Kicking Up A (cytokine) Storm

The New Year brings with it many new possibilities, including, unfortunately a new flu season.

So far, the number of flu cases in 2012 is down, thanks largely to the unprecedented mild weather over most of the US. A sharp contrast to 2009 when H1N1 (or swine flu) killed more than 18,000 people worldwide or 1918 when the flu virus infected around a third of the world’s population and killed at least 50 million people.

New research shows that the reason so many people died in both of those years wasn’t the influenza virus itself, but the immune system’s reaction to it.  It turns out that the virus destroys its host by turning the body’s own defenses against itself.

“While trying to destroy flu-infected cells, your immune system also destroys legions of perfectly healthy cells all over your body. This is why, even though the virus itself rarely ventures outside the lungs, the symptoms of the flu are so widespread” says , Michael Oldstone, a virologist at the Scripps Research Institute in La Jolla, Calif.

Most of the time this immune response isn’t too severe. As the virus runs its course, the response subsides. But in some cases, an infection can trigger a reaction so destructive it can be fatal. Scientists call this a cytokine storm, because of the violent way immune cells respond to a virus. Cytokines usually help fight off infections by telling the immune system which specific viral cells it should be attacking, but sometimes an overabundance of cytokines floods into a part of the body, and that’s when you get a storm.

Cytokine storms are rare, but they may be more common among younger people because they have stronger immune systems, and are more prone to overreactions. This may explain one of the more surprising outcomes of the 2009 swine flu: that it was deadlier among young people than it was among the elderly.

Cytokine storms can cause serious damage throughout the body, especially in the lungs, which is why most flu deaths are attributed to pneumonia.

After 5 years of research, Oldstone and his colleagues have identified a cell — they call S1P1 – that responds to cytokines. More importantly they’ve also figured out how to turn off that cell’s signals. This could pave the way for a new class of immune-reaction-blocking drugs that could provide protection against cytokine storms and be more effective than antiviral drugs.

Cytokine-blocking drugs could target the flu effects that cause the most damage to the body and would avoid the problems of virus mutation because they don’t affect the virus itself.

Still, it will probably be many years before those drugs reach your local pharmacy. Although preliminary experiments in mice have shown very promising results they still have to replicate these in ferrets, then primates and finally, humans.

Do you have any flu stories to share? SRxA’s Word on Health would love to hear from you.

The skinny on blood transfusions: a modern day miracle?

Most of us have read the biblical accounts of water being turned into wine.  Now Canadian scientists have discovered how to turn skin into blood.  This miraculous breakthrough could revolutionize cancer treatments and solve the blood donor shortage.

What is more because the blood is made from the patient’s own cells, there is no danger of either rejection or infection.

The team from McMaster University, Ontario say that the process has been so successful that treatment could be available within two years.

Dr Mick Bhatia who headed the team said “People will effectively become their own donors. We are very excited and very enthusiastic about it. There is a lot of work to be done but I would be disappointed if we were not trying it on patients by 2012.”

The research, published in Nature, is part of ongoing attempts across the world to revert adult cells back to their original stem cell form. Stem cells are “master cells” which can potentially be manipulated in a laboratory to become any other cell in the body.

Human Skin Cells

What’s unique about this process is that it misses out the “in-between” stage of turning the skin cells back to stem cells and then converting them to blood cells. Instead, the cell is reprogrammed directly by inserting a specific transcription factor – a protein that interacts with DNA to activate genes – and applying cytokines or signaling molecules.

The result – within a month the skin is converted to blood.

Leukemia patients are likely to be the first to receive transfusions of perfectly matched blood generated from their own skin. In future, laboratory manufactured blood could help to plug the gap caused by donor shortages. The technique also holds out the promise of making other kinds of cell, including neurons with the potential to treat brain diseases such as Parkinson’s and Alzheimer’s.

Skin cells from both young and old people were used in the research to prove that age of donor made no difference to the process.

Next the team plans to assess what kind of production capacity might be possible with the cells, and whether they can successfully be stored in deep freeze.

As always, SRxA’s Word on Health will be watching these developments and bringing them straight to you.

Pac-Man Physiology

Yes, I admit it.  This Word on Health blogger has probably been spending way too much time recently think about blood cells. In the last week alone I have been re-learning basic anatomy and physiology as part of my paramedic course, providing training on infection control and cellular immunity to new emergency services recruits and preparing presentations on blood and coagulation disorders for one of our favorite clients.

So, it’s probably not altogether surprising that a news story about the expanded role of macrophages caught my eye.

For most of our readers, I suspect that the term “macrophage” conjures images of a hungry white blood cell gobbling invading bacteria, in a manner reminiscent of  the 1980’s iconic Pac-man.

It emerges however, that macrophages do much more than that.  Not only do they act as antimicrobial warriors, they also play critical roles in immune regulation and wound-healing.   Additionally, they can respond to a variety of cellular signals and change their physiology in response to local cues.

“There has been a huge outpouring of research about host defense that has overshadowed the many diverse activities that these cells do all the time,” said Dr. David Mosser, Professor of Cell Biology and Molecular Genetics at the University of Maryland.  “We’d like to dispel the narrow notion most people have that macrophages’ only role is defense, and expand it to include their role in homeostasis.”

So what are macrophages?  Well, they exist in nearly all tissues and are produced when specialized white blood cells called monocytes leave the blood and differentiate in a tissue-specific manner. The type of macrophage that results from monocyte differentiation depends on the type(s) of cytokines that these cells encounter on their journey. Cytokines, for those not in the know, are proteins produced by immune cells that can influence cell behavior and affect interactions between cells.

For example, macrophages that battle microbial invaders appear in response to interferon-γ, a cytokine that is produced during a cellular immune response involving helper T-cells and the factors they produce. These macrophages are considered to be “classically activated.”

However, when monocytes differentiate in response to stimuli such as prostaglandins or glucocorticoids, the resulting macrophages will assume a “regulatory” phenotype.

Alternately, wound-healing macrophages arise when monocytes differentiate in response to interleukin-4, a cytokine which is released during tissue injury.

According to Dr. Mosser, macrophages can change their physiology and switch types. For example, in healthy, non-obese people, macrophages in fat tend to function as wound-healing macrophages. They are also thought to maintain insulin sensitivity in adipose cells. However, should an individual become obese, macrophages in fat will instead promote inflammation and cause the adipose cells to become resistant to insulin.  Similarly, immune-regulating macrophages produce high levels of the cytokine interleukin-10, which helps suppress the body’s immune response. Suppressing an immune response may seem counter-intuitive, but in the later stages of immunity it comes in handy because it limits inflammation.

According to Mosser, immune-regulating macrophages may hold the key to developing treatments for autoimmune diseases such as multiple sclerosis or rheumatoid arthritis. The focus of new research is on reprogramming the macrophages to assume a regulatory phenotype and prevent autoimmunity.

“It might be possible to manipulate macrophages to make better vaccines, prevent immunosuppression, or develop novel therapeutics that promote anti-inflammatory immune responses.”

All of which kind of leads me back to the Pac-man analogy. In the video arcade game, when all the initial dots are eaten, Pac-Man is taken to the next stage where he gets to take on other enemies.   Here, despite the seemingly random nature of the enemies movements, they are in fact strictly deterministic.  Exactly, the same it seems, as it is with macrophages.

Suddenly learning Anatomy and Physiology may get a whole load more interesting for those back-to-school teens!