T cells to the Rescue!

This looks like a job for the immune system!

Arggh!  November was hectic!  I haven’t abandoned you Omnimmune!  Sometimes getting a paper published takes precedence.  But I just came across this Time article with exciting news that Washington University scientists are closer to a vaccine to target breast cancer.  The original article was published at Clinical Cancer Research here, and once again highlights the power of the immune system!

This was a Phase I clinical trial to determine the safety of a vaccine targeting a protein called MAM-A.  The vaccine is a DNA vaccine that makes use of little circular bits of DNA that can be made in bacterial cells.  The bacteria are engineered so that they have the “DNA code” for MAM-A.  MAM-A is a protein that is specific to breast cancer as opposed to other cancers, and 40-80% of primary breast cancers make too much of it. Using bacteria allows for the production of lots of this DNA relatively easily.  An added benefit is that DNA from humans and bacteria look slightly different.  That means the immune system will see this DNA as foreign (danger! danger!)….basically it amps up your immune cells. When the vaccine is injected into a patient, cells (usually muscle) take up the DNA and make the protein (MAM-A).  Immune cells “eat” these proteins and present bits of MAM-A to T cells and B cells.  The T cells, particularly CD8+ T cells, then circulate throughout the body until they encounter breast cancer cells that make MAM-A. Because the CD8+ T cells have been “activated” (they’ve already been educated about the danger) they are able to kill those cancerous cells.

This study showed that the vaccine was safe to use.  But the most exciting part is that the vaccine caused CD8+ T cells specific to MAM-A to increase in number and to make the weapons needed to kill cancerous cells (one of those weapons being Interferon-γ).  They were in fact also able to kill cancerous cells, and patients receiving the vaccine had  improved “Progression Free Survival” compared to patients not receiving the vaccine.

This is a great example of cancer therapies taking advantage of the immune system!

Dangers of Fear and Neglect

Ebola

Maryn McKenna is a science journalist over at Wired with the blog Superbug.  I’ve been following her for a while and really enjoy her writing. Perhaps because she has a strong focus on the dangers of antibiotics usage in meat production, a topic I am very interested in and concerned about.  She also writes a lot about disease outbreaks including many posts on the current Ebola outbreak. (I’ve written about Ebola here).  Her most recent one regarding this virus is an interview with experts in the field of risk-communication. Regarding the quarantine of a nurse recently returned to the U.S. from caring for Ebola patients, she asks the question:

“What happens if this kind of punitive detention — which went far beyond what medical authorities recommend — deters aid workers from going to West Africa to help?”

Take a look here to read about the very concerning events that could take place if Ebola is not controlled at its source with help from nations around the world.

Hashimotos-A case of rogue immune cells

So far this blog has focused heavily on the immune system’s role in fighting infections.  Preventing the invasion of these foreign “aliens” is arguably the reason we have immune systems in the first place.  The other main reason for the immune system that I haven’t discussed yet but will one of these days is it’s role in getting rid of cancerous cells. Each of these is a way in which the immune system is helpful, protecting us from bad things either external or internal.  Sometimes our immune system turns on us though and becomes the bad guy, destroying our healthy tissues and therefore causing us serious harm.  This takes the form of many autoimmune diseases including Type I Diabetes, Rheumatoid Arthritis, and lupus to name a few.

When our immune system destroys cells in our thyroid, we can develop Hashimoto’s disease named for the doctor who discovered it.

The thyroid

The thyroid is a large endocrine gland in our necks that produces thyroid hormone which regulates a vast number of processes including the consumption of energy, production of proteins, and the body’s sensitivity to other hormones.  The destruction of thyroid cells leads to hypothyroidism with symptoms including fatigue, sensitivity to cold, and weight gain to name a few.

Hashimoto’s disease is the result of both genetic and environmental causes.  There is usually a genetic predispostion (mutations in one more more genes that would normally control the immune response) but symptoms don’t develop simply because of this.  Many environmental factors can cooperate with those genetic factors to cause the development of Hashimoto’s including excessive consumption of iodine, deficiency in Vitamin D, infection with certain viruses, environmental pollutants, drugs, being female, and having gone through pregnancy. The immune component of Hashimoto’s (as well as a lot of other autoimmune diseases) is the result of T cells and B cells that are autoreactive, or capable of attacking our own healthy cells.

Normally, we are very good at preventing autoreactive immune cells from causing us harm.  If they are made during development, they are killed but if they escape the development process, other cells including regulatory T cells are able to keep them in check.  During Hashimoto’s autoreactive immune cells cause hypothyroidism due to the destruction of the thyroid cells.  But how do they do that?

Autoreactive B cells

B cells are components of the adaptive immune system that are responsible for making antibodies (see figure). During infection, antibodies can grab viruses or bacteria and block them from entering our cells or they can target them to be killed by other immune cells.  Antibodies have regions (called antigen-binding sites in the figure) that allow them to recognize and grab hold of very specific parts of cells.  In the case of Hashimoto’s disease, these antibodies bind to two different unique parts of thyroid cells not found on liver cells or immune cells or heart cells: thyroglobulin and thyroid peroxidase. Both thyroblobulin and thyroid peroxidase are important in the main function of this endocrine gland, the production of thyroid hormone.  When antibodies grab hold of these two different components of a thyroid cell, they are setting the cell up for destruction by something called the membrane attack complex.  This complex basically pokes holes in the surface of the thyroid cell, allowing lots of water to rush inside.  When the volume gets to be too much, the cell essentially dies because it has burst open like a water balloon.  This is a very messy form of cell death called necrosis, and distinct from the kind of cell death that autoreactive T cells cause discussed in the next section.

 

Autoreactive T cells

Like B cells, T cells are also a component of the adaptive immune system.  These cells can come in two forms: they either help other cells including B cells to be better at their job (these are CD4+ T cells, kind of like a cheerleader or career counselor), or they kill virally infected or cancerous cells (CD8+ T cells).  In Hashimoto’s disease, autoreactive CD8+ T cells recognize components of the thyroid cell in a similar way to B cells.  Instead of antibodies though, T cells use their “T cell receptors” which actually look somewhat similar to an antibody.  Instead of causing the thyroid cells to explode as happens when an antibody binds to the cell, T cells cause a very orchestrated cell death.  T cells latch on to thyroid cells, make pores, and introduce enzymes that cause the cell to die.  Unlike the explosive “necrosis” caused by antibodies, T cells cause a very contained cell death called apoptosis.  Explosive cell death as discussed above can cause a lot of inflammation which can lead to more cell death while the contained cell death is done in such a way that inflammation does not occur.  Follow the link below to see an amazing video of a T cell killing a target cell.  The blue cell is the T cell and it holds on tight to the cell it is killing.

https://www.facebook.com/video.php?v=10152786132839591

Regardless of whether or not thyroid cells die in the explosive or contained manner, the end result is the same: decreased numbers of thyroid cells capable of making the thyroid hormone that controls so many of our functions.  Treatment for Hashimoto’s disease usually comes once enough thyroid cells have died and hormone levels have decreased dramatically.  In this case, it may be necessary to treat with synthetic thyroid hormone. Hashimoto’s disease is one of many examples of the immune system causing autoimmune disease.

 

Ebola

The New Yorker just released a really great, in depth article on Ebola describing how the outbreak began and what scientist are doing to monitor how Ebola is changing as it infects more and more people.  Spoiler alert….scientists do not think this virus will become airborne!  They also cite this recent Science article documenting these changes in Ebola.  Several of the authors have since died from the infection while caring for patients in Africa.

The scientists responsible for monitoring Ebola DNA

Fighting to cure ALS

The Chicago Tribune just published an article about a group at Northwestern studying ALS.  The brilliant scientist shown below has lead a group in finding a possible cause of ALS (discussed earlier on this blog here)!  It’s been known for a while that, in patients with this disease, nerve cells have a problem with getting rid of proteins that are damaged or are made incorrectly.  Dr. Siddique found that, at least in a subset of patients who have the hereditary version of the disease, the protein ubiquilin 2 is not able to perform its function of getting rid of these proteins.  This basically leads to a hoarding situation for the cell where “trash” piles up to such an extent within the cell that it can no longer function.  This is an exciting breakthrough and will hopefully help scientists to discover a cure for ALS.

Breakthrough for ALS!

The original research article was published in Nature and can be found here.

Move it, move it

Have you ever been in a raging bad mood, snapping at friends for no reason, hating the world? Maybe all of that pent up energy eventually motivated you to get out of your toxic mind and into the gym or out for a run?  And then, poof!  Your mood has been reset, you’re calmer, your anger has dissipated.  There’s a plethora of reasons why staying physically active is beneficial, and it just so happens that tempering the immune system can be added to the list.

As with lots of things however, it’s possible to have too much of a good thing.  The effects of exercise on the immune system can be pictured as an upside down “J” as seen in the figure below.

Slide1

Exercise and immune function http://www.ncbi.nlm.nih.gov/pubmed/20569522

Too little or too much and immune function is poor.  Like Goldilocks, you need just the right amount for optimum immune function. I myself try to stay pretty active with volleyball, yoga, biking to work sometimes, hiking, and walking my dog.  But you’ll never see me training for a marathon because I want my immune system to be at its best.  (That’s not true at all.  I hate running and the thought of 26.2 miles screams Hell to me, and I don’t think the human body was made for such insane distances!  And apparently my method isn’t fail-safe as I’m fighting a cold while writing this!)

The overall view is that the positive effect of exercise on your immune system is to keep inflammation under control.  Inflammation is the root cause of a lot of diseases including cardiovascular diseases, chronic obstructive pulmonary disease, various cancers, dementia, and even depression.  In this post, I’ll talk about a few of the ways exercise turns down the immune system’s anger (inflammation) including decreasing fatty tissue, stimulating muscle cells to make anti-inflammatory molecules, and preventing infiltration of macrophages (those important cells in the innate immune system named, ironically in this case, for their “big eating” habit).

Not this

This

Fatty tissue and inflammation

Of course the main motivating factor behind all of us exercising is to trim down and burn away some of that fat.  I always know when my pants start filling out a bit too much that it’s time for some yoga.  It turns out though that growing waist bands (even more so than growing bums or legs or arms) are not just bad for our vanity but also for the immune system.  That’s because the fat tissue, also called adipose tissue, causes chronic, low level inflammation.  This comes in the form of chemical messengers called cytokines whose slow, steady release into the bloodstream can be damaging to tissue and cause the immune system to get all fired up.  It’s like that low level annoyance that you have towards a coworker that initially is no big deal but its continued presence leads to an explosion….or in this case the development of Type 2 Diabetes or cardiovascular disease.  So battling the bulge is good for the health in part because it prevents the accumulation of fat cells that can cause systemic inflammation.

Muscles and anti-inflammatory messages

While lack of exercise causes the accumulation of pro-inflammatory adipose tissue, engaging in physical activity promotes the opposite of that or an anti-inflammatory state.  Even after short periods of moderate exercise, muscles (not tissue we normally think of as having an immune role) start to produce signals that can calm down the immune cells.  This comes in the form of a cytokine or message called IL-6 which is released quickly after a workout and then starts a cascade of production of other anti-inflammatory signals.

In obese patients, the fatty tissue has lots of macrophages that can instigate an inflammatory state.  Physical activity can prevent these cells from infiltrating into the fatty tissue.  One way this might occur is through decreased production of the docking site for macrophages.  For immune cells to go from traveling through the bloodstream at high speeds to entering a tissue they need to go through several steps that slow the cells down.  Exercise can interrupt this process and therefore block inflammatory macrophages from entering fat tissue.

Too much exercise!

So it seems like exercise decreases inflammation but of course inflammation has its purposes, particularly in protecting us from infection.  So does that mean exercise makes us more susceptible to infections?  It turns out that elite athletes oftentimes get more upper respiratory tract infections especially after intense training.   Within our salivary glands are lots of antibodies (called soluble IgA) that are the first barrier that prevent infections from occurring.  These antibodies act like bouncers at a bar; they bind to viruses and bacteria entering through our airways and stop them from getting into our bodies.  Intense workouts in elite athletes have decreased levels of these antibodies and are therefore more susceptible to respiratory infections. Their susceptibility may also be affected by the anti-inflammatory state created by intense workouts.

Moderate exercise therefore has an overall positive effect on our immune systems. It prevents the accumulation of pro-inflammatory fat cells and promotes muscle cells to create an overall anti-inflammatory environment.  These are pretty cool examples of non immune cells (fat and muscle) playing a role in our immune system.  The importance of the immune system is demonstrated here, where exercise influences inflammation and inflammation influences the progression to disease.  Happy workouts lead to happy immune systems!

These articles were used for this post: here, here, here, and especially here.

It’s…a laser

photo 3

The laser

photo 1

MOFLO

Sometimes in immunology we want to know what a specific cell is doing….say a macrophage hanging out in the lung.  Is it helping to calm down inflammation after an influenza infection?  Is it making inflammation worse?  Is it talking to other immune cells after a transplant?  Is it killing its neighbors?   We may have a whole slurry of cells…T cells, B cells, macrophages, neutrophils.   But we only care about what is going on with the macrophages.   To figure this out we need to go from having a gigantic pool of all sorts of cells to a pure sample of only the macrophages. If we find out some information about what these specific cells are doing, maybe there is a way that we can target this cell type with drugs.   “Cell sorting” is the tool we use to make a pure solution of a certain type of cell, and this Soviet-era looking equipment on the left is what helps us to do this.   It’s got a pretty cool name….”MoFlo” and it’s the control center for setting everything up.  The laser shown above actually does the sorting.  The macrophages that we want to purify have certain molecules on their surface that are unique from the molecules on other cell types.  We use colorful antibodies to bind these unique markers.  You notice the thin line shooting down in the lower half of the laser picture? That’s a single stream of cells flowing through….one cell at a time. The horizontal beam of light is the laser that shines different wavelengths of light at the cells.  When a cell goes through with the specific colors we are looking for, the laser detects this and the cell will be “sorted” or separated from the rest of the cells into its own tube.  This colorful image below is an example of how we tell MoFlo what to do.  It’s our “gating” strategy….saying we want these cells that are green a purple but not those cells that are green and red.   Once cells are sorted lots of different things can be done with them including looking at what molecules they are making and incubating them with other cells to see what effect they have.  And not all cell sorters are so ancient looking!  Many of them look quite futuristic!photo 2

 

Shoo Flu!

It’s October!  The start of my favorite season: trees turn to fire, crisp cool air makes hiking spectacular, and if you live in St. Louis the Cardinals are fighting to get to the World Series!

I mean that video is some infectious happiness  brought on by a game-winning home run!  But this is a very serious immunology blog so let’s get back to other infectious business. What else does October bring?  The start of flu season!  And therefore time to get the influenza vaccine!

The basis of the influenza vaccine is something called immunological memory…a fancy way of saying that cells of the immune system remember a virus they have seen before and are therefore able to get rid of it more effectively.  Cells of the adaptive immune system (B cells and T cells) are the cells responsible for this memory.  If you have an intruder one time (say into the White House), hopefully you take precautions to prevent it from happening again…like locking the door or keeping security guards nearby to tackle said intruder!  One way our immune system “locks the door” is by creating neutralizing antibodies.  Take a look at the picture of influenza below. The virus is coated in proteins.  Two are very important: hemmaglutinin (HA) and neuraminidase (NA).  HA allows the virus to attach to and gain entry into your cells.  Once inside the cell, influenza hijacks your cells and makes a whole bunch of new virus.  But all of these new viruses need to get out so that they can infect more cells. NA (in green) allow the virus to make its exit.

Influenza Virus–Note the Hemmaglutinin (HA in yellow) and Neuraminidase (NA in green). http://viralzone.expasy.org/all_by_species/6.html

“Not in my house!”

B cells make antibodies that bind to these proteins (especially HA) and therefore block their ability to get into your cells.  Certain types of B cells (memory B cells) are specialized to stick around for a long time after initial infection so that if you are reinfected with the same strain of influenza, lots of these antibodies can be made very quickly.  The influenza vaccines are designed to jump start these B cells.  If you’re infected at a later time during that season, the B cells will be ready to go.  Lots of antibodies will be made preventing the influenza virus from causing you too much sickness.

HA and NA are the basis for the naming system of different influenza strains.  The strains of virus that we are vaccinated with every fall are called H3N2 and H1N1.  These are the strains that cause seasonal influenza.  We’ve all been infected with these viruses, so why isn’t our “immunological memory” able to prevent reinfection? The answer is that influenza is very good at mutating (or changing) itself to avoid our immune response. Especially those HA and NA proteins that are on its surface, the ones we are able to make antibodies against.  In affect, influenza changes so that the antibodies that we make are no longer able to block infection or at least decrease their efficiency at doing so.  Every year, the World Health Organization, collects more than 500,000 samples from patients around the world who have influenza.  They then use these samples to make predictions about what next year’s strain of influenza will look like, particularly regarding HA.  Using this information, WHO is then able to guide production of the next year’s influenza vaccine.

Is it possible to create a vaccine that would be able to last for more than one season and against more strains of influenza?  Of course, scientists are attempting to do this.  If you look at the image above, you can see that HA kind of looks like a tree.  The big leafy parts of the “tree” are what mutates so easily in this virus.  The trunk of the virus stays pretty much the same regardless of strain, making it a good target for vaccines. Another target would be the M2 ion channel shown in the figure.  Like the trunks of HA, M2 doesn’t change too much from strain to strain.  Therefore, vaccines that generate antibodies to these different proteins would be effective against lots of different strains of virus from year to year.

We mostly think of influenza as a nuisance that makes us miss work occasionally.  But during the hysteria over the Ebola outbreak, we should also remember that influenza can be very deadly….50 million people died during the Spanish influenza epidemic in 1918.  More recently, the 2009 H1N1 pandemic caused 200,000 deaths within a year.

Go here for more information on the influenza vaccine.  This post was written with the help of this article.

And one more thing….poll time!  

Spooky science in honor of October

By Jessica Spahn

The Scream!!

This ghostly picture, remeniscint of The Scream by Edvard Munch, is actually depicting the lung using a technique called immunofluorescence. This technique makes use of antibodies (the “immuno”) to detect specific cell types or cells making a certain protein.  Antibodies are made by B cells to neutralize viruses and bacteria but they serve many uses in the laboratory.  The antibody is connected to a colorful molecule that makes light (the “fluorescence”).  In this picture the blue is simply a dye used to stain the nucleus of cells (the “organ” in a cell that contains all of the DNA….all cells in our bodies, except red blood cells, have a nucleus so all cells are stained with this dye).  The green is an antibody that is supposed to detect macrophages although in this case the antibody is very sticky and most of the green you are seeing is just background and not really macrophages.  The two large eyes at the top are bronchial epithelium (where lots of the mucous is made in the lungs) and the lower mouth is some sort of blood vessel.  Happy October!