Background Information
The Immune System
The human immune system is an amazingly complex network of organs, tissues and specialized cells that function together in intricate ways to protect our bodies from disease and injury. There are three levels of defense: first, the skin and mucous membranes, which provide a barrier for infection, our innate or nonspecific immunity, which is our second line of defense if the invading pathogens breach the skin, and third, specific immunity that targets pathogens not taken care of by the innate immune system.
First Line of Defense
Our first line of defense, the skin, and the mucous membranes of our respiratory, digestive, and urogenital tracts, provide a physical and chemical barrier to infection. Cells in the outer layer of the epidermis of the skin are constantly shed, along with microbes that may have attached to those cells. These cells also produce the protein keratin which helps form a tough, water resistant and microbe resistant barrier. Oil and sweat glands in the dermal layer of the skin secrete their products onto the surface of the skin. This keeps the skin flexible and reduces the chance of cracks forming which might allow the introduction of microbes. The secretions also create a slightly acidic environment (pH 3 to pH 5) which inhibits the growth of microbes 1. Pathogens can also enter the body through the respiratory, digestive and urogenital tracts, as well as the eyes. These areas have mucosal cells among the epithelial cells lining these tracts. Just like the skin, the epithelial cells of these areas are constantly shed. The mucous that covers the cells traps microbes so they can be eliminated. Microbes ingested with our food may be destroyed by enzymes in the saliva, by strong stomach acid, or be out-competed by the normal microbial population of our intestines. Cilia in the bronchial tubes sweeps microbes trapped in mucous up to the esophagus where they are swallowed and destroyed by stomach acids. Acidic urine and vaginal secretions create a less than favorable environment for invading microbes and help wash them out 2. However, all microbes are not completely inhibited. There are numerous species of bacteria and fungi, both mutualistic and commensalistic, which inhabit our bodies. These include Staphylococcus aureus, Staphylococcus epidermidis, and Escherichia coli. A good source of information and pictures of the various microbes that inhabit our skin and mucous membranes is at http://www.textbookofbacteriology.net/normalflora.html. Under normal conditions, these microbes help to protect us from pathogenic microbes which attempt to colonize or invade our skin. However, some of them may become pathogenic if introduced into the skin or if the immune system becomes compromised 3.
Second Line of Defense
Our second line of defense is innate or nonspecific immunity. This system attacks any invaders without specificity. It is composed of several types of cells, complement proteins and the immune response. Several types of leukocytes—white blood cells—are involved. Monocytes mature into macrophages—phagocytic cells similar to amoeba, which engulf their prey and then digest them with the aid of lysosomal enzymes. These cells can be found patrolling the interstitial fluid around cells. Langerhans cells are macrophages that live in the skin. Neutrophils make up 50 to 70% of all leukocytes, but live only about one day. They use chemotaxis to find foreign invaders and then phagocytosis to engulf them. Hydrogen peroxide and enzymes are used to destroy the invader, which leads to death of the neutrophil. Pus is an accumulation of dead neutrophils and other remnants of an infection. Eosinophils attack parasites, and basophils release histamines, causing an inflammatory response to infection 4. Natural Killer (NK) cells kill cells of the body that have been infected by viruses. The NK cells bind to the infected cell and release vesicles filled with perforin proteins and granzymes. The perforins form pores in the cell membrane of the infected cell, allowing entry to the granzymes which trigger apoptosis in the cell. As the cell is broken down, macrophages clean up the debris. Of course, the NK cells must find the infected cell and destroy it before viruses are assembled, otherwise it will be releasing viruses that can go on and infect other cells 5. In addition to these cells, several chemicals are produced. About thirty different kinds of complement proteins are produced which become activated by antibodies during an inflammatory response and insert themselves into a pathogen's membrane, forming a membrane attack complex, which creates pores in the cell. The cell is destroyed as extracellular fluid diffuses in, bursting the cell. Complement proteins can also trigger the release of histamine from mast cells and basophil cells, dilating capillaries. Interferons are proteins that are released by viral-infected cells to stimulate nearby cells to block virus production 6.
The Inflammatory Response
When cells are damaged, they release chemicals—histamine, prostaglandins, and bradykinin— which dilate nearby blood vessels and increase the flow of blood to the area 7. This causes several things to happen. The area will appear red from the increased flow of blood, bringing nutrients and oxygen to help heal the tissues. The warmth from the increased blood flow will help in the healing process as metabolism speeds up. Blood fluid leaking into the injured area causes swelling and pain as pressure builds up on nerve endings in the area. This increases the chance you will not use the injured area, giving it time to heal. Macrophages also enter the tissue from the blood, searching for bacteria that may have gained access. If they encounter bacteria, the macrophages release interleukin which travels to the brain, stimulating the hypothalamus to raise body temperature. Fever causes the liver and spleen to withhold iron from the blood. Because iron is an essential requirement for bacterial growth, this may be an adaptive response against the bacteria 8,9. Taking medication to reduce the fever may make us feel better, but may prolong the infection by allowing the bacteria access to an essential nutrient. However, fever may also be a manipulation of the host by the pathogen to create a more ideal environment for growth. It just depends on the type of pathogen. At times, the cost of letting the fever run its course may be greater than its benefits—being unable to carry out necessary activities, a drain on the body's nutrient reserves and tissue damage due to an elevated temperature 10.
Third Line of Defense—The Specific Immune Response
If invaders get past our innate immune system, then the specific immune system kicks in. It is sometimes called the adaptive immune system because it responds to specific types of pathogens that we come in contact with and it "remembers" them so that a return engagement is less likely to have dire consequences. For this to work, the system must be able to distinguish "self" from "non-self". The basis of this recognition system are antigens—molecules, often proteins, that may be fragments of a microorganism, surface proteins or glycoproteins on cell membranes, food items, pollen, or toxins. Antigens are also present on the cell surfaces of our own cells and are coded for by major histocompatibility complex genes (MHC). These genes are highly variable with hundreds of different alleles. The chance is rare that two people have exactly the same MHC alleles and therefore the same antigens. They are our label of "self". Recognition of the MHC proteins on our cell surfaces lets our immune system know what cells are friendly and which are not.
Two types of lymphocyte cells are involved in specific immunity and produce proteins which bind to foreign antigens—T cells and B cells. Both are formed by stem cells in the bone marrow. B-cells mature in the bone marrow; T cells mature in the thymus gland. B cells produce antibodies. Antibodies are made of 4 protein chains—2 longer heavy chains, and 2 shorter light chains that create a Y-shaped molecule. Both the heavy chains and the light chains have a variable region and a constant region. It is the variable regions which bind to antigens. During development of the B cells in the bone marrow, portions of the genes that code for these variable regions move around in the chromosome, rearranging themselves into different combinations in each B cell with the result that each B cell produces slightly different variable regions in these immunoglobin proteins. So at any one time, you have millions of different kinds of antibody-presenting B cells even though there are not millions of different genes for those antibodies. Then when an antigen comes along, the B cells that bind to that antigen with the right antibody (still on its surface) are partially activated. They take in the antigen and present fragments of it on their surface which helper T cells bind to. T cells finish the activation of the B cells by releasing cytokines which cause that B cell to start dividing; forming plasma cells which make the kind of antibodies that were first presented on the cell surface of the B cell—the ones that had the right variable region to bind to the antigen. So...no switching around of the variable gene segments this time; these clones will all make the same kind of antibodies which are now secreted from the cells.
If the maturing B cells in the bone marrow have made immunoglobin proteins which bind to self antigens on bone marrow stromal cells, they will self-destruct. Only about 10% will survive the cull. T cells go through a similar process in the thymus. When T cells migrate to the thymus, T cell receptor (TCR) proteins are produced by gene rearrangement that results in an enormous variety of different T cells—similar to the gene rearrangement that occurs with the B cells. TCRs are similar to the immunoglobins made by B cells but they are composed of only two protein chains, each with a constant region and a variable region. Like the immunoglobins, the variable region of the TCR binds to a self-MHC and peptide complex. Unlike immunoglobins, they remain in the cell membrane of the T cells and are not secreted. If they bind too tightly, or fail to bind at all to MHC antigens on specialized epithelial cells or to dendritic cells in the thymus, apoptosis is triggered. Only about 2-5% will have just the right amount of binding to MHC proteins and be released from the thymus 11.
T cells are the stars of cell-mediated immunity—one form of specific immunity. The two types of T cells are cytotoxic T cells and helper T cells. Most often, activation of cytotoxic T cells occurs when they encounter a non-self antigen presented on an MHC molecule on the surface of a dendritic cell in the lymph nodes. If the T cell has the right TCRs, it will bind to the MHC-peptide complex. This induces the T cell to begin dividing, creating more cytotoxic T cells with the same kind of TRCs, and memory cytotoxic T cells which will remain after the immune response. Activated cytotoxic T cells will induce apoptosis in any cell they find displaying the same MHC-peptide complex, in the same manner that natural killer cells do, using perforin proteins to rupture the cell membrane of the infected cell. Helper T cells are activated when macrophages that have engulfed some microbe, release interleukin-1, attracting the Helper T cells, which then bind to MHC-peptide complexes on macrophages. The Helper T cells begin dividing and producing more helper T cells and memory cells with identical TCRs to the first cell. They also release interleukin-2, which stimulates cytotoxic T cells to multiply. When the infection is under control, suppressor T cells turn off the response. Each variant of helper T cell releases a specific type of cytokine that binds to receptors on target cells of the immune system. The cytokine interferon stimulates and attracts macrophages. Interleukin-2 is also released when helper T cells bind to antigen presenting B cells, and activates the humoral response in B cells. 12,13
If T cells are the stars of the cell-mediated response, B cells rule the humoral response. They do not actively kill infected cells or invading microbes, but mark them for destruction by other members of the immune team. When a B cell encounters an antigen from an invading microbe that fits its surface immunoglobins (antibodies), it will phagocytize the antigen and present fragments of it on MHC proteins on its surface. Then a helper T cell will bind to the antigen-MHC complex and activate the B cell to start multiplying. In addition, the binding of free antigen alone can stimulate the B cells to divide. Some of these B cells will become memory B cells for future encounters with the pathogen, the rest become plasma cells, which begin producing and secreting antibodies which will bind to the foreign antigens, neutralizing them until macrophages or cytotoxic T cells can finish them off. There are five typesof antibodies. IgM, IgG, and IgD antibodies are surface receptors for antigens. IgM antibodies are the first type released in an immune response. They are composed of five Y-shaped immunoglobin proteins arranged in a ring. Both IgM and IgG antibodies, which are released in secondary responses, bind to antigens, causing agglutination. In the case of IgM antibodies, this attracts complement proteins which will perforate and kill the invading pathogen. IgG antibodies are more likely to attract macrophages which phagocytize the cell. IgA antibodies are found in secretions such as saliva and breast milk. IgE antibodies promote the release of histamine and are to blame for the overreaction of an allergy attack. 14
Diabetes
When food is digested, starch and other carbohydrates are broken down by enzymes into monosaccharides and pass from the cells lining the small intestines into the bloodstream. Beta cells in the islets of Langerhans in the pancreas detect the increasing levels of glucose in the blood as it passes through the pancreas and release insulin which stimulates liver and skeletal muscle cells to take up glucose from the blood stream and store it in the form of glycogen, and adipose cells to store the glucose as fat. When a person has not eaten for a while, or is exercising and cells are using up their supply of glucose, blood sugar levels drop and the hormone glucagon is released from alpha cells in the islets of Langerhans, stimulating liver cells to convert stored glycogen into glucose and release it into the bloodstream 15.
Diabetes mellitus is a disease that affects the body's ability to take up glucose sugar from the blood and into cells, either because of a lack of insulin or because the cells have reduced sensitivity to insulin. Without insulin, the body's cells are deprived of glucose, and blood sugar levels rise. There are two types of diabetes. Type 1, or juvenile diabetes, is an autoimmune disease in which the immune system attacks the beta cells in the pancreas which produce insulin. Type I diabetes is found in only 5 to 10 percent of all diabetics. It is only treatable with careful monitoring of blood sugar levels and diet, and insulin injections. Type 2 diabetes occurs most often in adults, and is associated with overeating. It is increasingly being diagnosed in children who are obese. Insulin is produced, but tissues in the body may be resistant to it. It is often treated simply by careful monitoring of the diet, exercise, and weight loss and rarely requires injections of insulin 16,17.
With either type of diabetes, when glucose levels in the bloodstream increase because glucose is not being taken up by the cells, damage can occur leading to dehydration, coma, and death. Glucose in the blood vessels reacts with proteins, causing vessel walls to thicken and the vessels to narrow. Nerve cells are damaged. Even when treated, the results of diabetes can be blindness, high blood pressure, heart disease, strokes, and tissue damage that leads to amputation. One of the first symptoms of diabetes is the production of high amounts of sugary urine 18. So what possible selective advantage could there have been in having such a disease?
In his book Survival of the Sickest, Dr. Sharon Moalem proposes a possible scenario for how having Type 1 diabetes might have given a survival advantage. First he describes the interesting case of two very different organisms and their rather similar reaction to cold temperatures. In the first case, a German vintner had a crop of grapes which were hit by frost. He went ahead and made wine from them anyway and it turned out to be an extraordinarily sweet wine—now called ice wine. The grapes had responded to the cold weather by getting rid of excess water, increasing their sugar concentration. This higher sugar concentration effectively acted as antifreeze, lowering the freezing point and protecting the grape cells from being ruptured by the ice crystals which would have formed 19.
The second story was about a small wood frog, Rana sylvatica, which survives the winters of North America by freezing. Its heart stops beating, it does not breathe and its brain does not appear to function. And yet, in the springtime, it thaws out and is perfectly fine. Its trick is that when the skin of the frog senses that the temperature is nearing the freezing point, water is moved out of its organs and blood and is collected in the abdomen. The liver releases large amounts of glucose into the blood, lowering the freezing point. The ice that forms, as the water in the abdominal cavity freezes, keeps the frog's organs on ice, without the dire consequences of ice crystal formation in the tissues. Large amounts of a clotting factor, fibrinogen, are also produced by the frog which will help protect it from any damage that occurs from being frozen 20.
The empty promises of cryogenics aside, humans do not have this capability. Or do we? Just after the last Ice Age, another brief period of cold weather occurred from about 13,000 years ago until 12,000 years ago 21. The humans who had migrated to northern Europe prior to this would have been tested by this fairly rapid climatic change. Many would have frozen to death, and yet many also survived. How? Some adaptations for living in cold environments have been observed in populations such as the Inuit and Norwegian fishermen. Hunter's response is the periodic re-dilation of blood vessels in the extremities that reduces the chance of frostbite in extremely cold weather. People who live in very cold conditions often have higher levels of brown fat—fat that contains a high concentration of mitochondria. It does not function in the same way that regular fat tissue does. Brown fat in the body does not require insulin to absorb glucose from the blood and it converts glucose into heat immediately, rather than storing it away. In babies, brown fat burns glucose to regulate body temperature until the baby is older. It is also active when a person is exposed to cold temperatures for a certain amount of time 22. Finally, people often have to urinate when exposed to the cold. This may be partially due to a rise in blood pressure due to the constriction of blood vessels in the extremities, which signals the kidneys to get rid of excess fluids. Dr. Moalem suggests that it may also be the same reason that the grapes and frogs rid themselves of water—to concentrate sugars in the blood and lower the freezing point 23.
One key to the answer, suggests Dr. Moalem, is to look at the rates of Type I diabetes. It is most common in people of Northern European descent—Finland, Sweden, the United Kingdom, and Norway—the area where this brief climatic cold spell occurred 24. A coincidence? Or is it the result of natural selection acting on a population living under extreme conditions? Could having diabetes have been a survival advantage in the extreme conditions of this area 13-12,000 years ago? Dr. Moalem says yes. Hunter's response might have helped them in gathering food. In this population, people who had inherited the genes that would increase blood sugar levels and eliminate water might have had an advantage in being able to withstand the cold conditions. Although in today's environment a rise in blood sugar might be fatal, they would have had so little food that blood sugar levels would already be low. The presence of more brown fat because of the cold would have helped them maintain body temperature, but also would have burned away some of the blood sugar (no insulin required) and the symptoms of these Ice-age diabetics might not have been so detrimental. If the diabetes-like condition was temporary, perhaps triggered by temperature, these individuals might have been able to survive long enough to reproduce. In fact, one of the possible triggers for Type 1 diabetes today may be cold weather. Most cases of Type 1 diabetes are diagnosed as temperatures start to drop and many diabetics observe seasonal changes in their blood glucose levels. Even levels of fibrinogen—the same protein that helps repair frog tissues when frozen—rise in humans in the winter months 25.
This theory has been given little support from other scientists. However, it does suggest how such diseases might give some selective advantage in a particular environment. Another theory proposed by University of California physiologist Jared Diamond suggests that one of the many genes for Type 1 diabetes (gene DR3) might confer a reproductive advantage—reducing the chances of miscarriage if the baby has inherited one copy of the DR3 gene 26. Inheriting one copy of this gene often results in late onset of Type 1 diabetes—when the person could have already reproduced 27.
Obesity
For millions of years our hominid ancestors were hunter-gatherers whose diet consisted of complex carbohydrates and very lean meat sources. Grains were rarely consumed. Then with the advent of farming and the domestication of animals about 10,000 years ago, the human diet started changing. Today our diets are largely dependent on highly processed grains and refined sugars. These grains are deficient in many important nutrients. The meat that we consume today from domesticated animals is much fattier than that of wild game. However, without this menu change brought about by the advent of agricultural practices, the human population would long ago have reached the carrying capacity of the earth for a hunter-gatherer type of diet based on wild food sources 28. Today, people rarely grow their own food, relying instead on highly processed food sources. We barely recognize where our food comes from. In wealthy countries like the U.S., the easy availability of food year round and the cultural push to buy more and eat more, coupled with a decrease in activity levels, have resulted in an increase in the incidence of obesity. When compared with the diet of a foraging population, the American diet consists of much less protein and much higher levels of simple carbohydrates and refined grains. These kinds of carbohydrates cause rapid increases in blood glucose levels, and a prolonged diet of these kinds of foods can lead to insulin resistance and the development of Type 2 diabetes. 29 Salt, sugar, and fats would have been in short supply for our Stone Age ancestors. It would have been an adaptive feature for them to eat as much of these things as possible when they had the chance. Today, when these items are available in great quantities, all the time, this adaptive craving causes us to overindulge. 30
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