Immune System

The immune system is one of the 11 major systems in the human body. It protects us from invading microbes and pathogens such as bacteria, fungi, viruses, parasites, etc. In addition, the immune system plays a major role in helping our body to repair and heal itself from injury, a pathogen invasion or disease.

Whether you're diabetic or not, it is important that you keep your immune system strong to protect you against most diseases and illness, including the flu and the common cold.  

Your immune system protects your body against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from your own healthy cells and tissues in order to function properly. Detection is complicated as pathogens can evolve rapidly, and adapt to avoid the immune system and allow the pathogens to successfully infect our bodies.

When you catch a cold or the flu; or, when you develop a disease such as diabetes or cancer, the primary reason is due to inflammation and a weakened immune system that is unable to defend your body against the invading pathogens, viruses, fungi, and parasites; and the other health issues such as insulin resistance, high blood pressure, nutrient deficiencies, poor diet, and toxins.

Consequently, two of the most critical steps in being able to successfully prevent or  defeat any illness or disease are to reduce the inflammation and strengthen the immune system. But, first, let's take a look at how the immune system works.

Immune System: 3 Lines of Defense

The immune system is a collection of special cells, tissues and molecules that protects the body from numerous pathogenic microbes and toxins, utilizing 3 lines of defense:

1. Physical and Chemical Barriers (Innate Immunity)

2. Nonspecific Resistance (Innate Immunity)

3. Specific Resistance (Acquired or Adaptive Immunity)

1^st Line of Defense: Physical and Chemical Barriers

Physical Barriers include: the skin; mucous membranes; hair within the nose; cilia which lines the upper respiratory tract; urine which flushes microbes out of the urethra; defecation and vomiting which expel microorganisms.

Chemical Barriers include: lysozyme, an enzyme produced in tears, perspiration, and saliva can break down cell walls and thus acts as an antibiotic (kills bacteria); stomach gastric juice which destroys bacteria and most toxins; sebum (unsaturated fatty acids) provides a protective film on the skin and inhibits growth.

2^nd Line of Defense: Nonspecific Resistance (Innate Immunity)

The second line of defense is nonspecific resistance that destroys invaders in a generalized way without targeting specific individuals. White blood cells (called phagocytes) ingest and destroy all microbes that pass into body tissues. 

In addition, there is an inflammatory response in the localized tissue where the pathogen invaded the body or where the tissue was damaged due to a cut or wound. Inflammation brings more white blood cells to the site where the microbes have invaded. The inflammatory response produces swelling, redness, heat, pain and fever. Fever inhibits bacterial growth and increases the rate of tissue repair during an infection.

3^rd Line of Defense: Specific Resistance (Acquired Immunity)

The third line of defense is specific resistance. This system relies on antibodies, which are produced by specific immune cells (called B cells) in response to the antigens on the surface of the invading pathogens.

When an antigen is detected by a macrophage, this causes the T cells to become activated. The activation of T cells by a specific antigen is called cell-mediated immunity. The body contains millions of different T cells, each able to respond to one specific antigen.

The T cells secrete interleukin 2, which causes the proliferation of certain cytotoxic T cells and B cells. T cells stimulate B cells to divide, forming plasma cells that are able to produce antibodies and memory B cells.

If the same antigen enters the body later, the memory B cells divide to make more plasma cells and memory cells that can protect against future attacks by the same antigen.

When the T cells activate (stimulate) the B cells to divide into plasma cells, this is called antibody-mediated immunity.

Antibodies (also called immunoglobulins) are Y-shaped proteins that circulate through the blood stream and bind to specific antigens, thereby attacking microbes. The antibodies are transported through the blood and the lymph to the pathogen invasion site.

The body contains millions of different B cells, each able to respond to one specific antigen. 

Antibodies bind to an antigen, preventing its normal function or making it easier for phagocytic cells to ingest them; or, they activate a complement protein that kills the pathogen or signals other white blood cells; or they binds to the surface of macrophages to further facilitate phagocytosis.

Immune System Components

The major components of the immune system include the following:

Thymus: is located between your breast bone and your heart and is responsible for producing thymosin, which helps to activate T cells.  As we get older, this organ shrinks over 80% and produces less  thymosin and may be one of the reasons why our immune system weakens and we become more susceptible to certain diseases.

Spleen: filters the blood looking for foreign cells (the spleen is also looking for old red blood cells in need of replacement). A person missing their spleen gets sick much more often than someone with a spleen.

Lymph system: includes the tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. The channels that carry lymph are also part of this system.

Lymph is a clear-like liquid that bathes the cells with water and nutrients. Lymph is blood plasma -- the liquid that makes up blood minus the red and white cells. Think about it -- each cell does not have its own private blood vessel feeding it, yet it has to get food, water, and oxygen to survive. Blood transfers these materials to the lymph through the capillary walls, and lymph carries it to the cells.

The cells also produce proteins and waste products and the lymph absorbs these products and carries them away. Any random bacteria that enter the body also find their way into this inter-cell fluid. One job of the lymph system is to drain and filter these fluids to detect and remove the bacteria. Small lymph vessels collect the liquid and move it toward larger vessels so that the fluid finally arrives at the lymph nodes for processing.

Bone marrow: produces new blood cells, both red and white including B cells. In the case of red blood cells the cells are fully formed in the marrow and then enter the bloodstream. In the case of some white blood cells, the cells mature elsewhere. The marrow produces all blood cells from stem cells. They are called "stem cells" because they can branch off and become many different types of cells - they are precursors to different cell types. Stem cells change into actual, specific types of white blood cells.

White blood cells: also called leukocytes, are probably the most important part of your immune system. These cells work together to destroy bacteria and viruses. The different types of white blood cells include: Neutrophils, Eosinophils, Basophils, Monocytes, Lymphocytes, B cells, T cells, Helper T cells, Suppressor T cells, Killer T cells, Granulocytes, Plasma cells, Phagocytes, Dendritic cells, Natural Killer cells, and Macrophages.

Antibodies: (also referred to as immunoglobulins) are produced by white blood B cells. They are Y-shaped proteins that each respond to a specific antigen (bacteria, virus or toxin). Antibodies come in five classes: Immunoglobulin A (IgE), Immunoglobulin D (IgE), Immunoglobulin E (IgE), Immunoglobulin G (IgG), and Immunoglobulin M (IBM).

Antigen: The surface of every cell is covered with molecules that give it a unique set of characteristics. These molecules are called antigens. Antigens are generally fragments of protein or carbohydrate molecules. There are millions of different antigens and each one has a unique shape that can be recognized by white blood cells. The white blood cells then produce antibodies to match the shape of the antigens.

Some antigens (e.g. associated with bacteria, viruses, pollen, etc.) stimulate an immune response by a white blood (B) cell to generate antibodies specific to that antigen that matches the shape of the antigen.

Now the antibody can bind to that specific antigen to make it easier for other white blood cells to engulf or attack the bacteria or virus who brings the antigen with them.

The antigens on the surface of bacteria, viruses and other pathogenic cells are different from those on the surface of your own cells. This enables your immune system to distinguish pathogens from cells that are part of your body. Antigens are also found in foods like peanuts and on the surface of foreign materials like pollen, pet hairs and house dust where they can be responsible for triggering an allergy, hay-fever or asthma attacks.

Note: An antigen can be any substance (not just bacteria or viruses) that causes your immune system to produce antibodies against it, e.g. peanuts, pollen.

Lymphokines: are several hormones generated by components of the immune system. It is also known that certain hormones in the body suppress the immune system. Steroids and corticosteroids (components of adrenaline) suppress the immune system.

Tymosin (thought to be produced by the thymus) is a hormone that encourages lymphocyte production.

Interleukins are another type of hormone generated by white blood cells. For example, Interleukin-1 is produced by macrophages after they eat a foreign cell. IL-1 has an interesting side-effect - when it reaches the hypothalamus it produces fever and fatigue. The raised temperature of a fever is known to kill some bacteria.

Lymphokines are a subset of cytokines that are produced by lymphocytes. They are protein mediators typically produced by T cells to direct the immune system response by signaling between its cells. 

Lymphokines have many roles, including the attraction of other immune cells, including macrophages and other lymphocytes, to an infected site and their subsequent activation to prepare them to mount an immune response. Circulating lymphocytes can detect a very small concentration of lymphokine and then move up the concentration gradient towards where the immune response is required. Lymphokines aid B cells to produce antibodies.

Important lymphokines secreted by the T helper cell include: interleukin 2, 3, 4, 5, 6; granulocyte-macrophage colony-stimulating factor; and interferon-gamma.

Cytokines: are small peptides that act as signaling systems within the body. Because they facilitate communication between the innate and adaptive immune systems, cytokines are a key factor in fighting infection and maintaining homeostasis.

Cytokines include chemokines, interferons, interleukins, lymphokines, tumor necrosis factor. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells.

Proinflammatory cytokines such as interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) are released defensively in response to infection and trauma. Anti-inflammatory cytokines such as transforming growth factor beta (TGF-beta) and IL-10 oppose the action of the proinflammatory cytokines and promote healing. 

Some cytokines are chemical switches that turn certain immune cell types on and off. One cytokine, interleukin 2 (IL-2), triggers the immune system to produce T cells. IL-2’s immunity-boosting properties have traditionally made it a promising treatment for several illnesses. 

Elevated plasma levels of proinflammatory cytokines are biomarkers of inflammation and/or disease. An imbalance between the activity of proinflammatory and anti-inflammatory cytokines is believed to affect disease onset, course, and duration.

Anti-inflammatory cytokines is a general term for those immunoregulatory cytokines that counteract various aspects of inflammation, for example cell activation or the production of pro-inflammatory cytokines, and thus contribute to the control of the magnitude of the inflammatory responses. These mediators act mainly by the inhibition of the production of pro-inflammatory cytokines. 

The major anti-inflammatory cytokines are IL4, IL10, and IL13, and IL35. Other anti-inflammatory mediators include IL16, IFN-alpha, TGF-beta, IL1ra, G-CSF, as well as soluble receptors for TNF or IL6.

Tonsils: are lymphoepithelial tissues facing into the aerodigestive tract. These tissues are the immune system's first line of defense against ingested or inhaled foreign pathogens. The fundamental immunological roles of tonsils aren't yet understood.

Lymph nodes are distributed widely throughout areas of the body, including the armpit and stomach, and linked by lymphatic vessels. Lymph nodes are garrisons of B, T and other immune cells. Lymph nodes act as filters or traps for foreign particles and are important in the proper functioning of the immune system. They are packed tightly with the white blood cells, called lymphocytes and macrophages.

Skin: is one of the most important parts of the body because it interfaces with the environment, and is the first line of defense from external factors, acting as an anatomical barrier from pathogens and damage between the internal and external environment in bodily defense. Langerhans cells in the skin are part of the adaptive immune system.

Liver: has a wide range of functions, including immunological effects—the reticuloendothelial system of the liver contains many immunologically active cells, acting as a "sieve" for antigens carried to it via the portal system.

Bowel: There is lymphatic tissue in the bowel and in other mucous membranes in the body. The bowel plays a central role in defending the body against pathogens: More than half of all cells that produce antibodies are found in the bowel wall, especially in the last part of the small bowel and in the appendix. These cells recognize pathogens and other non-self substances, and mark and destroy them.

They also store information on these non-self substances to be able to react faster the next time. The large bowel also contains bacteria that belong to the body, called gut flora. These good bacteria in the large bowel make it difficult for other pathogens to settle and to enter the body.

Innate and Adaptive Immunity

The protection provided by the immune system is divided into two types of reactions: reactions of innate immunity and reactions of adaptive or acquired immunity. 

The innate immune system consists of cells and proteins that are always present and ready to mobilize and fight microbes at the site of infection. The main components of the innate immune system are 1) physical epithelial barriers; 2) phagocytic leukocytes (neutrophils, eosinophils, basophils); 3) monocytes (which develop into macrophages); 4) dendritic cells; 5) a special type of lymphocyte called natural killer (NK) cells; and, 6) circulating plasma proteins. Other participants in innate immunity include the complement system and cytokines such as interleukin 2 (IL-2). 

Innate immune cells express genetically encoded receptors, called Toll-like receptors (TLRs), which recognize general danger- or pathogen-associated patterns. Collectively, these receptors can broadly recognize viruses, bacteria, fungi, and even non-infectious problems. However, they cannot distinguish between specific strains of bacteria or viruses.

There are numerous types of innate immune cells with specialized functions. They include neutrophils, eosinophils, basophils, mast cells, monocytes, dendritic cells, and macrophages. 

Their main feature is the ability to respond quickly and broadly when a problem arises, typically leading to inflammation. Innate immune cells also are important for activating adaptive immunity. Innate cells are critical for host defense, and disorders in innate cell function may cause chronic susceptibility to infection.

The adaptive (or acquired) immune system is called into action against pathogens that are able to evade or overcome innate immune defenses. Components of the adaptive immune system are normally silent; however, when activated, these components “adapt” to the presence of infectious agents by activating, proliferating, and creating potent mechanisms for neutralizing or eliminating the microbes. There are two types of adaptive immune responses: 1) humoral immunity, mediated by antibodies produced by B lymphocytes; and, 2) cell-mediated immunity, mediated by T lymphocytes. 

The adaptive immune response is more complex than the innate. The antigen first must be processed and recognized. Once an antigen has been recognized, the adaptive immune system creates an army of immune cells specifically designed to attack that antigen. Adaptive immunity also includes a "memory" that makes future responses against a specific antigen more efficient.

Adaptive immune cells are more specialized, with each adaptive B or T cell bearing unique receptors, B-cell receptors (BCRs) and T-cell receptors (TCRs), that recognize specific signals rather than general patterns. 

Each receptor recognizes an antigen, which is simply any molecule that may bind to a BCR or TCR. Antigens are derived from a variety of sources including pathogens, host cells, and allergens. Antigens are typically processed by innate immune cells and presented to adaptive cells in the lymph nodes.

If a B or T cell has a receptor that recognizes an antigen from a pathogen and also receives cues from innate cells that something is wrong, the B or T cell will activate, divide, and disperse to address the problem. B cells make antibodies, which neutralize pathogens, rendering them harmless. T cells carry out multiple functions, including killing infected cells and activating or recruiting other immune cells. 

Certain T cells (Helper T) help activate B cells to secrete antibodies and macrophages to destroy ingested microbes. They also help activate other T cells called cytotoxic T cells to kill infected target cells. As dramatically demonstrated in AIDS patients, without Helper T cells we cannot defend ourselves even against many microbes that are normally harmless.

However, Helper T cells themselves can only function when activated to become effector cells. They are activated on the surface of antigen-presenting cells (APC), which mature during the innate immune responses triggered by an infection.

The innate responses also dictate what kind of effector cell a Helper T cell will develop into and thereby determine the nature of the adaptive immune response elicited.

The adaptive immune response has a system of checks and balances to prevent unnecessary activation that could cause damage to the host. If a B or T cell is auto-reactive, meaning its receptor recognizes antigens from the body's own cells, the cell will be deleted. Also, if a B or T cell does not receive signals from innate cells, it will not be optimally activated.

Immune memory is a feature of the adaptive immune response. After B or T cells are activated, they expand rapidly. As the problem resolves, cells stop dividing and are retained in the body as memory cells. The next time this same pathogen enters the body, a memory cell is already poised to react and can clear away the pathogen before it establishes itself.

A further aspect of the adaptive immune system worth mentioning is its role in monitoring body cells to check that they aren't infected by viruses or bacteria, for instance, or in order to make sure that they haven't become cancerous. Cancer occurs when certain body cells 'go wrong' and start dividing in an uncontrolled way.

The Major Cells of the Immune System

The key tissues and organs involved with the immune system include the lymph nodes, spleen, tonsils, bone marrow, thymus, and lymphatic tissue. The key immune cells are white blood cells (or leukocytes). The (3) major categories of white blood cells are: granulocytes, lymphocytes and monocytes.

Granulocytes are  characterized by the presence of granules in their cytoplasm which contain digestive enzymes that kill various types of bacteria and parasites. Granulocytes are also called polymorphonuclear leukocytes (PMN, PML, or PMNL) because of the varying shapes of the nucleus, which is usually lobed into three segments. The principal types of granulocytes are neutrophils, eosinophils, basophils, and mast cells.

Lymphocytes come in three major types: B-lymphocytes (or B cells), T-lymphocytes(or T cells) and natural killer (NK) cells.

Lymphocytes start out in the bone marrow and either stay there and mature into B cells, or they leave for the thymus gland, where they mature into T cells.

B cells produce antibodies in the humoral immune response and are like the body's military intelligence system, seeking out their targets and sending defenses to lock onto them. With the help of T cells, B cells make special Y-shaped protein antibodies, which stick to antigens on the surface of bacteria, stopping them in their tracks, creating clumps that alert your body to the presence of intruders.

Plasma cells, also called plasma B cells, secrete large volumes of antibodies.

Memory B cells are important in generating an accelerated and more robust antibody-mediated immune response in the case of re-infection (also known as a secondary immune response).

Regulatory B cells (Bregs) participates in immunomodulations and in suppression of immune responses. via production of anti-inflammatory cytokine interleukin 10 (IL-10).

T cells recognize and kill virus-infected cells directly. Some help B cells to make antibodies, which circulate and bind to antigens. Others send chemical instructions (cytokines) to the rest of the immune system. Types of T cells include Helper T (Th), Memory T (Tm), Cytotoxic T (Tc), Suppressor T (Treg), and Effector T cells.

Helper T Cells (Th) help activate B cells to secrete antibodies and macrophages to destroy ingested microbes, but they also help activate cytotoxic T cells to kill infected target cells. Note: In AIDS patients, without helper T cells we cannot defend ourselves even against many microbes that are normally harmless.

Memory T Cells (Tm) are derived from normal T cells that have learned how to overcome an invader by ‘remembering’ the strategy used to defeat previous infections. At a second encounter with the invader, memory T cells can reproduce to mount a faster and stronger immune response than the first time the immune system responded to the invader.

Cytotoxic T Cells (Tc) are lymphocytes that kill invading pathogens including cancer cells, cells that are infected (particularly with viruses), or cells that are damaged in other ways. Tc cells kill their targets by programming them to undergo apoptosis. The elimination of infected cells without the destruction of healthy tissue requires the cytotoxic mechanisms of CD8 T cells to be both powerful and accurately targeted.

Suppressor T Cells (Treg) suppress the immune response after invading organisms are destroyed by releasing their own lymphokines to signal all other immune-system participants to cease their attack.

Effector T cells (also called Helper T (Th) cells), are the functional cells for executing immune functions. Balanced immune responses can only be achieved by proper regulation of the differentiation and function of Th cells.

Natural killer (NK) cells are cytotoxic cells that participate in the innate immune response and attack in packs by releasing substances that perforate the "skin" of their victims -- this is death by cell lysis.

Monocytes, which are the largest of all leukocytes, fight off bacteria, viruses and fungi. Originally formed in the bone marrow, they are released into the blood and tissues. When certain germs enter the body, they quickly rush to the site for attack within 8–12 hours.

Monocytes have several functions to help you ward off diseases and infections. To help you remember what they do, note that each function begins with the letter 'M': Munch, Mount and Mend.

Munch: Monocytes have the ability to change into another cell form called macrophages before facing the germs. In response to inflammation signals, monocytes move quickly to sites of infection in the tissues and divide/differentiate into macrophages and dendritic cells to elicit an immune response. They change into macrophages when they move from the bloodstream to the tissues.

They consume, or munch, on harmful bacteria, fungi and viruses. Then, enzymes in the monocyte kill and break down the germs into pieces.

Mount: Monocytes help other white blood cells identify the type of germs that have invaded the body. After consuming the germs, the monocytes take parts of those germs, called antigens, and mount them outside their body like flags. Other white blood cells see the antigens and make antibodies designed to kill those specific types of germs.

Mend: Monocytes help mend damaged tissue by stopping the inflammation process. They remove dead cells from the sites of infection, which repairs wounds. They have also shown to influence the formation of some organs, like the heart and brain, by helping the components that hold tissues together.

Macrophages are derived from monocytes, granulocyte stem cells, or the cell division of pre-existing macrophages. Macrophages do not have granules but have receptors to detect, capture and ingest pathogens. Macrophages are found throughout the body in almost all tissues and organs, just below the surface of the skin and mucous membranes — any place where a pathogen could get through the first line of defense. Macrophages cause inflammation through the production of interleukin-1, interleukin-6, and TNF-alpha. Macrophages are usually only found in tissue and are rarely seen in blood circulation.

They take up and destroy necrotic cell debris and foreign material including viruses, bacteria, and tattoo ink. In wound healing, macrophages take on the role of wound protector by fighting infection and overseeing the repair process. Macrophages also produce chemical messengers, called growth factors, which help repair the wound.

When inflammation occurs, monocytes undergo a series of changes to become macrophages and target cells that need eliminating.

Once engulfed, cellular enzymes inside the macrophage destroy the ingested particle. Some macrophages act as scavengers, removing dead cells while others engulf microbes.

Another function of macrophages is to alert the immune system to microbial invasion. After ingesting a microbe, a macrophage presents a protein on its cell surface called an antigen, which signals the presence of the antigen to a corresponding T helper cell.

Macrophages change into foam cells in the blood vessel walls (endothelium), where they try to fight atherosclerosis by engulfing excessive cholesterol engulf large amounts of fatty substances, usually cholesterol. Foam cells are created when the body sends macrophages to the site of a fatty deposit on the blood vessel walls. The macrophage wraps around the fatty material in an attempt to destroy it and becomes filled with lipids (fats). The lipids engulfed by the macrophage give it a "foamy" appearance.

Foam cells are often found in the fatty streaks and plaques inside the blood vessel walls. Foam cells do not give off any specific signs or symptoms, but they are part of the cause of atherosclerosis. Foam cell development can be slowed, however. Decreasing low density lipoprotein (LDL) cholesterol and increasing high density lipoprotein (HDL) cholesterol will remove the lipids that the macrophages engulf to become foam cells.

In addition to the monocytes and macrophages, the other types of white blood cells include neutrophils, basophils, eosinophils, mast cells and dendritic cells.

Neutrophils defend against bacterial or fungal infection and other very small inflammatory processes. They are usually the first responders to microbial infection; their activity and death in large numbers forms pus.

Basophils are chiefly responsible for allergic reactions and antigen response by releasing the chemical histamine, which helps to trigger inflammation, and heparin, which prevents blood from clotting.

Eosinophils primarily deal with parasitic worm infections. They are also the predominant inflammatory cells in allergic reactions.

Mast cell is a type of granular basophil cell in connective tissue that releases heparin, histamine, and serotonin during inflammation and allergic reactions.

Dendritic cells (DCs), which can also develop from monocytes, are an important antigen-presenting cell (APC) whose main function is to process antigen material and present it on the cell surface to the T cells in order to activate the T cells. They act as messengers between the innate and the adaptive immune systems. Once activated, dendritic cells migrate to the lymph nodes where they interact with T cells and B cells to initiate and shape the adaptive immune response.

Note: Antigens are molecules from pathogens, host cells, and allergens that may be recognized by adaptive immune cells.

Antigen-presenting cells (APCs) like DCs are responsible for processing large molecules into "readable" fragments (antigens) recognized by adaptive B or T cells in order to activate them. However, antigens alone cannot activate T cells. They must be presented with the appropriate major histocompatibility complex (MHC) molecule "tags" expressed on the APC. MHC provides a checkpoint and helps immune cells distinguish between self and non-self cells.

An APC can be any of various cells (as a macrophage or a B cell) that take up and process an antigen into a form that when displayed at the cell surface in combination with an MHC molecule is recognized by and serves to activate a specific helper T cell using their T-cell receptors (TCRs).