overload problems or instead, with lymphocyte deficiencies have again found links between excess of iron in the body and deficient IS further supporting de Sousa's “immuno-iron idea”.

And meanwhile, human lymphocytes were shown to produce several proteins crucial for the regulation of iron levels – ferritin, which acts as the body storage of iron (so holding to it when there is too much in the body or releasing it when there is deficiency) and ferroportin, which is the cells' iron “exit door” (again releasing or retaining iron as necessary) . The fact that lymphocytes had both proteins gave them the potential to be a “mobile” and easily “mobilizable” iron-storage compartment, characteristics perfect for an important role in iron homeostasis.

Nevertheless, the exact mechanism how this could happen remained elusive

But hepcidin, the central piece of iron regulation, is known to be also an important player in the immune response what has raised the possibility that it could be in it the clue to this problem. In fact, during infection hepcidin shuts down the “door” through which iron leaves the cell (ferroportin) reducing iron availability in the plasma and thus helping to control infection – as bacteria need iron to divide. And now several studies have shown that hepcidin is produced by a variety of cells involved in the immune response. Finally, last year, a study suggested, for the first time, that lymphocytes were also capable of producing the protein putting the possibility that hepcidin could actually be “the missing link” of de Sousa's theory.

To clarify this hypothesis Jorge Pinto, Maria de Sousa and colleagues at the Institute for Molecular and Cell Biology (IBMC) of Porto University looked at hepcidin production in human lymphocytes in situations of toxic iron concentrations or immune activation, as de Sousa's theory proposed that lymphocytes could play a role in both situations. They found that hepcidin not only was produced by all classes of lymphocytes, but also that its production increased both in the presence of high quantities of iron, and when lymphocytes were activated, backing de Sousa's proposals.

Pinto explains: “We show, for the first time, that lymphocytes can “feel” the toxic levels of iron in circulation and respond by increasing their own capacity to retain it within, restoring “normality”. The same mechanism is seen being used in situations of (iron) demand, such as when the cells are activated by the occurrence of an infection and need to divide.”

They also found something else totally unexpected – that hepcidin was involved in this second mechanism, suggesting an even closer dependence between the two systems than de Sousa had thought.

To Hal Drakesmith, a researcher at the University of Oxford working on the possibility of manipulating iron transport as a way to combat infections such as HIV, malaria and Hepatitis C these results raise particularly interesting questions as he explains “This seems to suggest that control of iron metabolism may be an integral component of lymphocyte immunity. Withholding iron from pathogens is an accepted part of our defence against infection, but a role for lymphocytes in controlling iron transport has not been proposed before.

“Crucially – says Pinto – we still believe that the main regulator of systemic iron levels is the liver but not only are lymphocytes (and not liver cells) able to sense toxic forms of iron, but they are also able to travel and be activated in specific places where the pathogens accumulate helping to control infection. “

These results are a major step to understand the link between the IS and iron and, if confirmed in live organisms –all this work was done on human cells in the laboratory – can be the beginning of a totally different view of what the immune system is and how to approach immunologic problems.

As Hal Drakesmith says “the paper describes several new findings which are highly likely to be of interest and importance to the iron and immunity fields of research” A simple example is the anaemia that usually accompanies chronic inflammatory diseases and that so far can not be clearly explained. Pinto and Sousa's results suggest that lymphocyte chronic activation, so characteristic of these diseases, by leading to hepcidin production could be part of the phenomenon as iron is an integral part of red blood cells.

Pinto, de Sousa and colleagues now plan to go back to those diseases of iron overload associated to immune abnormalities and see if hepcidin proves to be, in fact, the connection between them. Other possibility is the construction of mice without the hepcidin gene in the bone marrow – where lymphocytes develop – to analyse the changes that this could bring to both iron homeostasis and the immune response.

Whatever happens this is a strikingly interesting story with decades of persistence and believe behind it and which, I am sure, still has much to tell us.

By Catarina Amorim

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Fat clue to TB awakening

The factors instrumental in triggering latent tuberculosis (TB) infection to progress into active disease have long remained elusive to researchers. New insight into the mystery is provided by Professor David Russell, speaking at the Society for General Microbiology's spring meeting in Edinburgh today. His work could help develop innovative strategies for treating the disease.

Professor Russell and his group at Cornell University in New York, USA, have demonstrated that TB-causing bacteria are able to hijack fat metabolism in the host to drive the progression of the disease. The team's research shows that Mycobacterium tuberculosis (Mtb) is able to stimulate macrophages – the immune cells the bacterium infects – to accumulate fat droplets, turning them into “foamy” cells. This cellular transformation can trigger a reawakening of the TB infection from its latent state.

Following initial infection by Mtb, the infected immune cells in the body can clump together in the lungs in a cellular mass that is surrounded by a fibrous cuff. This containing structure, called a
tubercle, physically protects the bacteria from being destroyed by the immune system. This allows them to persist inside the host for years during a latent period in which the host shows no symptoms. The respiratory infection is reactivated only in a small percentage of individuals (often those who are immunosuppressed) in whom it progressively destroys lung tissue. Very little is known about the exact causes of reactivation and the relative roles of the host and the pathogen.

Professor Russell's group discovered that inside the tubercle, surface molecules of Mtb prompted host macrophage cells to take up vast quantities of cholesterol-type lipids from the surrounding blood
vessels. “We think that the lipids in the newly-formed foamy cell are then expelled into the cellular environment, which contributes to the collapse of the tubercle,” he said.

Once freed from their containing structure, the infectious bacteria are able to leak out into the airways where they can progressively destroy lung tissue. “If our model is correct, it has huge implications for
vaccines and chemotherapy programmes. A more detailed knowledge of the bacterium's life cycle and its host interactions will allow us to spot new targets for drugs – opening up new possibilities for treatment,” said Professor Russell.

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General Information

Definition

Chronic Fatigue Syndrome (CFS) was originally defined in 1988 when the Center for Disease Control (CDC) in the US brought together a number of researchers who had been investigating a strange syndrome characterized by overwhelming fatigue. This definition however was reviewed by a panel of international experts in 1994 and subsequently revised.

CFS is very difficult to diagnose because the main symptom of fatigue is present in so many other illnesses. However, once other illnesses have been ruled out through laboratory tests and physical examination, a diagnosis of CFS may be given if the following criteria are met:

Clinically evaluated, unexplained persistent or relapsing chronic fatigue that is of new or definite onset (i.e., not lifelong), is not the result of ongoing exertion, is not substantially alleviated by rest, and results in substantial reduction in previous levels of occupational, educational, social, or personal activities.The concurrent occurrence of four or more of the following symptoms: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; muscle pain; multi-joint pain without swelling or redness; headaches of a new type, pattern, or severity; unrefreshing sleep; and post-exertional malaise lasting more than 24 hours. These symptoms must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue.

The full text of the revised definition can be found at the CDC website: http://www.cdc.gov/ncidod/diseases/cfs/about/definition/index.htm

Symptoms and General Information

Obviously, as is implied by the various names, fatigue is the major symptom in CFS. People often have the misconception that this is the only symptom and hence they assume that sufferers simply like to complain about the normal tiredness that everyone experiences after a day at work etc. CFS is actually much more than fatigue, and the fatigue experienced is a lot more severe than simple tiredness. The following is a list of the major symptoms of CFS.

  • Fatigue
    • Exercise Intolerance
    • Severe Malaise
    • Muscle and Joint Aches
    • Cognitive Dysfunction
    • Chronic Headache
    • Balance Disturbance
    • Recurrent Sore Throat
    • Mood and Sleep Disturbances
    • Abdominal Pain/Digestive Disturbances
    • Sensitivity to Light and/or Sound
    • Visual Disturbances
    • Skin Sensitivity

Possible Causes

The cause, or causes of ME/CFS are still not clear. There are a number of theories that have been proposed, the main ones propose the following factors as the cause or causes of the illness:

  • Viral Infection
  • Mycoplasma Infection
  • Immune or Endocrine Dysfunction
  • Autonomic Nervous System Dysfunction
  • Environmental Toxins
  • Genetic Factors
  • Candida Overgrowth
  • Gut Dysbiosis
  • Heavy Metal Sensitivity
  • Emotional Stress or Trauma

There may be a large number of abnormalities in multiple body systems in CFS patients. These abnormalities centre around the nervous, endocrine and immune systems and the way these interact with each other. Although these abnormalities have been identified it is still unclear which are causes and which are effects. New research will hopefully shed more light on this but until then doctors who are seeing the best results with patients seem to be those who take a multifactorial approach and try to correct as many of the abnormalities discussed as they possibly can, using currently available treatments.

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