Immune System

The immune system is composed of cells, organs, tissues, and molecules that protect the body from disease. The term “immunity” comes from the Latin word immunitas. It is roughly divided into two branches, “innate immunity” and “acquired (adaptive) immunity.” These two branches may interact to produce an immune response to protect the body from attack by infectious bacteria, viruses, parasites, or fungi, as well as abnormal conditions that may arise, such as cancer. Innate immunity refers to immunity that does not require prior contact with the attacking pathogen (organism that causes disease) in order to quickly initiate protective measures, rather, this type of immunity may be thought of as a defense system that is waiting on “stand-by” for attack by an unknown enemy, attempting to identify and destroy it. The other type of immunity, specific acquired immunity or adaptive immunity, acts somewhat like a “special forces unit” that develops in response to a specific, recognized enemy. Acquired immunity may arise as a result of previous exposure to a pathogen (i.e., the immunity one would obtain from a vaccination) or called into action by the innate immune system. Though very specific, acquired immunity requires time for development. Both branches of immunity, innate and acquired, work together in a coordinated effort to mount an amazingly orchestrated immune response to pathogenic attack, injury, and disease.

Some form of innate immunity can be found in a wide variety of organisms, ranging from plants, worms and fruit flies all the way to animals and humans. This ancient form of immunity has evolved as the first line of defense in the protection from disease. In humans, this type of immune response was once thought to be nonspecific and was previously referred to as nonspecific immunity. It is now known to involve specialized molecules (pattern recognition receptors) that have evolved over time that recognize specific molecular patterns on the surfaces of pathogens. In this regard, innate immunity is very efficient and works rapidly (within minutes) to mount an immune response. Innate immunity is involved in the protection of the body by preventing the offending pathogen from spreading by capturing it in phagocytic cells where they can be destroyed. It also assists in the recognition of molecules considered to be “nonself” (not part of the body) and presents them to the acquired immune system. The innate immune system is comprised of several elements that work in a coordinated fashion: physical barriers, phagocytic cells, pattern recognition receptors, immune pathways (complement and lectin), chemical messengers (i.e., cytokines, chemokines, interferons). Clearly, the interactions between all of these players are highly complex, and many details await discovery with critical implications for disease prevention and management.

Often, the invading pathogens first encounter the mucosal epithelia surfaces found in areas such as lungs, respiratory, gastrointestinal, and urogenital tracts. These areas are lined with epithelial cells and a mucus layer that prevents the attachment of the pathogens. Epithelial cells may be rapidly shed in areas such as the intestine, quickly eliminating infected cells from the system. The mucosal surfaces may secrete lysozyme and other substances such as lactoferrin, a protein that binds to iron and traps it so that it cannot be used by invading bacteria for growth. The cilia of the lung lungs are small, fine projections that help to move bacteria trapped in mucus out of the lungs and nose during coughing and sneezing, transporting secretions to the throat where they can be swallowed and destroyed by stomach acid. The lungs also produce surfactant proteins that help special cells of the immune system, the macrophages, engulf and destroy pathogens.

There are some types of bacteria, the “microflora,” that inhabit the skin surface, yet do not cause disease under normal conditions. The microflora may produce substances that kill other more harmful, pathogenic bacteria and fungi. The microflora may also consume some of the nutrients required by other pathogens. This gives rise to a competitive relationship between the microflora and the pathogens that limits the growth of the pathogens. In this regard, the microflora provide a helpful, delicate balance that helps to protect the body from disease.

MOLECULES AND CELLS INVOLVED IN INNATE IMMUNITY. Upon initial invasion into the body, as when the skin is broken due to injuries or burns, harmful bacteria may enter and establish a site of infection. Bacteria, viruses fungi, and parasites may be recognized by special molecules of the innate immune system called pattern recognition receptors (PRR). These receptors, found on a variety of cells in the body, recognize specific, common molecular patterns on pathogens that are required for their growth and survival (pathogen-associated molecular patterns or PAMPs). This highly efficient strategy allows the cells of the immune system to recognize a variety of harmful pathogens using a smaller pool receptors, thus, greatly simplifying the process.

PRRs are of several basic types including acute phase proteins, transmembrane proteins (those that span the membrane of the host cell), as well as intracellular PRR that can identify bacteria and viruses. During the course of an infection, several types of PRR may be used to fight an infection.

The acute phase proteins are involved in the inflammatory reaction that results in the development of a fever during an infection or an injury. One such acute phase protein, CRP (C-reactive protein), acts as a antibacterial protein, and high levels of this protein in the blood may indicate the presence of an infection or a chronic disease. Another acute phase protein, mannose-binding lectin recognizes a pattern of sugar molecules found in bacteria and viruses and assists in their destruction without affecting the host cells. Additional acute phase proteins include clotting factors and fibrinogen, which helps to prevent the pathogens from spreading through the bloodstream, some components of the complement proteins, protease inhibitors, proteins involved in transport, and proteins such as alpha-1 glycogprotein and serum amyloid A.

Of the transmembrane proteins, one particularly well-studied group is the Toll-like receptors. These receptors, named after receptors with similar structure identified in fruit flies (Drosophila melanogaster), are involved in the production of antimicrobial peptides. The Toll-like receptors in mammals, including humans, are found in many tissues on the surfaces of immune cells such as dendritic cells and macrophages. Once the Toll-like receptors recognize PAMPs on the pathogens, they may quickly jump-start a more specific immune response by causing the activation of special cells, the antigen-presenting cells (APC), to display portions of the foreign pathogens to the acquired immune system. The Toll-like receptors also cause phagocytic cells, such as macrophages and dendritic cells, to produce substances called cytokines and chemokines.

Chemokines are special proteins that affect other cells and attract them to sites of infection, and are involved in wound healing and affect the growth of tumors. Chemokines may also help to link the innate and adaptive immune systems together so that they can work in a coordinated way to eliminate the pathogens. Cytokines and chemokines, working together, constitute an immune response known as inflammation, which may be clinically observed by redness, swelling, pain, and heat.

Interferons (alpha and beta) are proteins that are produced when a cell is attacked and infected by a virus, and may prevent the spread of the virus to healthy cells. Interferons also activate the NK cells, a type of immune cell that can kill cells infected with viruses and those that harbor microbes.

The complement system is a group of proteins in the plasma or on cell surfaces that work together to cause inflammation and help to opsonize pathogens (coating them to enhance their uptake by immune cells for phagocytosis). The complement proteins become activated in areas of infection and initiate a series of enzymatic reactions that promote inflammation and lysis of the pathogens. Some parts of the complement proteins draw phagocytic cells to the site of infections, while other parts of complement may form membrane-attack complexes that damage bacteria by putting holes (pores) in their membranes.

If a micro-organism or other particle is able to invade the physical barriers of the body, there are a number of cells in the circulation that recognize the pathogen, using PRRs, and respond to the attack. The polymorphonuclear leukocytes (PMNs) are a group of cells that display a characteristic staining of granules in blood smears. These cells have a short life span in the blood (about two or three days), and make up the majority of the white blood cells under normal conditions (approximately 40%–75% of the blood). The neutrophils are some of the first responders to the site of an infection and are critical in the development of the immune response to pathogens. In response to cytokines produced by other cells, the neutrophil progenitor cells in the bone marrow rapidly produced large numbers of neutrophils that enter the bloodstream. The neutrophils can then migrate from the blood into the tissues during infection by a process known as chemotaxis (the movement of cells in response to and external chemical stimulation).

Once they encounter a pathogen or particle and recognize it, they may engulf it by a process known as phagocytosis, whereby a part of the neutrophils cell membrane engulfs the pathogen or particle and encloses it inside the cell within a vesicle called a phagosome where it may be destroyed by molecules that can kill it, such as lysozyme, myeloperoxidase, defensins, and lactoferrin. Neutrophils that have phagocytized a pathogen and destroyed it die shortly thereafter, and they are a large amount of the pus that is formed during some bacterial infections.

Special types of cells, the myeloid progenitor cells, reside within the bone marrow. These cells develop into monocytes that enter the bloodstream where they compose 2%–10% of the blood. After approximately one or two days, the monocytes then migrate into the tissues and become macrophages, where they may survive for long periods of time. The macrophages take on certain traits that depend on the type of tissue in which they are residing (alveolar macrophagesin the lung, Kupffer cells in the liver, microglial cells in the brain, spleen, lymph nodes, etc.). This distribution of macrophages throughout the body is called the mononuclear phagocyte system, which acts somewhat like a giant filter, assisting in the removal and destruction of harmful pathogens such as bacteria and fungi, as well as particles, dead cells, dust, etc. Like neutrophils, macrophages are capable of removing and ingesting microorganisms by phagocytosis. Macrophages may destroy phagocytized pathogens they have entrapped with lysosomal enzymes and special molecules called reactive oxygen intermediates, nitric oxide, and lysosomal proteases. Macrophages also produce cytokines, help heal injured tissue, and cause other types of acquired immune cells, the T cells, to become active.

The NK cells are a type of lymphocyte and comprise approximately 3% of normal blood circulation. NK cells can kill cells that are infected with viruses, as well as those that may harbor microbes within. Viruses cannot replicate without the help of the host cell. An infected cell must be recognized and destroyed before it can multiply within the host cell. One way in which NK cells can attack their targets with one of the components found in their granules (perforin), is to create a pore in the cell membrane of the target that allows destruction. NK cells can also induce their target to undergo a process called apoptosis (programmed cell death). Cells that are infected with viruses also secrete interferons that enhance the killing activities of the NK cells. NK cells are also capable of killing some tumor cells.

Mast cells are distributed in the connective tissues, especially in the skin and mucosal surfaces of the respiratory, gastrointestinal, and urogenital tract, in the blood vessels, as well as in the eye. Mast cells contain granules that contain histamine, leukotrienes, and prostoglandin. Histamine causes dilation of the smaller blood vessels and increases vascular permeability, and leukotrienes cause contraction of smooth muscle. Mast cells also release cytokines and chemokines. These cells are involved in defenses against parasitic and bacterial infections and are also highly active in the allergic response.

There are several other cell types involved in the innate immune response. The eosinophils are mainly involved in an immune response to parasitic infection (worms) and also play a role in the allergic response, and comprise only 1%–6% of the blood. The basophils, normally present in low numbers in the circulation (less than 1% of the blood), are thought to play a role in the inflammation and damage to tissue associated with allergic reactions. Platelets are cell fragments in the blood that are involved in blood clotting and inflammation.

The adaptive immunity is called into action when the innate system is unable to keep the invaders in check, and some pathogens may be able to escape detection by the innate immune system. This requires a more advanced strategy with specific recognition abilities and the means to prevent reinfection with immunological memory. This role is met by the acquired (adaptive) immune system, which may be likened to the “guided missle” of the immune response. This is dependent upon two broad divisions of special cells, the T and B cells (lymphocytes), which comprise 20%–50% of the white blood cells in normal adult human circulation. It also involves coordination with the cells of the innate immune system, the specialized substances produced to facilitate the cellular interactions, such as cytokines, chemokines, and complement, as well as lymphatic systems, organs, and tissues of the immune system.

CELLS INVOLVED IN ACQUIRED IMMUNITY.

A type of lymphocyte, T cells derive from stem cells in the bone marrow, but mature and differentiate in the thymus gland (hence the “T” designation). T cells assist in cellular immune responses, primarily detecting those host cells that have been infected and carry foreign material within them (intracellular infections). These recognize the presence of foreign antigens (materials that are not part of “self” that give rise to an immune response). The T cell may produce cytokines and toxic substances that may cause the infected cell to be killed, or possibly produce substances that activate other cell types, such as macrophages and B cells, to be become activated so that they can assist in the response.

The B cells mature in the bone marrow, and each B cell is designed to make a specific type of antibody that works against an antigen of the invader. B cells can recognize antigens with the help of T cells. Upon activation, B cells give rise to plasma cells, found in the lymph nodes, spleen, and bone marrow, which may rapidly produce more antibodies (immunoglobulins) at rates up to approximately 100,000 molecules per minute. The cells that recognize the antigen produce more cells of the same type to make antibody by a process called clonal selection. This builds up the antibody over a period of a few days so that a sufficient amount of antibody is generated to fight the infection.

Different types of antibodies are involved in specific activities, and they are incredibly diverse in their ability to recognize antigens. Antibodies can recognize almost any foreign invader or even synthetically produced molecules generated in the laboratory, which is very useful for drug development and biomedical research. There are several broad ways that antibodies work to help in immune responses. Antibodies may neutralize toxins that are produced by bacteria, Antibodies bind with pathogen proteins or antigens, and then the antibodies can be recognized by other cells and molecules of the innate immune system, such as macrophages and complement, to help remove the invader from the system. The B cells also give rise to memory cells that remain alive for long periods of time and assist in a more effective immune response upon the next exposure to the same antigen that is more pronounced, faster, and more specific. This is the principal behind the concept of vaccination, which makes use of immunological memory and B and T cell interactions to prepare an individual to mount an effective immune response when exposed to a pathogen.

CENTRAL LYMPHOID TISSUES. The central lymphoid organs include the bone marrow and thymus. At these sites, the lymphocytes interact with other cells to enhance their development or increase their ability to assist in an immune response. They also acquire the ability to recognize specific antigens before they actually become exposed to them, and are antigen-independent. At this stage the lymphocytes are called naive lymphocytes because they have not yet been exposed to antigens. The bone marrow is the site of hematopoiesis. Both B-lymphocytes and T-lymphocytes come from this site, but only the B cells undergo maturation in this area.

PERIPHERAL LYMPHOID TISSUES. The peripheral lymphoid tissues include the lymphatic vessels, lymph nodes, various lymphoid tissues, and spleen. The events that occur in these areas require exposure to an antigen, and are called antigen-dependent events.

LYMPHATIC VESSELS. The filtration of the blood results in the production of extracellular fluid called lymph. The lymphatic vessels that carry the fluid back to the bloodstream also carries cells that will present antigens. These antigens come from other sites within the body where infection may be present. The fluid passes through the lymph nodes. This fluid is eventually returned to the blood via lymphatic vessels. All the lymph from the body is carried back to the heart by way of the thoracic duct.

LYMPH NODES AND LYMPHOID TISSUE. Lymph nodes are distributed along lymphatic vessel pathways and act as a filter for the lymph. The lymph nodes are distributed throughout the lymphatic system, and are especially prominent in the neck, axilla (underarm), and groin. These fibrous nodes contain immune cells such as lymphocytes, macrophages, and dendritic cells. Dendritic cells have long, filamentous cytoplasmic processes. These processes have the ability to bind antibodies such that the antibodies can also bind with their specific antigens. This creates a web that traps antigens. The macrophages in the lymph nodes degrade debris and extract material that contains antigens, such as those from pathogenic bacteria. The structure of the lymph nodes is such that both T and B cells are exposed to this antigenic material. The cells that recognize this material are held in the lymphoid nodes and tissues where they multiply and differentiate. These cells become effector cells that are capable of fighting disease. The lymph node may enlarge during this process, giving rise to the clinical observation of swollen glands.

Lymphocytes can also be found in several other areas throughout the body. The gut-associated lymphoid tissue is a broad term that describes lymphoid tissue found in the Peyer patches of the intestine, appendix, adenoids, and tonsils. Cells that protect the respiratory tract are called bronchial-associated lymphoid tissue. Other mucosal areas are protected as well, and are collectively known as mucosal-associated lymphoid tissue.

SPLEEN. Blood is filtered in the spleen, where damaged or dead red blood cells are removed from the blood as well as antigens. This organ also serves as a site for storage of erythrocytes and platelets. In the fetus, it is the site of erythropoiesis (formation of red blood cells). Within this organ reside B cells, T cells, macrophages, and dendritic cells. As in the lymph nodes, lymphocytes are trapped in this organ. Antibodies and effector cells are produced in the spleen.

The function of the immune system is to defend against infection and disease. This body system works to detect, contain, and eliminate infection. It also helps control damage to cells in the body, and reacts in response to exposure or re-exposure of infection in individuals.

Hypersensitivity reactions result from an immunemediated inflammatory response to an antigen that would normally be innocuous (causing no harm to the body). Examples include allergic reactions, such as hay fever, asthma, reactions to insect bites, and the systemic anaphylactic shock that occurs in response to bee stings, allergies to antibiotics, and foods.

Delayed-type hypersensitivity reactions are due to the release of lymphokines. These lymphokines are small polypetides produced by lymphocytes that have been stimulated by an antigen, affecting other cells. This hypersensitivity reaction may occur as part of the normal immune response to infection by bacteria and viruses. This effect is responsible for the tissue damage in the lungs due to tuberculosis, the skin lesions that occur in leprosy and herpes, and rashes associated with chicken pox and measles. This may also occur via skin exposure to cosmetics, poison ivy, and allergy to metals in jewelry, resulting in contact dermatitis.

Autoimmune diseases occur when the immune system begins to attack the body or “self.” In Grave disease, antibodies are produced against the thyroidstimulating hormone (TSH) receptor. In multiple sclerosis (MS), antibodies are produced against elements of the myelin sheaths in the brain and spinal cord. The effects of myasthenia gravis are traced to antibodies directed against the acetylcholine receptor. Following a heart attack, antibodies may form against heart muscle antigens resulting in autoimmune myocarditis. Rheumatoid arthritis (RA) develops from complexes of antibodies to immunoglobulin G (IgG) in the joints and connective tissue. In systemic lupus erythematosus, the body produces antibodies directed against nuclear antigens and DNA.

There is considerable research interest in understanding the role of the immune system in a variety of clinical situations that affect public health. The underlying mechanisms of septic shock, a major cause of death, are currently the subject of intense research efforts. The link between sleep and immunity is under investigation, as well as the role of immunity in psychological disorders such as depression. The issue of defense against possible bioterrorism poses unique questions with regard to immunity. The problem of combating the spread of avian flu is the subject of much investigation, with difficulties due to the different subtypes of the antigens and the ability of the virus to mutate and change over time. Though understanding of immune system has grown considerably, it is clear that investigation will always be needed to combat the next challenge on the horizon.

There are many good reasons to exercise, one of which is that exercising helps strengthen the immune system. When physically active, the body increases white blood cells, helping individuals be more resistant to colds and flu, and enhancing the ability to resist allergic reactions.

Regular, moderate exercise clears the lungs and helps strengthen the immune system by improving blood flow and blood circulation in the body. In addition, muscle movement while walking, swimming, and lifting light weights support the lymph system to carry important immune cells throughout the body to ward of germs and remove bacteria. Daily exercise helps immune system cells travel effectively, going to where they are needed to fight infection.

Exercise also helps individuals achieve and maintain a healthy weight. Research studies indicate that obesity is linked to a decrease in immunity that is normally derived from a healthy immune system.

Engaging in exercise also helps reduce stress and anxiety, both of which can weaken the immune system. Exercise decreases the levels of stress hormones released by the body, boosting immune system activity and the ability to better respond to harmful organisms.

Because the immune system works in part at the cellular level, the practice of good nutrition is an integral part to staying healthy. There are many foods and nutrients that help to strengthen the immune system including:

See also Nutritional supplements .