Defending the Body: Neutrophils
Editor's note: Physicians have a special place among the thinkers who have elaborated the argument for intelligent design. Perhaps that's because, more than evolutionary biologists, they are familiar with the challenges of maintaining a functioning complex system, the human body. With that in mind, Evolution News is delighted to offer this series, "The Designed Body." For the complete series, see here. Dr. Glicksman practices palliative medicine for a hospice organization.
Life must not only obey the physical and chemical laws of nature, but must also protect itself from many of the other organisms that exist in the environment. Nature contains a multitude of different microbes that, though our senses cannot detect them, are always trying to enter our body so they can multiply. The first line of defense against infection by these microorganisms is the skin and the epithelial tissues that line the respiratory, gastrointestinal, and genitourinary tracts. Deprived of any one of those, our earliest ancestors could not have survived long enough to reproduce. However, if by injury or functional ability, microbes penetrate to the tissues below, then they come up against the second line of defense: the immune system.
In previous articles I've shown that the immune system can be divided into two categories: the innate immune system that each of us is born with and the adaptive immune system which develops over time as we are exposed to the environment. Each of these systems has its unique cells and proteins that are needed for the body to defend against microbial invasion. In my last article I looked at the first responders of the innate immune system and how they act like sentries defending a walled town. Now let's look at the main immune cells in the blood that respond to the call to arms by the sentries and how they do their job to help keep the body alive.
Blood consists of about 55 percent fluid and 45 percent cells, of which there are three main types. The most numerous are the red blood cells (erythrocytes) that produce hemoglobin to transport oxygen to the tissues. The platelets (thrombocytes) are smaller than red blood cells and help the body control bleeding when injury takes place by sticking together and providing a base for fibrin clot formation. Finally, the least numerous but largest cells are the white blood cells (leukocytes), which help to defend the body from infection.
The leukocytes can be divided into two main types: mononuclear agranulocytes, which have uniform nuclei and no granules within the cytosol (lymphocytes and monocytes), and polymorphonuclear granulocytes,which have multi-lobar nuclei and granules within the cytosol (neutrophils, eosinophils and basophils). The former make up about 30 percent of the white blood cells in the blood and the latter about 70 percent.
The lymphocytes are part of the adaptive immune system, which we'll discuss later. The monocytes are basically wandering macrophages within the blood that enter sites of infection and, like the fixed macrophages in the tissues, are one of the first responders that kill invading microbes and process their chemicals to provide important information to the cells of the adaptive immune system.
Of the polymorphonuclear granulocytes, it is the neutrophils that are the main defenders against infection. Let's see how they do their job and what clinical experience tells us about how important they are for survival.
Like red blood cells and platelets, neutrophils are produced in the bone marrow and with maturation move out into the blood. Neutrophils are usually the first immune cells from the blood to come to the field of battle. They are attracted to the war zone by cytokines, which are chemical messengers released from injured tissue and activated mast cells, macrophages, and dendritic cells. The process by which they move into the field of battle and toward invading microbes is called chemotaxis. This involves using specific receptors on their plasma membrane to move toward areas of increasing concentration of these chemicals. It's similar to how a bloodhound moves towards its prey by sensing the increasing concentration of the scent, or a shark to blood. Moreover, the same cells that send out cytokines to attract neutrophils and other immune cells also release chemicals that cause inflammation. Inflammation allows the neutrophils to squeeze through the narrow openings between the cells that line the capillaries into the tissues so they can seek out and destroy the enemy.
Once inside the tissues and brought toward the invading microbes by chemotaxis, the neutrophils activate by using specific receptors on their plasma membrane to attach to specific chemicals on the surface of the intruder. The activated neutrophil usually engulfs the microbe in a process called phagocytosis (phagein is Greek for "to eat"). Once the microbe is inside, the neutrophil releases various chemicals and enzymes to kill and literally digest it. Neutrophils also kill microbes by releasing the chemical contents of their granules into the tissues, in a process called degranulation, where not only the microbes but also host cells may suffer damage.
However, some pathogens have developed the ability to defend themselves from this initial attack by the neutrophils. In later articles I will show how both the innate and adaptive immune systems produce specific proteins to help bolster the effects of the neutrophils to bring about a counterattack. After neutrophils do their job, they usually die and are phagocytosed by macrophages. Dead neutrophils make up most of the cellular content of pus. Finally, like all activated immune cells, neutrophils release cytokines to promote inflammation, attract other immune cells to the battlefield, and increase the metabolism, often causing fever.
The body is constantly being exposed to many different types of microbes. Therefore it must have enough defenders with enough fire power to protect itself from overwhelming infection. The analogy of the inhabitants of a walled town defending themselves from invasion only works up to a point. A town usually faces a finite number of attackers that usually diminish as the battle goes on. However, a microbial infection usually involves a relatively small invading force that, given the chance, is able to multiply rapidly once inside the body. In contrast, neutrophils do not multiply and generally only live a few hours to a few days.
The number of defenders and their ability to move fast enough and have enough firepower to protect against an invading force determined the survival of a town. In the same way, the body must have enough neutrophils that can move fast enough from the blood into the tissues with enough firepower to protect against life-threatening infection. The normal neutrophil count is about 3 to 7.5 billion per liter of blood, but having at least 1.5 billion per liter usually provides an adequate defense against life-threatening infection. Due to their short lifespan, the bone marrow must produce about one hundred billion neutrophils per day to have enough neutrophils in the blood and tissues. That means the body makes about one million neutrophils per second!
Furthermore, to maintain this constant production, support cells in the bone marrow release a cytokine called Granulocyte Colony Stimulating Factor (G-CSF), which attaches to specific G-CSF receptors on the stem cells in the bone marrow, stimulating them to develop into neutrophils.
Finally, in response to infection and inflammation, some immune cells also release G-CSF, which can often result in a doubling or even tripling of the amount of neutrophils. So, although neutrophils cannot multiply on their own (like microbes can), in response to infection and inflammation some immune cells stimulate the bone marrow to increase neutrophil production. This increase makes more defenders available that can be sent to the battlefield. It is by the release of these cytokines that the body not only develops a fever, but also raises the white blood cell count (leukocytosis), the two main tell-tale signs of infection.
However, when it comes to life and the ability to defend against invading microbes, real numbers have real consequences. Clinical experience shows that when the body doesn't have enough properly working neutrophils to track down and kill enough invading microbes, it usually dies. The commonest clinical cause for this is the use of radiation and chemotherapy in cancer treatment, which often reduces bone marrow function and results in a condition called neutropenia.
Severe neutropenia is having a neutrophil blood count less than 500 million per liter and is often associated with a very high risk of septicemia and death. With severe neutropenia, there just aren't enough neutrophils around to patrol the body against intruders. This is like not having enough defenders to prevent invaders from scaling the walls and taking over the town.
In addition to not having enough neutrophils, having too many, as with acute leukemia, where there may be in excess of one hundred billion per liter of blood, can cause problems as well. Remember, leukocytes, like other blood cells, float within fluid. So, just like having too many food particles in the kitchen sink can clog up the drain, so too, having too many neutrophils in the blood can slow down blood flow. Besides taking over the bone marrow and reducing the production of red blood cells and platelets, this complication of leukemia can result in multi-organ failure and death. The mere presence of neutrophils in the blood does not guarantee survival. You not only have to have the right number of them, but they also have to work properly as well. For our earliest ancestors this would have been a matter of life and death.
Evolutionary biologists seek to explain how life came into being but they pay attention predominantly to how it looks, not how it must work within the laws of nature to survive. They may speculate on how neutrophils and the control mechanisms involved in their production must have come into being by chance and the laws of nature alone. But this doesn't take into account that this system is irreducibly complex, requiring cells that can produce G-CSF and ones that have specific G-CSF receptors, so they can be instructed to become neutrophils, and cytokines to allow neutrophils to leave the bloodstream, and with specific receptors move toward their prey.
It also requires natural survival capacity. For our earliest ancestors to have survived long enough to reproduce, this one part of their innate immune system must not only have constantly produced enough neutrophils within enough time, but also must have been able to get them to the field of battle fast enough and with enough firepower to get the job done. What evolutionary biology tries to explain is how the defenders of a walled town came to be where they are, not how there just happen to be enough of them to get the job done and how they do it.
Now that you've seen how some of the immune cells of the innate system work, it's time to look at how its proteins work. After all, a good defense requires many different weapons and strategies. We'll turn to that subject next time.