Month: September 2014

The confused immune system, asthma, and EV-D68

School’s back in session and with it has come the unavoidable spread of infectious diseases.  Kids don’t always like to share their toys, but they can’t seem to help but bestowing upon their friends their nasty infections!  Gross!  It’s ok…I’m all about exposing kids to lots of germs….good practice for the immune system!  The infection to start out the 2014-2015 school year seems to be one called Enterovirus D68.  As of September 25, 2014, 220 people in 32 states have been confirmed to be infected with the virus.  That’s not such a huge number and it’s definitely not something that we should be flipping out about.

http://mashable.com/2013/06/18/panic-gifs/

Don’t panic!

Most people who are infected have symptoms of a common cold and recover after a few days of coughing, sneezing, and generally feeling blah. But it is causing hospitalizations especially among children who have a history of asthma.  Since there’s not a lot out there about the specific immune response to enterovirus, this week I thought I would discuss one of the reasons why those affected with asthma are oftentimes more prone to suffering complications due to viral infections.

There are a lot of reasons that people develop asthma, but about 50% of those afflicted are considered TH2 high.  Before we get into how this affects infections and asthma, we probably need to understand what TH2 means.  Helper T cells (one type of cell in the adaptive immune system) come in lots of flavors including TH1, TH2, TH17, TH22, TFH, TReg, yada yada yada.  It’s kind of ridiculous, and scientists are constantly adding to that list, probably just to make immunology as confusing as possible.  Or maybe the immune system is just that complicated! We’ll narrow down to TH1 and TH2 though.  TH1 cells “help” (thus the H) other cells to kill viruses and bacteria, usually the sort of nasty bugs that live inside of a cell. Think influenza, HIV, Tuberculosis, enterovirus D68.  TH2 cells on the other hand “help” other cells to kill parasites, worms, and some bacteria that live outside of cells.  (See picture below).  Getting rid of these two different types of pathogens (those that live inside the cell versus those that live outside of the cell) requires different weapons.  Kind of how a police force would use a different approach to a bad guy with hostages inside a house versus a bad guy running around on the streets.Slide1

A TH1 response is required to get rid of viruses, like the enterovirus that is causing so many hospitalizations.  In a lot of people with asthma, the immune system is a little confused and tends to respond to viruses (and other things like allergens) with the wrong “weapons”, using TH2 instead of TH1. One of the weapons that should be used during viral infection is the cytokine Interferon which tells cells go into antiviral mode.  Asthma patients seem to make less of this weapon and instead make use of other weapons that aren’t as useful for getting rid of a virus. (For more information about Interferon and Enterovirus D68 go to the nerd boost!)  Since the wrong (TH2) weapons are being used however, the virus is able to avoid the immune response and to survive much longer.

The use of TH2 also causes them to have asthma exacerbations.  One reason this might be the case is that the virus causes damage to the cells of the lung making it more permeable (or accessible) to allergens and other irritants.  In addition, lots of immune cells are brought to the lung, pummeling the tissue with all sorts of inflammatory stuff that cause the typical features of asthma to show up…wheezing, breathlessness, chest tightness, and coughing. Complications from these asthma flare ups leads to breathing difficulties and might make necessary a trip to the ER.

So to wrap up, Enterovirus D68 isn’t really a bug that the general population needs to be worried about.  But if you have asthma or know of someone who does, it would be wise to keep a close eye on symptoms if you’re feeling sick.  But otherwise, go out into the world, enjoy life, but wash your hands and cover your cough to protect your asthmatic friends!

 

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EV-D68–Nerd boost

EV-D68 (as discussed in the main post) is a virus in the same family as the polio virus and coxsackievirus (which can cause meningitis).  The innate immune system is critical in preventing viral infections from getting out of control and talking with the adaptive immune system if they do get out of hand.  Let’s say you were given pictures of a villain and a superhero, but you don’t recognize either of them.  Chances are that based off of clues in the expressions on their faces, physical features, or background colors you would be able to pick who was good and who was bad.

Captain Marvel

Doctor Sivana

Cells of the innate immune system recognize viruses and bacteria using similar mechanisms. They see very broad features that are common to lots of different types of viruses or lots of different types of bacteria.  These broad features are called Pathogen Associated Molecular Patterns (PAMPs) and are recognized by innate immune cells using Pattern Recognition Receptors (PRR).  For enterovirus, the PAMP is double stranded RNA (dsRNA).  RNA is in our own cells as well and is used to make proteins, but we don’t generally have it in this double stranded form so it’s seen as foreign. Innate immune cells recognize this RNA with a PRR molecule called TLR3.  Binding of dsRNA to TLR3 starts a series of actions that tells cells to go into anti-viral mode partly through telling the cell to make the cytokine called Interferon.  (This cytokine was also discussed in the nerd boost about Ebola).  EV-D68 interrupts these events from occurring by cutting up one of the “signaling molecules” that allows the cell to go from recognizing the danger to producing the Interferon.  This disruption prevents the anti-viral mode from going into full action.

Luckily this virus hasn’t proven to be deadly and only causes a few days of cold-like symptoms.  This is an indication that most likely the immune system adjusts and the T cells and B cells of the adaptive immune system are able to eventually take over and get rid of the virus.

The Dr. Jekyll and Mr. Hyde of ALS

Ice bucket challenges were dominating all of our Facebook feeds a couple of weeks ago with people showing appalled shock as they dumped ice water on their heads.  It seemed like such a silly craze to me.  Why not just donate instead of putting yourself through this momentary misery?What this challenge did by stepping away from the more conventional “Walk to end…” campaigns was gain an immense amount of visibility and awareness for ALS.  Largely contributing to its success was the heavy involvement of celebrities (see the Youtube clip above….my particular favorite is Dave Grohl around the 2 minute mark!).  It proved to be an insanely successful campaign raising $113.3 million as of September 15, 2014, this for an organization whose annual budget is generally around $25 million per year.

The disease at the center of this campaign is ALS or Amyotrophic Lateral Sclerosis, a neurodegenerative disease affecting the motor neurons in the body.  Only about 10% of cases of ALS are hereditary, and the rest are sporadic.  Sensory nerves are not damaged during ALS keeping the ability to see, hear, and feel in tact.  Towards the end of disease progression,  massive death of motor neurons traps patients in their bodies making them incapable of functions that the mind is still capable of imagining.  Disease onset begins between the 40s and 70s and progresses quickly with most patients dying due to respiratory failure within 3-5 years of symptoms occurring.

Scratching an itch, hitting the snooze bar, going for a run: these are all actions that depend on your motor neurons. For a muscle to move, a message needs to be transported from the brain to the spinal cord and then from the spinal cord to the muscle (see figure below).  These messages are transported on nerve cells.  During ALS, these nerves cells die and are no longer able to communicate with the muscles.  Without communication from the nerve cells, the muscles eventually wither away.Slide3

The role of the immune system in ALS is an area of lots of research and the results are oftentimes conflicting. Many different immune cells play a role in the progression of this disease but much of the focus has been on microglia, brain-resident macrophages (a broad category of cells literally meaning “big eaters”).  These cells are normally very helpful and supportive to nerve cells providing growth factors (nourishment) to keep them healthy and happy. Another role of microglia is to clean up after a cell has died as happens with nerve cells in ALS.   This process of “taking out the trash” is important in restoring a healthy state after injury.  By getting rid of these dead nerve cells in early stages of the disease, microglia provide a protective effect on the living motor neurons.  As the disease progresses however, microglia basically go from being Dr. Jekyll to Mr. Hyde.  (Go to the nerd boost for more information about this!)  Mr. Hyde microglia start to release inflammatory cytokines and other toxic substances that can directly kill the motor neurons causing progression of the disease.

Immune cells aren’t all bad during ALS though.  One subset of cells called Regulatory T cells makes an attempt to control inflammation at early stages of the disease.  These T cells are a component of the adaptive immune system and normally help to keep inflammation in check.  One of their main roles is to prevent autoimmune diseases from occurring…they prevent other immune cells from attacking your tissues.  When Regulatory T cells are recruited to the brain and spinal cord during ALS, they can help microglia to be more Dr. Jekyll than Mr. Hyde.  They might also be able to directly help nerves to survive.  At later stages of the disease however, these Regulatory T cells are no longer able to control the inflammation or the death of the motor neurons.

The immune component of ALS is a reaction to an initial problem with the motor neurons dying so there are definitely components of the disease that are not immune-mediated.  But figuring out how to prevent microglia from becoming Mr. Hyde or how to enhance the recruitment and activity of those Regulatory T cells are potential targets for future therapeutic options to slow or halt disease progression.

To learn more about ALS and/or to participate in the ice bucket challenge, go here.

Sources for this articles can be found, here, here, here, here, and here.

Dr. Jekyll–Nerd Boost

The transition of microglia from Dr. Jekyll to Mr. Hyde (as discussed in the main post) is influenced by many other cells in the brain.  Some cells, including the nerve cells, can actively prevent microglia from becoming the more inflammatory Mr. Hyde.  In a healthy brain, the nerve cells are helping themselves by keeping the microglia in a more supportive role.  As these nerve cells die off in ALS however, the brakes are released and microglia are able to become more destructive.  As discussed in the main post, Regulatory T cells help to keep microglia in a protective state during early stages.  But as the disease progresses, other T cells seem to take over and influence microglia to become inflammatory and destructive.  

Astrocytes

Mr. Hyde microglia release lots of damaging, inflammatory molecules into the brain, which then have effects on other cells besides just the nerve cells.  The astrocytes pictured above are not immune cells but play an important role in protecting nerve cells in the healthy brain and helping them to communicate their messages. Astrocytes are located near the Blood-Brain-Barrier which puts them in a prime location to influence cells outside of the brain (those immune cells that are in the bloodstream).  The communication between microglia and astrocytes amps up the inflammation and leads to the recruitment of immune cells into the brain where access would normally be forbidden.

Involvement of immune cells in ALS is very complicated with lots of different types of cells talking to one another. While Regulatory T cells try to maintain a “civil” conversation, the interaction of all of these cells ends up being very heated and damaging to the motor neurons.  ALS is not exactly an immune-mediated disease,  but the inflammation that results can lead to its progression.

References can be found here and here.

Hijacked by Ebola–Nerd boost

This aside is a “nerd boost” for the main article found here.

Those immune cells infected by Ebola are monocytes, macrophages, and dendritic cells. These are all cells whose mission is to respond quickly to invasions by foreigners. Monocytes circulate throughout your bloodstream and once they enter into tissue (be it lung, liver, heart, or spleen), they morph into either macrophages (literally “big eaters”) or dendritic cells (very good at presenting evidence of infection to other immune cells).   Within these tissues, macrophages and dendritic cells are situated at prime locations to monitor the entry of foreign pathogens (including Ebola).

One of the cytokines (again the words used for communication) normally produced upon infection by viruses is called Interferon.   Interferons tell infected cells to slow down or stop the process of making DNA and protein so that the virus can’t hijack those functions to make more virus. Interferons also tell infected cells to identify themselves to immune cells so that if needed those cells can be killed. They do this by displaying bits of the virus on the cell surface.  Kind of like waving a red flag to attract the attention of immune cells (particularly T cells) that are well-suited for eliminating infections.  Ebola prevents these defense mechanisms from happening by making proteins, VP35 and VP24, which blocks the functions of Interferons.

The dendritic cells mentioned above are also severely impaired during infection.  The Interferon discussed would normally help the dendritic cells to act as the pep rally for the troops (specifically those T cells).  But by interfering with Interferon production, Ebola forces the dendritic cell to communicate a message of “No problem here” instead of “Danger!  Danger!”.

Interrupting all of these levels of the immune system creates a very deadly virus.

 

 

An interview with myself

Somehow I couldn’t get the New York Times to interview me for the exciting release of my new blog. So I decided to do it myself….bear with me.

Jessica (Interviewer): So what made you want to do a blog?

Jessica (Responder):   I really enjoy doing research and I love Immunology.  Being in the lab is great, but I also get a lot of satisfaction out of either writing about it or discussing it with people who aren’t exactly in my field. Those opportunities to effectively communicate what I know with others are times I feel accomplished and useful! I have also considered teaching as a career. And writing about the immune system on a weekly basis will help me to think up new ways to relate this complex system to students.

Jessica (I): So are students your target audience?

Jessica (R): Well I do hope that students read this blog and find it useful in understanding what they are learning. But I hope that the general public will also read.

Jessica (I): Why would the general public even care about the immune system?

Jessica (R): It’s such a cool system!!! There is so much going on with the immune system: different types of cells, ways they communicate, ways they get from one place to another, all of the foreign pathogens (those are things like viruses and bacteria and parasites) that it needs to protect us from. It has such a tough role of making sure to protect us from those pathogens but also protecting us from bad things that happen in our own bodies that aren’t foreign (think cancer).   And if that wasn’t enough the immune system also need to recognize our own healthy tissue as safe and not something to be attacked.   The immune system is kind of omnipresent….thus the blog’s name: Omnimmune.   From the food we eat, to different diseases like diabetes and multiple sclerosis, to trauma, to heart attacks…the immune system is effecting all of those things. And that’s the point of this blog. To explore the immune system in all of these different processes.

Jessica (I): So the point is to explore the immune system in diseases? What else will readers learn from your blog?

Jessica (R): I’m planning on going off of what is in the news at the time. So Ebola is big in the news and that will be my first post. Describing what the immune system is doing during this infection and why it oftentimes can’t control it. ALS is in the news a lot too. That’s not really a disease that is associated with or caused by the immune system. But it’s there, and it’s definitely having an impact on those that have the disease. Immunology (the study of the immune system) is dense in the lingo so you’ll also find a page called “So much immuno lingo”. This will help readers to follow along if I start using jargon. I hope that there will be a wide spectrum of readers with different backgrounds in the sciences. So I will target the main post to readers without any biology background and have links to expand on ideas for those who are interested.

Jessica (I): Why should people trust you?

Jessica (R): Great question. I’ve had about ten years of training in Immunology and received my PhD in 2010 from the University of Rochester. A lot of the topics that I’ll be writing about aren’t exactly in my area of expertise. But I have the knowledge base to research them on my own and report back. Hopefully in a manner that will be easy for the reader to understand and relate to and fun at the same time.

Jessica (I): Do you have a life outside of science?

Jessica (R): Luckily yes….I mean it’s not the most exciting life in the world but it makes me happy! I’ve got a good base of friends here in St. Louis (and worldwide!!) that keep me busy. We’re just finishing up a beautiful summer and the weather was perfect for lots of outdoor concerts and movies in the park. I play volleyball once a week which has been really fun to get back into…thank you Maria! I do lots of yoga…mostly for the health benefits but it does relax me as well. I love reading fiction….I wish I was more of a nonfiction reader but they just don’t grab my attention all that often. I like to knit, and go to concerts, and travel (anyone wanna take me to Cambodia…or I’ll settle for the Caribbean?). I’m obviously a bit of a nerd as evidenced by the format of this first post and the blog topic in general. But I’ve embraced my nerdiness and you should embrace yours too! I have loved living in St. Louis after about 12 years away. My parents live here and my sister and her family are nearby. Great to be back by two crazy nieces and a nephew and watch them grow! And fun to explore a city that I grew up in with new adult eyes! Oh and I have a really fun dog named Huckleberry who is quite neurotic but oh so lovable!

Jessica (I): Anything else we should know?

Jessica (R): I think that’s about it for the blog. Check in weekly to look for new posts. I hope you enjoy it and would love to hear suggestions for things I should write about!

Neurotic dog, Huckleberry

Hijacked by Ebola

So you may have heard that there’s an Ebola outbreak in the western part of Africa. Sadly it’s one of the more deadly strains, with more than 3,500 infected and more than 1,800 suspected deaths. Four missionaries from the United States have returned with the infection for treatment. Two have fully recovered and two have only recently been admitted.   While so far it seems to be contained to Africa, fear of its spread to other corners of the world is high. As an immunologist, I often wonder what the immune system is doing during such a rampant infection. Read on to gain an understanding of the immune system’s attempt to control the infection and why it oftentimes is unable to do so.

Ebola virus starts out by infecting the very cells that are supposed to destroy viruses and bacteria. These are immune cells that respond quickly to invasions by foreigners, the first line of defense. When all goes well, these cells kill viruses or bacteria before they become a problem and also help to recruit other immune cells that are highly specialized in preventing infections from becoming unchecked.

The body is full of complex systems including the circulatory, nervous, and reproductive systems. Each of these systems depends on lots of different cell types that need to communicate with each other, i.e. the nerve cells that tell the heart cells to beat. Like these other systems, cells in the immune system rely heavily on communication. And like any good relationship this requires both speaking and listening.  One of the ways that immune cells talk to each other is through making molecules called cytokines. These cytokines are the words that are spoken, giving information to the cell that is listening which is done when the cytokine binds to a receptor (the ears).

When viruses infect those initial immune cells, one cytokine is made that acts as a warning to neighboring cells. It communicates two important messages to cells in the area. 1. Don’t let this virus hijack you to make more virus. Prepare all of your defenses to combat the virus if you encounter it. 2. If you have already been infected notify us so we can kill you. It seems a little harsh, but better to get rid of a few infected cells than to let the virus kill the person. Ebola prevents these defense mechanisms from happening by making proteins, VP35 and VP24, which block the cytokine or message from being made and prevents other cells in the area from hearing it even if it is made. Ebola in effect makes the cells in our body hostages and helpless in defending against it.

If you’re interested in more information go to the Nerd Boost!

By foiling the early method of controlling Ebola infection, the virus is able to accumulate to a level that is beyond the control of our defense mechanisms. And unfortunately, while critical virus-fighting cytokines are impaired after infection, other inflammatory cytokines are made in excessive amounts. This starts a vicious cycle where viral load increases leading to more production of inflammatory cytokines. Inflammation has its uses and is critical in keeping us healthy. But left unchecked it can cause serious harm. The inflammatory cytokines made in an attempt to control Ebola fall on deaf ears as the immune cells that would normally respond to them increasingly die off. What they do target however are blood vessels, causing them to dilate and become “leaky” resulting in the hemorrhage associated with Ebola infection and eventual organ failure.

There is hope however.   As you may have heard, the two patients who were flown to Emory in Atlanta have recovered from infection possibly due to treatment with a drug called ZMapp, a cocktail of antibodies directed against the virus. This drug likely neutralizes the virus, preventing it from gaining access to cells. ZMapp hasn’t been successful in every patient receiving it, but at this point it is the best option for a cure from this deadly virus. Here’s hoping, the company that makes it (Mapp Biopharmaceutical) will be able to ramp up production, as the supply is currently depleted.

To make a donation to the brave doctors, nurses, and missionaries trying to combat this epidemic, go to the following organizations:

I used the following papers to write this article: here, here, here, and here.