CAUTION: ENZYMES AT WORK
PART IV: IMMUNITY
Let’s review some of the things these articles have shown are needed for human survival. The body is made up of trillions of cells each of which must control its volume and chemical content while receiving what it needs from the blood to live, grow and work properly. Since it is made up of matter the body is subject to the laws of nature which demand that it constantly take in oxygen to provide itself with the energy it needs to live because, unlike glucose, it can’t store it for future use. They also demand that the body have the right amounts and distributions of water, sodium and potassium, to have enough blood volume and a proper resting membrane potential for adequate nerve, muscle and heart function. Additionally, since blood has mass, it needs the heart to pump it with enough pressure against natural forces like inertia, vascular resistance and gravity through the circulatory system so there is enough blood flow to its organs and tissues matching their metabolic needs. But, if the body doesn’t have the right amount of oxygen, or water, or sodium, or potassium, or blood pressure or blood flow, then cell death takes place. When the cells in the brainstem die, the ones that tell the body to breathe, control its circulation and make it conscious of its surroundings, the body is dead. However, the commonest path to death is cardiopulmonary arrest. Without respiration the body can’t bring in new supplies of oxygen and get rid of toxic carbon dioxide and without the heart pumping there isn’t enough blood flow to the brain, so, together this causes it to malfunction and die.
Common sense tells us that life does not exist within a vacuum or the imaginations of evolutionary biologists. The last two articles showed that many of the small blood vessels of the body are constantly undergoing injury due to the active and physical nature of life. Clinical experience shows that for our earliest ancestors to have survived long enough to reproduce they would have had to have had a properly controlled clotting mechanism (hemostasis) in place that would turn on only when needed and turn off and stay off when it’s not. Bleeding disorders can cause death from minimal trauma brain hemorrhage or spontaneous bleeding from the gastrointestinal tract and hypercoagulable states with excessive clotting can cause death from heart attack, stroke or pulmonary embolism. Properly controlled hemostasis and human survival is dependent on a finely-tuned system of pro- and anti- clotting factors that must be produced in adequate quantities by the endothelium that lines the blood vessels and the liver as well.
Hemostasis is a type of defensive system the body has to prevent itself from bleeding to death from what it encounters in nature. But that’s not the only one it has. The bones, muscles and nerves work together to let the body detect danger and either avoid or physically defend itself from it. But living within the world also requires the body to be able to defend itself from enemies that it can’t detect with the five senses nor avoid by running away. We are always being exposed to micro-organisms that are too small to be seen with the naked eye. These consist mostly of bacteria, viruses and fungi, and less often protozoa and parasitic worms. Clinical experience shows that if these microbes invade the body and become widespread, then serious disease, debility and death are the usual results.
When it comes to microbial attack, the body has a two-pronged defense strategy. The first line of defense is the epithelium which is tissue that separates and protects the interior cells of the body from the effects of the outside world. The skin is an epithelial tissue consisting of many different types of cells that provides resistance to invasion by microbes and inhibits bacterial growth by secreting various chemicals. In addition, the skin also protects the body from mechanical and chemical injury, ultraviolet radiation, extreme hot and cold, excessive fluid loss and also helps the body control its temperature as well. The respiratory, gastrointestinal and genitourinary systems each have an epithelial lining that separates their underlying tissue from the effects of the environment. Microbes that are inhaled, or swallowed, or are able to enter the urinary tract, come up against these barriers to foreign invasion.
If the invading micro-organisms breach the first line of defense and enter into the tissues, then the second line, called the immune system, swings into action. When invaders breached the walls of a well-defended town they usually met armed resistance. By using their weapons and shields for protection, the intruders would kill and loot their way through the town to conquer it. Similarly, after breaching a barrier like the skin, usually through an area of injury, invading microbes are able to loot the body by using the nutrients within its fluids to live, grow, and multiply. As opposed to a town being stormed by a finite amount of attackers, a microbial infection usually involves a small invading force that, once inside the body, is able to rapidly multiply by using the resources of its host. It’s the job of the immune system to limit this activity as much as possible to preserve organ function and allow for survival.
There are many different types of micro-organisms and the few that have developed the ability to breach the first line of defense and do battle with the immune system are called pathogens (Gk. pathos = disease + gennan = to produce). Some of these pathogenic organisms enter the cells, take over their metabolism, rapidly reproduce and then send out the next generation of microbes into the body after the cell dies. Many others can live within the tissue fluid between the cells and multiply and spread locally.
Infections are possible in almost every organ of the body. Progression of infection within a given organ such as the lung (pneumonia), gastrointestinal tract (gastroenteritis) or the brain (meningitis) can lead to severe malfunction and death. If the pathogens are not stopped within the tissues they initially infect they can migrate into the lymphatic system which consists of very tiny thin-walled channels that carry lymph, a watery liquid that eventually drains into the main veins. By working their way through the lymphatics and into the bloodstream these pathogenic organisms can cause septicemia and irreversible shock which results in death more often than not in 250,000 people in this country yearly.
Without the epithelial tissue of the body protecting it from microbial invasion life would have been impossible for our earliest ancestors. But the experience of death-dealing infections throughout the world tells us that without a properly working immune system, the same applies to us as well. How the immune system uses enzymes to do its job and what it takes to control it so we can live within the world of microbes is what this article is about. So let’s first see what enzymes are and how they work within the body.
Enzymes are special molecules (mostly proteins) that are made in the cell which help other molecules undergo chemical reactions when they come in contact with each other. When these reactions occur energy is either released or used up and different molecules are produced. Every biochemical process in the body requires enzymes to work properly.
Molecules are made up of atoms joined together by chemical bonds. There are very small molecules, like molecular oxygen, which is made up of two oxygen atoms joined together (O2) and water which is made up of two hydrogen atoms joined to one oxygen atom (H2O). There are also slightly larger molecules, like glucose, a sugar that is made up of six atoms of carbon and oxygen joined to twelve atoms of hydrogen (C6H12O6). And there are very large molecules, like carbohydrates, fats, and proteins, many of which are made up of hundreds or even thousands of atoms joined together.
When molecules meet up with each other they sometimes react. A reaction between molecules simply means that chemical bonds between atoms are created and destroyed. This usually causes some of the atoms in the reacting molecules to change places with each other to form different molecules. Enzymes help chemical bonds be destroyed in larger molecules to form smaller ones and be created between smaller molecules to make larger ones. During this process energy may be released or used up. At the end of the reaction the enzymes are not altered so they can continue to promote more reactions. And, the total number of atoms present in the molecules that are produced at the end of the reaction is the same as there were in the molecules that reacted in the first place. In other words, in a chemical reaction no new atoms are created or destroyed, just the bonds between them and this often results in the release or use of energy and the atoms involved changing partners to form different molecules.
One important example of a chemical reaction that occurs within our cells involves how they get the energy they need from the chemical bonds within the glucose molecule. Cellular respiration uses specific enzymes to help breakdown one glucose molecule (C6H12O6), in the presence of six oxygen molecules (6 O2), to release the energy the cell needs, while at the same time producing six carbon dioxide molecules (6 CO2) and six molecules of water (6 H2O). Notice that the chemical reaction starts off with a total of six carbon atoms, twelve hydrogen atoms and eighteen oxygen atoms from one molecule of glucose (C6H12O6) and six molecules of oxygen gas (6 O2). And it ends up with the same amount of carbon, hydrogen and oxygen atoms, but they make up the six molecules of carbon dioxide gas (6 CO2) and the six molecules of water (6 H2O) instead.
The laws of nature determine how fast specific molecules will react with each other. But the addition of an enzyme makes this reaction take place much faster. By speeding things up, enzymes help to produce many more new molecules, usually in the order of thousands or millions of times more, than what would normally happen at random. This is why enzymes are called catalysts. They help bring molecules together to react much faster than what would happen if they were dependent on the random forces of nature alone.
If our body were to be left only to the random laws of nature the thousands of chemical reactions we need to help keep us alive would not take place fast enough and we would die. Enzymes can catalyze chemical reactions because their specific chemical nature and shape allows them to bring specific molecules together to react in a specific way. This is similar to how hormones have their specific effect(s) in the specific cells of specific target tissues by locking on to specific receptors (see prior articles entitled Caution: Hormones At Work). It is also important to note here that the body also produces different proteins called enzyme inhibitors as well. It is the specific chemical nature and shape of the enzyme inhibitor that enables it to bind to a specific type of enzyme and either slow down or totally block its metabolic effect. Enzyme inhibition is one of the main ways the body is able to control many of its metabolic processes.
There are thousands of different enzymes in the body each of which have a specific effect on a specific molecule. As noted above, it is the shape and chemical nature of the enzyme that determines which molecules it will work on and what type of reaction it will catalyze. The first part of the chemical name of an enzyme usually indicates the specific molecule or class of molecules for which it catalyzes reactions. And the last part of its name usually ends in “ase”. For example, lactase is the enzyme that helps to breakdown lactose, a sugar in milk that is made up of one molecule of glucose joined to one molecule of galactose. And a protease is a class of enzymes that helps to breakdown proteins which are made up of two or more amino acids joined together.
The body often uses several specific enzymes in a specific order (pathway), in a chain reaction, to bring about what is needed for survival. The first molecule undergoes a reaction catalyzed by the first enzyme, and one of the products of that reaction becomes the second molecule in the pathway. The second molecule, in turn, undergoes a reaction catalyzed by the second enzyme, and one of the products of that reaction becomes the third molecule in the pathway. The third molecule, in turn, undergoes a reaction catalyzed by the third enzyme, and one of the products becomes the fourth molecule in the pathway, and so on. This process continues until the required molecule is produced so it can do what the body needs it to do. Note that if any one of the enzymes in the chemical pathway were to be missing or not working properly then not enough of the final product would be produced and life could hang in the balance.
Finally, it is important to understand that since enzymes are made up of hundreds or thousands of atoms chemically bonded together, their chemical stability and capacity to work properly can be affected by the laws of nature as well. Things like temperature, hydrogen ion concentration and the body’s water content can affect the chemical structure of enzymes. When any of these three important parameters falls out of the normal range the enzymes in our body start to malfunction and so does our body. Serious deviations can even result in death. That is why our body must be able to control these three, and other vital parameters to allow us to survive within the laws of nature. (see prior articles called Caution: Hormones At Work).
For videos explaining enzymes and enzyme inhibition see:
Now that we know what enzymes and their inhibitors are and what they do let’s see how they work to help the body’s immune system fight against microbial invasion.
Immune System Overview
In ancient times, when invaders penetrated the surrounding protective wall of a town, the defenders generally had three important tasks to perform very quickly. The first was to detect and identify the enemy within the city. The second was to sound the alarm so that other defenders could be roused and directed to where the enemy was located. And the third was to repel, wound or kill the intruders so the residents would not suffer injury or loss of life, in addition to loss of possessions and destruction of property.
Similarly, once microbes get past the epithelium and penetrate into the tissues below, the body’s immune defense must have the ability to perform these same three important tasks as well. The first requires that the cells and proteins of the immune system have a way of detecting the presence of the microbes and be able to identify them as an invading force that needs to be destroyed. In other words, are these cells host cells (self), or are they foreign cells (not self). After all, the job of the immune system is to kill invading micro-organisms, so it better be sure that what it’s encountering is indeed foreign and in need of destruction, otherwise it may end up killing its own cells through friendly fire. One can then see that, just like for clotting, to survive it’s important that the immune system turn on only when it’s needed and turn off and stay off when it’s not.
After determining that there is a microbial invasion going on, the second task of the immune system is to send out messages to bring other forces to the field of combat. This usually involves releasing chemicals that increases the blood flow to the site of infection allowing the immune cells and proteins in the blood to leak out through the capillaries to be recruited to the battle field. This causes the area around the infection to swell up and become red in a process called inflammation.
Once the weapons of the immune system have been brought to the site of infection it’s up to them to kill the invading force and prevent the infection from spreading further and causing serious harm and even death. The immune cells and proteins involved have many different weapons at their disposal to accomplish this task.
Just like most military operations, the body’s immune system has regular and specialized forces as well. The regular forces make up what is called the innate (natural) immune system. It’s the microbial defense system with which everyone is born and by reacting within minutes is the first to encounter the enemy. However, clinical experience teaches that this system is, on its own, usually not able to protect the body from overwhelming infection because many pathogenic micro-organisms have the ability to remain invisible and resistant to its strategies which allows them to proliferate and spread throughout the body. The specialized forces that are needed to bolster and improve the effects of the innate immune system are called the adaptive (acquired) immune system. This system usually requires a few days to adjust to the idiosyncrasies of the invading microbes and when it swings into action provides extra intelligence, firepower, and precision accuracy that with the help of the innate immune system usually gets the job done. In contrast to the innate immune system which is present at birth, the adaptive immune system develops over time as the body is exposed to more and more different microbes in its environment.
The First Responders: The Cells of the Innate Immune System in the Tissues
In the olden days the first responders for a walled town defending itself from invasion were the sentries. They basically had four jobs to do; identify the enemy, sound the alarm to bring more defenders to the battle, provide strategic information about the invading force and repel, incapacitate or kill the intruders. Together, the first responders of the innate immune system perform these same four important tasks.
The sentries of long ago had to be able to listen for intruders and be able to see to positively identify them as being an enemy. Moreover, their fellow defenders had to be able to listen for a call to arms and be able to see where to go to engage the enemy as well. Furthermore, the defenders of a city would ultimately have needed to use all of their wits and motor skills to preserve their lives, their freedom and their property.
Rather than having eyes to see with and ears to hear with, the cells of the body interact with chemicals and other cells, both foreign and domestic, through the plasma membrane. The surface of the plasma membrane contains thousands of different molecules that relate to its structure and function. Moreover, to detect a specific set of chemicals on the surface of another cell, or a hormone or toxin in the tissue fluid, the plasma membrane must have a specific receptor. As noted in previous articles, these receptors consist of protein molecules containing a specific grouping of chemicals that result in a specific three dimensional shape which allows them to chemically bind, like a key in a lock, to the molecule being detected.
Pathogenic (disease causing) microbes have specific chemicals on their surface which relate to structure and function that are called pathogen-associated molecular patterns (PAMPs). The first responder cells of the innate immune system have specific molecular structures on the plasma membrane that are able to detect these PAMPs that are called pattern-recognition receptors. It is estimated that the immune cells of the body can identify about one thousand different PAMPs. Since these PAMPs only occur on microbes and not on human cells, this means that these specific receptors allow the cells of the innate immune system to identify invading micro-organisms as being foreign and in need of destruction.
As noted previously, when target cells, like the ones lining the tubules in the kidney, or the muscles surrounding the arterioles, lock on to a specific hormone or neurohormone this triggers them to do something. Similarly, when the first responder immune cells of the innate system use their receptors to lock-on to the specific chemicals on the surface of the invading microbes (PAMPs) they become activated. This activation triggers them to do something which altogether is to identify the enemy, sound the alarm to bring more defenders to the battle, provide strategic information about the invading force and repel, incapacitate or kill the intruders. Here’s the starting line-up and how they do it.
Mast cells derive their name from the mistaken impression that the granules they contain were used to feed the cells around them (German: mast = food). Mast cells are located in many of the tissues of the body, but especially in the skin and the mucous membranes (epithelium) of the respiratory and gastrointestinal tracts. They are usually the first cells that respond to foreign invasion by microbes. When mast cells use their receptors to attach to the specific chemicals on the surface of an invading microbe this activates them to release their granules into the surrounding tissue. The granules contain many different chemically active molecules, one of which is histamine which requires the use of different enzymes to be produced in the mast cell. Histamine promotes inflammation by causing vasodilation of the local small blood vessels and increases the permeability of fluid to leak out of the capillaries. This not only promotes increased mucous production but also allows immune cells and proteins within the blood to move out into the tissue to help in the fight against infection. In addition, the granules of the mast cells also contain chemicals called cytokines. Cytokines (cyto = cell + Gr. kinos = movement) attach to specific receptors on specific cells to not only promote inflammation but also recruit other immune cells to the battlefield as well.
Macrophages (large eaters), are immune cells located in all of the tissues and organs of the body which become activated when their receptors attach to specific molecules on the surface of foreign microbes. This triggers them to literally swallow up and engulf the invader and then using specific enzymes chemically digest and kill them in a process called phagocytosis (Gk. phagein = to eat). Macrophages not only kill invading microbes but also act as scavengers to rid the body of worn-out and abnormal cells in addition to debris from cellular death. They are part of the first responders of the innate immune system but by using enzymes to process the chemicals of the killed microbe they can also provide important information to the cells of the adaptive immune system as well. Also, like mast cells, activated macrophages release cytokines which causes further inflammation and helps to bring other immune cells and proteins to the battlefield.
Dendritic cells are so named because of their tree-like projections (Gk. dendron = tree) which resemble the dendrites of nerve cells. The dendritic cells are located in the skin, the epithelium of the respiratory, gastrointestinal, and genitourinary tracts, and the tissues that drain all of the lymphatic systems of the body. The main job of the dendritic cells is to use their receptors to attach to the specific chemical patterns on the surface of the microbe and by phagocytosis and the use of enzymes, kill it. Then, like macrophages, the dendritic cells use enzymes to process some of the molecules of the invading micro-organism to provide important information to the cells of the adaptive immune system. Also, like mast cells and macrophages, activated dendritic cells release cytokines that help to improve and regulate the immune response to foreign microbial invasion.
In world history it has often been the element of surprise that has allowed a military operation to result in total destruction and surrender. Without sentries to quickly identify the enemy, sound the alarm, provide strategic information and begin to repel, incapacitate or kill the enemy, most defensive military operations fail. So too, to win the battle for survival, not only does the body need the skin and epithelial tissues of the various organ tracts to provide a resistance to microbial invasion but also the first responders of the innate immune system as well. Clinical experience teaches that, even if all of the other parts of the immune system were in place, if there hadn’t been enough mast cell, or macrophage, or dendritic cell function, then our earliest ancestors could never have defended themselves adequately from the invisible might of the microbial world.
Evolutionary biologists claim that human life has come about from chance and the laws of nature alone, by pointing out that the first responders of the innate immune system are present in some of the most ancient forms of life. However, this only verifies their absolute necessity for the body to survive within the world of microbes and not how they actually came into being in the first place. Nor does it explain how the body just happens to have enough of them located precisely where they need to be to get the job done. It’s like making the same conclusion after seeing the internal combustion engine and all the other things in common needed for a motorcycle, a car and a truck to perform properly. As mathematician William Dembski has said, the only two options on the table for how life came into being are either chance and the laws of nature alone or intelligent design. But we have yet to look at the roles played by the immune cells and proteins of the innate system present in the blood. After all, the inflammation brought on by the activated first responders works to allow them to come to the field of battle. So what is it that they do and how important is it for survival?
Neutrophils: The Main Blood Cells of the Innate Immune System
Blood consists of about 55% fluid and 45% 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 they help the body control bleeding when injury takes place by sticking together and providing a base for fibrin clot formation. Finally, the largest but least numerous cells are the white blood cells (leukocytes) which as part of the immune system 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% of the white blood cells in the blood and the latter about 70%. The lymphocytes are part of the adaptive immune system (see below). The monocytes are wandering macrophages within the blood that enter sites of infection and like the fixed macrophages in the tissues, which are the first responders kill invading microbes and by processing their chemicals provide important information to the cells of the adaptive immune system as well. Of the polymorphonuclear granulocytes it is the neutrophils that do the lion’s share of defending the body from infection.
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 chemicals released from injured tissue and invading microbes and cytokines from 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 other 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 become activated by using the specific receptors on their plasma membrane to attach to some of the molecules on the surface of the intruder. The activated neutrophil then usually engulfs the microbe by phagocytosis and in releasing various chemicals and enzymes kills and literally digests it. Neutrophils also kill some microbes by releasing the chemical contents of their granules into the tissues, a process called degranulation, where not only the microbes but also host cells may suffer damage. However, some pathogens have developed the ability to fend off this initial attack by the neutrophils and as noted below, 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. It is dead neutrophils that make up most of the cellular content of pus. Finally, like all activated immune cells that respond to infection, inflammation or trauma, neutrophils also release cytokines which promote inflammation, attract other immune cells to the battlefield and increases 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. The town usually faced a finite number of attackers and this usually diminished as the battle raged on. However, a microbial infection usually involves a relatively small invading force that, if given the chance, is able to multiply rapidly once inside the body. In contrast, neutrophils do not multiply and generally do not live longer than a few hours to a few days.
Just as 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, so too, the body must have enough neutrophils that can move fast enough from the blood into the tissues with enough firepower to protect itself against life-threatening infection. Clinical experience teaches that the normal neutrophil blood count is about 3-7.5 billion per liter and 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 working to defend the body from infection. 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 form 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 neutrophil blood count. 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) in the blood both of which are the two usual clinical signs of infection.
However, when it comes to life and being able to defend itself from invading microbes so as not to die from overwhelming infection, 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 cause for this is the treatment of cancer with radiation and chemotherapy which can negatively impact bone marrow function resulting in a condition called neutropenia. Severe neutropenia is a neutrophil blood count that is less than 500 million per liter and is usually associated with a very high risk of serious infection, septicemia and death. Having less than 500 million neutrophils per liter of blood to patrol the body against intruders is like not having enough defenders to prevent invaders from scaling the walls and taking over of a medieval town. Death and destruction are the likely results.
In addition, having too many neutrophils, like with a bone marrow cancer called leukemia, can cause problems as well. Remember, white blood cells float within the blood, and just like having too many food particles in the kitchen sink, which can clog up the drain, so too, having too many white blood cells can slow down blood flow in the small arteries and arterioles, which can compromise organ function. So, for human survival, clinical experience teaches that having the right number of properly working neutrophils is a matter of life and death.
Evolutionary biologists are very good at speculating 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, as biochemist Michael Behe would likely point out, since neutrophil production requires stem cells in the bone marrow to have specific G-CSF receptors and also requires other cells to produce G-CSF to stimulate them, the system is irreducibly complex. This means that unless the bone marrow stem cells have G-CSF receptors on their surface and other cells can produce G-CSF, the system fails. This means that for a common ancestor to have been able to produce neutrophils would have required the simultaneous development of G-CSF receptors on the bone marrow stem cells and the ability for other cells to produce and release G-CSF as well. But is that really enough to explain how our earliest ancestors could have survived within the world of microbes?
Clinical experience teaches that if they had had severe neutropenia, they never could have lived long enough to reproduce. In other words, not only do the bone marrow stem cells have to have G-CSF receptors and other cells to produce and release G-CSF, but they all must respond well enough to produce enough neutrophils quickly enough and at the right time to allow for survival. To do this requires that they would also have had to have had what I call a natural survival capacity to do what needs to be done. Now that you see how the immune cells of the innate system work, it’s time to look at how its proteins work. After all, a good defense requires having different weapons and strategies.
Complement: The Proteins of the Innate Immune System
The plasma proteins of innate immunity, which leak into the tissues when inflammation takes place, are collectively known as the complement system because they complement (complete) the function of its cellular components. The complement system consists of over thirty proteins which, like the clotting factors, are mostly produced in the liver and enter the blood in an inactive form. Also, just like for clotting, there is more than one pathway for activation and once it begins it progresses quickly in a cascading fashion, like falling dominoes. Finally, just like for the coagulation cascade, activation of complement requires that two key enzymatic steps take place to unleash its power and therefore, since inappropriate activation can result in significant injury, the body must make sure that it only turns on when it’s needed and stays or turns off when it’s not.
Just as the final common pathway for coagulation involves mainly two clotting factors (prothrombin and fibrinogen), so too, activation of the complement system involves mainly two complement proteins called C3 and C5. There are thought to be three chemical pathways by which foreign molecules on the surface of invading microbes triggers complement activation. All three of these pathways converge to form an enzyme called C3 convertase. C3 convertase, as its name implies, is an enzyme that breaks specific bonds within C3 and converts them into two fragments called C3a and C3b.
The smaller fragment, C3a, binds to specific receptors on mast cells and triggers them to release histamine from their granules to bring about inflammation which brings more immune cells and proteins to the battlefield. The larger fragment, C3b, usually does one of two things. C3b can attach to foreign proteins on microbes and allows neutrophils and macrophages to better identify and attach to them by using specific complement receptors so they can engulf and digest them using various chemicals and enzymes by phagocytosis. Or, C3b can join with C3 convertase to form another enzyme called C5 convertase which breaks C5 into two fragments called C5a and C5b.
Like C3a, the smaller fragment, C5a, triggers inflammation by attaching to complement receptors on mast cells to release chemicals like histamine. C5a also helps neutrophils and monocytes, (wandering macrophages), pass through the capillaries and attracts them to the battlefield by chemotaxis. The larger fragment, C5b, acts as an anchor to which several other complement proteins attach to form what is called the Membrane Attack Complex (MAC). The MAC is a weapon that chemically drills a hole through the cell membrane of the microbe to kill it.
However, just as in clotting, where inappropriate activation of the system can lead to severe debility and even death, so too, the explosive power of the complement system requires that the body be able to keep it under control. To control hemostasis the body has to have enough anti-clotting factors that can resist coagulation unless significant injury and bleeding takes place. Similarly, to control the activation of complement the body has enough different inhibiting proteins that resist the formation of both C3 and C5 convertase unless a significant infection is present.
So, in summary, when activated, the proteins of the complement system provide the body’s immune defense with assistance and firepower to fight against resistant pathogens. Activated complement proteins increase inflammation (C3a, C5a), attract phagocytes to the battlefield (C5a), help them attach to microbes for phagocytosis (C3b) and kills microbes (C5b—MAC). In addition, to prevent tissue damage the body must have enough inhibiting proteins so that complement only turns on when it’s needed and stays or turns off when it’s not. Deficiencies of specific complement proteins and their inhibitors are rare and usually manifest as either recurrent infections or allergic and auto-immune disease.
Evolutionary biologists look at how some of the components of the complement system are present in some earlier life forms, but not others, and conclude that their development can be explained by gene duplication. However, not only is the complement system of the body irreducibly complex, requiring all of the parts to work properly, but there has to be enough of them and each of their inhibitors as well. In other words, the body has to have a natural survival capacity to produce enough of each of these components, the control of which evolutionary biologists can’t explain because medical science doesn’t even know it yet. Now that you know the components of the innate immune system and how they work together to help defend the body from infection, it’s time to look at the adaptive immune system.
Lymphocytes: The Cells of the Adaptive Immune System
The cells of the adaptive immune system are the lymphocytes and are produced in the bone marrow. There are B-lymphocytes (B-cells), which stay in the bone marrow to mature and T-lymphocytes (T-cells) which enter the blood and migrate to the thymus. The thymus is located inside the chest between the breast bone and the heart and is not to be confused with the thyroid gland which is in the neck and secretes thyroid hormone. Once in the thymus the T-cells develop further and become subdivided into helper T-cells and cytotoxic T-cells. Since the lymphocytes come from the bone marrow and the thymus these regions are known as the primary lymphoid tissue.
Recall, using about a thousand different receptors, each of the immune cells of the innate system (mast cells, macrophages, dendritic cells, neutrophils) can detect about a thousand different chemical patterns present on the surface of invading microbes. These cells become activated when their receptors lock on to these foreign chemical patterns. Therefore, although the cells of the innate immune system are limited in how many different chemical patterns they can detect, they all have the same ability to do so. This means that when they encounter an intruder all of them can immediately start to work together as a large fighting force.
In contrast, each lymphocyte has about a hundred thousand identical receptors on its surface which can only detect a very small chemical pattern. This is usually just a few amino acids from within a very large protein molecule on the surface of a microbe. The first cells of the adaptive immune system to be understood were the B-cells. When B-cells become fully activated, by having their receptors lock on to these small chemical patterns on a microbe, they produce millions of specific proteins called antibodies. Each of these antibodies has the same small chemical pattern as the specific receptors on the surface of the B-cell that produced it. Since scientists realized that contact with one of these specific small chemical patterns on a microbe was responsible for generating specific antibodies from a B-cell, they decided to call them antigens. An antigen is a shorthand term for an anti(body) gen(erating) small chemical pattern on a microbe which can cause an immune response from B-cells or T-cells. As opposed to the immune cells of the innate system which can only detect about a thousand different chemical patterns, it is estimated that altogether, the cells of the adaptive immune system can detect about ten billion different antigens.
A lymphocyte becomes activated when its specific receptors lock on to the specific antigens that are present on the surface of a microbe. But, since there are ten billion different lymphocytes, each with a specific receptor that can detect only one specific small chemical pattern on a microbe, when they become activated there are too few of them around to provide an effective defense for the body. In other words, altogether, the cells of the adaptive immune system, with their ten billion different receptors, are much better at detecting foreign invasion but not at mounting an immediate response compared to the innate immune system with its only one thousand different receptors. The job of the adaptive immunity requires much more time than the one of innate immunity because it must take the specific information it has detected about the pathogen, integrate it, and then use specific effector cells to bring about a more effective defense.
On its way back to the bloodstream the fluid in the lymphatics travels through tissue that contains collections of lymphocytes. In this way the lymphocytes are exposed to antigens from microbes that are present within the lymph that is draining all the organs and tissues of the body. These regions are called the secondary lymphoid tissue and consist of the lymph nodes, the spleen, the tonsils and adenoids and the appendix. After they mature, lymphocytes migrate back and forth between the blood and the secondary lymphoid tissue patrolling for foreign antigens.
Each helper T-cell has about a hundred thousand specific T-cell receptors on its surface that can detect only one specific antigen. Upon digestion of microbes in the tissues dendritic cells and macrophages from the innate immune system migrate to the secondary lymphoid tissue. By placing some of the foreign protein they just used their enzymes to digest on their surface they present it to passing helper T-cells to activate them. After this takes place the dendritic cells and macrophages release cytokines that stimulate the helper T-cells to grow and multiply into thousands of identical clones. This converts the naïve helper T-cells into effector helper T-cells which have no direct killing power but can regulate the immune response by releasing cytokines that attach to specific receptors on other immune cells to improve their killing ability and help them multiply.
Since there are only a limited number of cells in the adaptive immune system that can identify a specific microbe, it is important to be able to increase their population quickly in response to an attack. In addition, some of the activated helper T-cells remain within the lymph nodes to act as memory cells so the immune system can respond faster the next time. It is through the helper T-cells that the immune system demonstrates a measure of intelligence, by being able to adapt by knowing which specific reserves to multiply and mobilize in defending the body, both during present and future infections.
Just like the helper T-cell, the cytotoxic T-cell also has about a hundred thousand specific T-cell receptors on its surface that can detect only one specific antigen. After migrating to the secondary lymphoid tissue, dendritic cells that are infected with a virus or bacteria place foreign antigens on their surface so that a passing naive cytotoxic T-cell can attach to it to become activated. With the release of cytokines from either the dendritic cells or nearby helper T-cells that have responded to the same antigen, the cytotoxic T-cells grow and multiply into thousands of identical clones. These, effector cytotoxic T-cells, are now able to destroy any other host cell that has been infected by the same virus or bacteria. They use their specific receptors to identify and attach to the foreign antigens on their surface and then release deadly chemicals and enzymes to kill them.
Like all lymphocytes, B-cells are made in the bone marrow, but in contrast to T-cells, they remain there to mature. Once released, they migrate back and forth between the secondary lymphoid tissue and the blood patrolling for antigens. Each B-cell has about a hundred thousand specific B cell receptors on its plasma membrane that allow it to identify and attach to just one specific antigen. Unlike T-cells, B-cells do not need other cells to present them with antigens and when one attaches to its specific receptors it is brought into the B-cell. Using enzymes, the captured antigen is then processed and placed back onto its surface and when the now activated B-cell connects up with an effector helper T-cell that has been activated by the same antigen the latter releases cytokines that attach to specific receptors on the B-cell and stimulates it to multiply and become numerous identical plasma cells. Each of these plasma cells can produce millions of identical antibodies which are shaped to react to the specific antigen that started the immune process in the first place. In addition, just like the effector helper T-cells, some of these effector B-cells become memory cells which are stored in the secondary lymphoid tissue so the body can react faster the next time it becomes infected by the same microbe.
Just as a walled medieval town had to have enough defenders to prevent itself from being overrun by invaders, so too, clinical experience teaches that the body’s immune system must have enough specific cells and proteins to protect itself from serious infection. As noted above, without the right amounts of each of the cells and proteins of the innate immune system our earliest ancestors could not have survived to reproduce. It also tells us that the blood must have at least 500 million helper T-cells per liter to be sure there are enough cytotoxic T-cells, to kill cells that have been taken over by bacteria and viruses, and B-cells, to produce millions of different antibodies which together can detect about ten billion different antigens on invading microbes. How do we know this? HIV
HIV, human immunodeficiency virus, targets helper T-cells and when chronic HIV infection causes their level in the blood to drop below 200 million per liter then the person is said to have AIDS (acquired immunodeficiency syndrome). A person with HIV-AIDS is usually prone to not only severe infections caused by pathogenic microbes, but also opportunistic infections caused by microbes that usually do not cause infection in a person with normal immunity. HIV-AIDS can affect almost every organ system in the body and often results in the formation of different types of cancer as well. Having a helper T-cell blood count below 200 million per liter is not sufficient for allowing the adaptive immune system to do its job and is equivalent to not having enough defenders to protect a walled medieval town. The result for our earliest ancestors would have been death from overwhelming infection and sepsis.
Evolutionary biologists have imaginative theories about how the adaptive immune system came into being but none of them really accounts for all of the irreducibly complex parts needed for it to work properly, nor the natural survival capacity needed to be sure that there are enough of each of them to get the job of survival done properly. Now we’ll look at how the proteins of the adaptive immune system, the antibodies, work to provide the body’s defense with extra intelligence, firepower and precision accuracy.
Antibodies: The Proteins of the Adaptive Immune System
Activated B-cells helped by helper T-cells become plasma cells and produce antibodies, also called immunoglobulins or gamma globulins,which circulate in the blood as plasma proteins. When inflammation, caused by the release of chemicals from the first responders of the innate immune system, takes place, this allows not only immune cells from the blood to come to the field of battle, but also proteins like complement and immunoglobulins as well. Antibodies are good at helping other immune cells identify and kill bacteria, neutralizing toxins and limiting the effects of free viruses before they can enter a cell. To understand how antibodies work it is important to first look at their structure.
The antibody molecule consists of four chains of amino acids bonded to each other; two identical pairs of heavy and light chains joined together in the shape of a Y. The two connected heavy chains provide the basis of the Y-shaped structure while each light chain is connected to the outside of the branching portion of the heavy chain. The tips of the Y-shaped antibody molecule consist of the amino acids from the ends of each identical light and heavy chain. Together they form a specific chemical pattern with a three-dimensional shape that is identical to the antigen receptors on the B-cell that produced them. These tips at the end of the antibody molecule act as antigen-binding sites and are known as the Fab portion (antigen binding fragment). The amino acid structure that makes up the base, or stem, of the Y-shaped antibody molecule remains constant and is therefore called the Fc piece (constant fragment). It is the Fc piece that becomes activated after the Fab portions attach to the specific antigen and makes the antibodies ready for action.
Human DNA is programmed to produce about one million different heavy chains and about ten thousand different light chains, each with their own unique amino acid pattern. Since each B-cell produces only one specific antibody, made up of two pairs of identical heavy and light chains, it has been estimated that the body is capable of making over ten billion, (one million x ten thousand), different antibodies each with its own distinct combination of binding sites. This gives the body a wide array of specific sentries that are able to detect specific chemical patterns on various different invading microbes. Here are some of the ways that activated antibodies help the immune system defend the body from infection.
Recall, the neutrophils and macrophages of the innate immune system have their own receptors that attach to large parts of foreign proteins on invading micro-organisms. However, many pathogenic microbes have developed ways to evade detection and/or destruction by these phagocytic immune cells. Often, they can make themselves invisible which allows them to multiply and spread throughout the body. When antibodies become activated by attaching their Fab portions to the specific antigens on the cell surface of these pathogens their ability to evade and resist the neutrophils and macrophages is lost. The neutrophils and macrophages have specific receptors on their surface that can attach to the activated Fc piece of the antibody which allows them to now see and capture the pathogen. This activity is called enhanced attachment, or opsonization (Gk. opsonein: to buy food), because the antibodies help phagocytes attach to microbes and literally make microbial food available to them.
Another very important mechanism by which antibodies help kill microbes and infected host cells is by complement activation. As noted previously, there are three different pathways that activate the complement system. The most efficient one requires a specific antibody to use its Fab to attach to a specific antigen on the cell surface of the microbe to activate its Fc piece. Complement then attaches to the activated Fc piece which triggers the various complement proteins to become activated and in some circumstances form the Membrane Attack Complex to chemically drill a hole into the microbe to kill it. Also, some of the fragments of activated complement, especially C3b, can attach themselves to micro-organisms as well. Neutrophils and macrophages have specific complement receptors which allow them to attach to the pathogen and kill it. So, with the help of antibodies activated complement can help the phagocytic cells of the innate immune system be more effective at killing intruders through opsonization as well.
In addition to enhanced attachment and complement activation when antibodies attach to specific antigens on infected host cells this activates NK cells (natural killer), which are part of the innate immune system, that attach to the activated Fc piece and in a process called antibody-dependent cellular cytotoxicity (ADCC), release chemicals and enzymes into the infected cell causing its death. Moreover, both viruses and bacteria have specific structures on their outer surfaces that allow them to grab on to human cells to cause infection. When antibodies attach to the specific antigens on these outer structures they block the virus or bacteria from attaching to human cells and prevent infection. Also, some bacteria release toxins that must attach to receptors on the surface of host cells to cause damage. When antibodies attach to the specific molecular patterns on these toxins they block them from attaching to the host cell and prevent them from causing serious bodily harm. Finally, microbes have structures, like flagella and cilia, for mobility, which allow them to spread throughout the body. When antibodies attach to antigens on these structures, they cause them to malfunction and block the ability for these microbes to spread and do damage.
Primary immunodeficiencies are genetic conditions a person is born with which result in a poor immune response to infection. One example involves defective B-cell function and an almost total absence of antibodies, called Agammaglobulinemia. Infants receive temporary immunity from their mothers by antibodies crossing through the placenta into their blood. However, after six months, children with agammaglobulinemia start to have many different infections which, if not for modern medicine, would quickly lead to death. This shows that even if our earliest ancestors had all of the other parts of their immune system working properly, without enough antibodies, they were as good as dead.
Finally, it’s important to realize that just like the coagulation cascade and the complement system, which must turn on only when needed and stay or turn off when not, so too, clinical experience shows that when antibodies cause the body to over-react to itself or relatively harmless antigens, this can lead to major debility and even death. Allergies, such as hay fever and asthma, are caused by certain antibody responses to pollens and other chemicals, and when applied to venom from a bee sting can lead to anaphylactic shock. And when antibodies react to normal tissue and turn on the immune system in what is called autoimmune disease, this can often lead to inflammation, injury and even destruction of many different tissues and organs. So, it’s vital that not only all of the components of the immune system be present but they must also be properly controlled as well.
Points To Ponder
Clinical experience teaches that each component of the innate and adaptive immune system is needed for body survival against microbes. Without the first responders of the innate immune system the body would be unable to be warned of being invaded, notify and help others come to the battlefield through inflammation and chemotaxis, provide information about the invader to the adaptive immune system and start to actively defend the body from overwhelming infection. However, their mere presence is not enough to get the job done right for there has to be enough of them and they have to work fast enough and be effective enough. Likewise the blood borne immune cells of the innate system, the neutrophils, are absolutely needed to come to the battlefield and kill off the invader. But clinical experience teaches that there has to be enough of them and they must work fast and well enough to prevent the invading microbes from multiplying or else the body dies of sepsis. And the complement system is absolutely needed to be able to kill microbes and facilitate the ability for phagocytes to identify and kill them as well. But there has to be enough of the complement proteins and also their inhibitors to make sure that the system only turns on when it's supposed to and turns off and stays off when it's not.
The cells of the adaptive immune system, the lymphocytes, are all needed as well. The helper T-cells are absolutely necessary to turn on the cytotoxic T-cells which kill infected cells, and the B-cells which produce antibodies. But clinical experience shows that a deficiency of helper T-cells such as happens in HIV-AIDS makes people susceptible to widespread infection, not only due to pathogenic organisms but also opportunistic organisms as well. Finally, the proteins of the adaptive immune system, the antibodies, are absolutely needed to facilitate neutrophil and complement function and clinical experience shows that a deficiency causes sepsis and death from infection.
Since each part of the immune system is needed for survival, it is a system that, as Michael Behe would say, is irreducibly complex, in that if any one part were to be missing or not working properly our earliest ancestors could never have lived long enough to reproduce. But, it must also have a natural survival capacity to produce enough immune cells and proteins that together work fast enough and are effective enough to get the job done. Evolutionary biologists must explain how a system that must be irreducibly complex and have a natural survival capacity could come about by chance and the laws of nature alone.
Comparing how the immune system works to a military exercise in which an enemy must be tracked down, identified and destroyed, is appropriate because this is how it really works to keep the body alive. Evolutionary biologists usually point to the ability for micro-organisms to develop resistance to the body’s immune system and medical therapies through genetic modification as proof that life came about by chance and the laws of nature alone. However, this assumes the presence of the hardware needed to not only survive in the world but also to reproduce as well. As someone in the 19th century once said “natural selection may explain the survival of the fittest but it cannot explain the arrival of the fittest.” Once you have the system in place, it’s obvious that life can change over time, which is all that the word evolution denotes. But, the ability for life to change over time doesn’t necessarily mean, as evolutionary biologists teach our children, that it came about by chance and the laws of nature alone. Now consider this scenario.
The date is December 14th, 1799, and George Washington is suffering from a severe case of tonsillitis. One of the more prominent theories of the day is that infections are caused by the presence of ill humors in the blood which must be treated by bloodletting. So, in the midst of suffering from an acute infection, his medical attendants remove about five pints of blood over the next several hours. Modern practitioners of medicine know that infections are caused by germs, not ill humors, and that bleeding someone who has an acute infection is not only likely to cause further weakness but possibly even death. Even though microbes had been observed under the microscope for almost two hundred years it was not until the late 19th century that science began to recognize that specific germs cause specific diseases. Moreover it was not until Louis Pasteur disproved the theory of spontaneous generation (the belief that life could originate from inanimate matter) that science realized that many infectious diseases were indeed preventable.
Clearly, the medical profession of George Washington’s day was in error when it came to its understanding of infections. Moreover, their misguided notions of what caused disease led them to apply the standard treatment of the day (bloodletting) which may have even contributed to his death. This demonstrates how a strongly held, but erroneous idea can lead to certain assumptions and actions that are detrimental to human life, development and prosperity. In other words, ideas have consequences. The present theory of how life came into being presented by evolutionary biologists to students of science would appear, in principle, to involve a type of spontaneous generation called abiogenesis. The current thinking is that inanimate matter (chemical elements), under the influence of chance and the laws of nature were solely responsible for the development of multi-system organisms with complex body plans, like us. For vertebrates like fish, birds, reptiles, amphibians, and mammals, this means that the complex immune response noted above arose by these processes alone. If you look at what evolutionary biologists say about how life came into being, you'll notice that they only try to explain how life looks but not how it actually works to stay alive within nature. And the consequences of this strongly held, but in my opinion, erroneous idea, have become pervasive, affecting every aspect of our culture.
Be sure to catch all of the articles in Dr. Glicksman's series, "Beyond Irreducible Complexity."
Howard Glicksman M. D. graduated from the University of Toronto in 1978. He practiced primary care medicine for almost 25 yrs in Oakville, Ontario and Spring Hill, Florida. He now practices palliative medicine for a Hospice organization in his community. He has a special interest in how the ethos of our culture has been influenced by modern science’s understanding and promotion of what it means to be a human being.
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