Let’s take a trip back in time for a moment to the 1860’s, when the United States was in the midst of a war. With nearly 620,000 casualties, the Civil War took a greater toll of American life than any other war. Of those casualties, though, only one-third died of battle wounds. The rest died of infection and disease. Most of the fatal illnesses resulted from the lack of sanitation in the Civil War era. The soldiers could fight each other, but they stood no chance against bacteria: the invisible army.

Most bacteria are harmless because your body can fight them off using the power of your immune system . Some are even beneficial, like the E. coli that naturally live in your gut to aid in digestion. Many, however, can be deadly. Good or bad, harmful or not, bacteria are everywhere. They are on the food you eat and in the water you drink. They are even on your skin, just waiting for the chance to infect you. Luckily, your skin is a barrier that does a pretty good job of keeping them out. However, when you scrape your knee or cut your finger, or in the case of the Civil War, get a bullet in your leg, it breaks the barrier and provides the perfect opportunity for the bacteria to jump on in.

For this reason, your body has fast-acting systems to prevent a bacterial invasion and plug the hole. You are probably very familiar with these systems from your own experience. Here is insight into how they work: for a smaller wound, after a few minutes your cut stops bleeding and the next day there is a scab over it . As your blood clotted to stop the bleeding, your immune system also responded to prevent infection. This month we are going to focus on the immune response.

Why do you bleed after you’ve cut your finger or scraped your knee? Bleeding is a sign of a broken blood vessel. Blood vessels transport blood from your heart to every part of your body and back again. If bacteria get into your blood stream, infection can spread to your entire body. This is called sepsis and, if untreated, can be fatal.

Blood contains different types of blood cells: red blood cells and white blood cells. White blood cells are also called leukocytes. In the event of a broken blood vessel, the white blood cells (leukocytes) are the first to “notice” the injury before the red blood cells work to repair it. How do the white blood cells know where to go?

Blood vessels all have a thin inner layer of special cells called endothelial cells. The layer itself is called the endothelium. When you cut or scrape yourself and a blood vessel is broken, it sets off an immediate response by the endothelial cells. Endothelial cells store little granules of a protein called P-selectin. When a blood vessel is broken and the endothelium is disturbed, these ready-made granules of P-selectin are released. P-selectin is sticky, so it slows down the white blood cells that are flowing through the blood vessel enough for them to notice special chemicals called chemoattractants. They guide leukocytes to the site of the injury. Another chemical, called integrin, stops the white blood cells so they can flatten and crawl through the vessel wall where they will engulf any bacteria and eliminate them from the body to prevent infection. At the same time, chemicals responsible for blood clotting plug up the hole. Once the hole is filled, bacteria can no longer get in. So this is the two-part system: trap invading bacteria and close the wound.

Dr. Denisa Wagner of the Immune Disease Institute and Harvard Medical School studies the role of P-selectin in the immune response. In her research, Dr. Wagner has found that
P-selectin is stored in granules called Weibel-Palade bodies that reside in endothelial cells. To test the importance of P-selectin in the immune response, Dr. Wagner and her team of researchers created mice that lack the P-selectin molecule in their endothelium. These mice are called knock-out mice because the gene that encodes for the protein P-selectin has been knocked out. Dr. Wagner and her team of researchers used a technique called intravital microscopy to watch blood flowing through the mice’s blood vessels while they slept under anesthesia. They found that white blood cells do not slow down at an injured site in P-selectin-deficient mice. [ A film of this intravital microscopy can be linked to on her website]. If the white cells don’t slow down, they cannot effectively perform their anti-bacterial function.

So the presence of P-selectin is crucial to helping us fight off bacterial infection. But like
most things about our bodies, it is important to have the right amount of P-selectin. Too little
exposes us to one kind of risk; as you’ll see below, having too much puts us at risk in a
different way.

There are no known humans who lack P-selectin. But if there is an excess of P-selectin, white blood cells will congregate around the site and restrict blood flow. Humans can develop this condition. If it occurs near the heart, it could induce a heart attack; if it occurs near the brain it could induce a stroke. Both are often fatal. Several drug companies are now in the process of creating drugs that could inhibit P-selectin (called P-selectin inhibitors) and thus reduce the risk of heart attack and stroke. They are also working on a test for P-selectin levels in the blood to determine a person’s risk for heart disease and stroke.

The effects of excess P-selectin can occur if the endothelium becomes irritated by something other than a wound. There are many ways this could happen. Two of the most common ways are through smoking and eating a high-fat diet.

When the chemicals in cigarettes enter the blood stream, they irritate the endothelium on the inside of the blood vessels. Upon irritation, the endothelial cells release P-selectin, just as they would have if the blood vessel had actually been damaged. As a result, the white blood cells come to the injured site even though there are no bacteria. They flatten and attach themselves to the endothelium where they can restrict blood flow. This is why smokers have a much higher risk of having a heart attack or stroke.

Too much fat in the blood stream will irritate the endothelium in the same way as smoking and cause the release of P-selectin. Then the white blood cells come and engulf the fat cells as they would engulf bacteria. The white blood cells become full of fat and look like foam. Really they are white blood cells with lots of fat in them. Since they cannot break down the fat, they become very large. The enlarged white blood cells activate the immune response, indicating damage even though they are just enlarged. The enlarged cells may release the fat into the bloodstream as crystals. The walls of the blood vessel sense injury and try to repair themselves by building up their walls with smooth muscle cells. This causes the blood vessel to become narrow. Narrowed blood vessels do not allow adequate oxygen and nutrients to the tissues and can cause pain, which can eventually lead to a heart attack or stroke. For this reason people who are overweight or people who have too much fat in their diet have an increased chance of having a heart attack or a stroke.

Smoking and eating a high-fat diet are two ways to badly manipulate an immune system that works extremely well. The time between the initial injury and the release of P-selectin and the flagging of the white blood cells takes seconds. This is the body’s preliminary measure to prevent infection. The longer a wound is open, the more time bacteria have to get into your body and infect you. It is equally important that you clean a wound to prevent bacteria that are already present from getting any further into you. Medicine has come a long way in understanding the body’s natural disease-prevention mechanism since the Civil War.

Dr. Denisa Wagner is a Professor of Pathology at Harvard Medical School. She researches
P-selectin and its role in immune response at the Immune Disease Institute and Harvard Medical School. Originally from the Czech Republic, Dr. Wagner has been interested in biology since her first science class in middle school. She attended college in Geneva, Switzerland and graduate school at MIT before coming to the Immune Disease Institute and Harvard Medical School.

The Wagner Lab Researchers


Dr. Denisa D. Wagner

"Rolling" Leukocytes

A Civil War Hospital

		Student Worksheet September 2007
		Teacher Guidance September 2007

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