The immune system is designed to defend the body against foreign or dangerous invaders. Such invaders include microorganisms (commonly called germs, such as bacteria, viruses, and fungi), parasites (such as worms), cancer cells, and even transplanted organs and tissues (see Biology of the Immune System: Plan of Action). To defend the body against these invaders, the immune system must be able to distinguish between what belongs in the body (self) and what does not (nonself or foreign). Any substances that are identified as nonself, particularly if they are perceived as dangerous (for example, if they can cause disease), stimulate an immune response in the body. Such substances are called antigens. Antigens include any substance that can be recognized by the immune system.

Antigens may be contained within or on bacteria, viruses, other microorganisms, or cancer cells. Antigens may also exist on their own—for example, as food molecules or pollen. A normal immune response consists of recognizing a potentially harmful foreign antigen, activating and mobilizing forces to defend against it, and attacking it. If the immune system malfunctions and mistakes self for nonself, it may attack the body's own tissues, causing an autoimmune disorder, such as rheumatoid arthritis, thyroiditis, or systemic lupus erythematosus (lupus).

Understanding the Immune System
Antibody (immunoglobulin): A protein that is produced by B cells and that tightly binds to the antigen of an invader, tagging the invader for attack or directly neutralizing it. Antigen: Any substance that the immune system can recognize and can thus stimulate an immune response. B cell (B lymphocyte): A white blood cell that produces antibodies specific to the antigen that stimulated their production. Basophil: A white blood cell that releases histamine (a substance involved in allergic reactions) and that produces substances to attract other white blood cells (neutrophils and eosinophils) to a trouble spot. Cell: The smallest unit of a living organism, composed of a nucleus and cytoplasm surrounded by a membrane. Chemotaxis: The process of using a chemical substance to attract cells to a particular site. Complement system: A group of proteins that are involved in a series of reactions (called the complement cascade) designed to defend the body—for example, by killing bacteria and other foreign cells, making foreign cells easier for macrophages to identify and ingest, and attracting macrophages and neutrophils to a trouble spot. Cytokines: Proteins that are secreted by immune and other cells that act as the immune system's messengers to help regulate an immune response. Dendritic cell: A cell that is derived from white blood cells, resides in tissues, and helps T cells recognize foreign antigens. Eosinophil: A white blood cell that kills bacteria, that kills other foreign cells too big to ingest, that may help immobilize and kill parasites, that participates in allergic reactions, and that may help destroy cancer cells. Helper T cell: A white blood cell that helps B cells produce antibodies against foreign antigens, that helps killer T cells become active, and that stimulates macrophages. Histocompatibility: Literally, compatibility of tissue. Determined by human leukocyte antigens (see below) and used to determine whether a transplanted tissue or organ will be accepted by the recipient. Human leukocyte antigens (HLA): A group of identification molecules that are located on the surface of all cells in a combination that is almost unique for each person, thereby enabling the body to distinguish self from nonself. Also called the major histocompatibility complex. Immune complex: An antibody attached to an antigen. Immune response: The reaction of the immune system to an antigen. Immunoglobulin: An antibody. Interleukin: A type of messenger (cytokine) secreted by some white blood cells to affect other white blood cells. Killer (cytotoxic) T cell: A T cell that attaches to infected cells and cancer cells and kills them. Leukocyte: A white blood cell, such as a monocyte, a neutrophil, an eosinophil, a basophil, or a lymphocyte (a B cell or T cell). Lymphocyte: The white blood cell responsible for acquired (specific) immunity, including producing antibodies (by B cells), distinguishing self from nonself (by T cells), and killing infected cells and cancer cells (by killer T cells). Macrophage: A large cell that develops from a white blood cell called a monocyte, that ingests bacteria and other foreign cells, that helps T cells identify microorganisms and other foreign substances, and that is normally present in the lungs, skin, liver, and other tissues. Major histocompatibility complex (MHC): A synonym for human leukocyte antigens. Mast cell: A cell in tissues that releases histamine and other substances involved in inflammatory and allergic reactions. Molecule: A group of atoms chemically combined to form a unique substance. Natural killer cell: A type of white blood cell that can recognize and kill abnormal cells, such as certain infected cells and cancer cells, without having to first learn that the cells are abnormal. Neutrophil: A white blood cell that ingests and kills bacteria and other foreign cells. Phagocyte: A type of cell (such as a neutrophil or macrophage) that ingests and kills or destroys invading microorganisms, other cells, and cell fragments. Phagocytosis: The process of a cell engulfing and ingesting an invading microorganism, another cell, or a cell fragment. Receptor: A molecule on a cell's surface or inside the cell that can identify specific molecules, which fit precisely in it—as a key fits in its lock. Regulatory (suppressor) T cell: A white blood cell that helps end an immune response. T cell (T lymphocyte): A white blood cell that is involved in acquired immunity and that may be one of three types: helper, killer (cytotoxic), or regulatory.

Disorders of the immune system occur when

• The body generates an immune response against itself (an autoimmune disorder—see Allergic Reactions and Other Hypersensitivity Disorders: Autoimmune Disorders).
• The body cannot generate appropriate immune responses against invading microorganisms (an immunodeficiency disorder—see Immunodeficiency Disorders: Overview of Immunodeficiency Disorders).
• An excessive immune response to often harmless foreign antigens damages normal tissues (an allergic reaction—see Allergic Reactions and Other Hypersensitivity Disorders: Overview of Allergic Reactions).

Lines of Defense

The body has a series of defenses. Defenses include physical barriers, white blood cells, and molecules such as antibodies and complement proteins.

Physical barriers: The first line of defense against invaders is mechanical or physical barriers:

• The skin
• The cornea of the eyes
• Membranes lining the respiratory, digestive, urinary, and reproductive tracts

As long as these barriers remain unbroken, many invaders cannot enter the body. If a barrier is broken—for example, if extensive burns damage the skin—the risk of infection is increased. In addition, the barriers are defended by secretions containing enzymes that can destroy bacteria. Examples are sweat, tears in the eyes, mucus in the respiratory and digestive tracts, and secretions in the vagina.

White blood cells: The next line of defense involves certain white blood cells (leukocytes) that travel through the bloodstream and into tissues, searching for and attacking microorganisms and other invaders. This defense has two parts: innate and acquired immunity.

Innate (natural) immunity (see Biology of the Immune System: Innate Immunity) does not require a previous encounter with a microorganism or other invader to work effectively. It responds to invaders immediately, without needing to learn to recognize them. Several types of white blood cells are involved:

• Phagocytes ingest invaders. Phagocytes include macrophages, neutrophils, monocytes, and dendritic cells.
• Natural killer cells are formed ready to recognize and kill cancer cells and cells that are infected with certain viruses.
• Antigen-presenting cells help T cells (T lymphocytes) recognize invaders. Antigen-presenting cells consist of dendritic cells (the most effective), macrophages, and B cells.
• Some white blood cells release substances involved in inflammation and allergic reactions, such as histamine. Some of these cells often act on their own to destroy invaders.

In acquired (adaptive or specific) immunity (see Biology of the Immune System: Acquired Immunity), lymphocytes (B cells and T cells) encounter an invader, learn how to attack it, and remember the specific invader so that they can attack it even more efficiently the next time they encounter it. Acquired immunity takes time to develop after the initial encounter with a new invader because the lymphocytes must adapt to it. However, thereafter, response is quick. B cells and T cells work together to destroy invaders. Some of these cells do not directly destroy invaders but instead enable other white blood cells to recognize and destroy invaders.

Molecules: Innate immunity and acquired immunity interact, influencing each other directly or through molecules that attract or activate other cells of the immune system—as part of the mobilization step in defense (see Biology of the Immune System: Activation and mobilization). These molecules include cytokines (which are the messengers of the immune system), antibodies, and complement proteins (which form the complement system). These substances are not contained in cells but are dissolved in a body fluid, such as plasma (the liquid part of blood).

Some of these molecules, including some cytokines, promote inflammation. Inflammation occurs because these molecules attract immune system cells to the affected tissue. To help get these cells to the tissue, the body sends more blood to the tissue. To carry more blood to the tissue, blood vessels expand and become more porous, allowing more fluids and cells to leave blood vessels and enter the tissue. Inflammation thus tends to cause redness, warmth, and swelling. The purpose of inflammation is to contain the infection so that it does not spread. Then other substances produced by the immune system help the inflammation resolve and damaged tissues heal. Although inflammation may be bothersome, it indicates that the immune system is doing its job. However, excessive or long-term (chronic) inflammation can be harmful.

Organs: The immune system includes several organs in addition to cells dispersed throughout the body. These organs are classified as primary or secondary lymphoid organs.

The primary lymphoid organs are the sites where white blood cells are produced and/or multiply:

• The bone marrow produces all the different types of white blood cells, including neutrophils, eosinophils, basophils, monocytes, B cells, and the cells that develop into T cells (T cell precursors).
• In the thymus, T cells multiply and are trained to recognize foreign antigens and to ignore the body's own antigens. (T cells are critical for acquired immunity.)

When needed to defend the body, the white blood cells are mobilized, mainly from the bone marrow. They then move into the bloodstream and travel to wherever they are needed.

Lymphatic System: Helping Defend Against Infection The lymphatic system is a vital part of the immune system, along with the thymus, bone marrow, spleen, tonsils, appendix, and Peyer patches in the small intestine. The lymphatic system is a network of lymph nodes connected by lymphatic vessels. This system transports lymph throughout the body. Lymph is formed from fluid that seeps through the thin walls of capillaries into the body's tissues. This fluid contains oxygen, proteins, and other nutrients that nourish the tissues. Some of this fluid reenters the capillaries and some of it enters the lymphatic vessels (becoming lymph). Small lymphatic vessels connect to larger ones and eventually form the thoracic duct. The thoracic duct is the largest lymphatic vessel. It joins with the subclavian vein and thus returns lymph to the bloodstream. Lymph also transports foreign substances (such as bacteria), cancer cells, and dead or damaged cells that may be present in tissues into the lymphatic vessels and to lymph organs for disposal. Lymph contains many white blood cells. All substances transported by the lymph pass through at least one lymph node, where foreign substances can be filtered out and destroyed before fluid is returned to the bloodstream. In the lymph nodes, white blood cells can collect, interact with each other and with antigens, and generate immune responses to foreign substances. Lymph nodes contain a mesh of tissue that is tightly packed with B cells, T cells, dendritic cells, and macrophages. Harmful microorganisms are filtered through the mesh, then identified and attacked by B cells and T cells. Lymph nodes are often clustered in areas where the lymphatic vessels branch off, such as the neck, armpits, and groin.

The secondary lymphoid organs include the spleen, lymph nodes, tonsils, appendix, and Peyer patches in the small intestine. These organs trap microorganisms and other foreign substances and provide a place for mature cells of the immune system to collect, interact with each other and with the foreign substances, and generate a specific immune response.

The lymph nodes are strategically placed in the body and are connected by an extensive network of lymphatic vessels, which act as the immune system's circulatory system. The lymphatic system transports microorganisms, other foreign substances, cancer cells, and dead or damaged cells from the tissues to the lymph nodes, where these substances and cells are filtered out and destroyed. Then the filtered lymph is returned to the bloodstream.

Lymph nodes are one of the first places that cancer cells can spread. Thus, doctors often evaluate lymph nodes to determine whether a cancer has spread. Cancer cells in a lymph node can cause the node to swell. Lymph nodes can also swell after an infection because immune responses to infections are generated in lymph nodes. Sometimes lymph nodes swell because bacteria that are carried to a lymph node are not killed and cause an infection in the lymph node (lymphadenitis).

Plan of Action

A successful immune response to invaders requires recognition, activation and mobilization, regulation, and resolution.

Recognition: To be able to destroy invaders, the immune system must first recognize them. That is, the immune system must be able to distinguish what is nonself (foreign) from what is self. The immune system can make this distinction because all cells have identification molecules on their surface. Microorganisms are recognized because the identification molecules on their surface are foreign. In people, the most important self-identification molecules are called human leukocyte antigens (HLA) or the major histocompatibility complex (MHC). HLA molecules are called antigens because if transplanted, as in a kidney or skin graft, they can provoke an immune response in another person (normally, they do not provoke an immune response in the person who has them). Each person has an almost unique combination of HLAs. Each person's immune system normally recognizes this unique combination as self. A cell with molecules on its surface that are not identical to those on the body's own cells is identified as being foreign. The immune system then attacks that cell. Such a cell may be a microorganism, a cell from transplanted tissue, or one of the body's cells that has been infected by an invading microorganism or altered by cancer. (HLA molecules are what doctors try to match when a person needs an organ transplant.)

Some white blood cells—B cells (B lymphocytes)—can recognize invaders directly. But others—T cells (T lymphocytes)—need help from other cells of the immune system (called antigen-presenting cells). These cells ingest an invader and break it into fragments. The antigen fragments from the invader are combined with HLA molecules as they are assembled in the antigen-presenting cell. The combination of antigen fragments and HLA molecules is moved to the cell's surface. T cells that come into contact with the antigen-presenting cell can then learn to recognize the invader's antigen fragments. T cells are then activated and can begin fighting the invaders that have that antigen.

How T Lymphocytes Recognize Antigens

How T Cells Recognize Antigens T cells are part of the immune surveillance system. They travel through the bloodstream and lymphatic system. When they reach the lymph nodes or another secondary lymphoid organ, they look for foreign substances (antigens) in the body. However, before they can fully recognize and respond to a foreign antigen, the antigen must be processed and presented to the T cell by another white blood cell, called an antigen-presenting cell. Antigen-presenting cells consist of dendritic cells (which are the most effective), macrophages, and B cells.

Activation and mobilization: White blood cells are activated when they recognize invaders. For example, when the antigen-presenting cell presents antigen fragments bound to HLA to a T cell, the T cell attaches to the fragments and is activated. B cells can be activated directly by invaders. Once activated, white blood cells ingest or kill the invader or do both. Usually, more than one type of white blood cell is needed to kill an invader.

Immune cells, such as macrophages and activated T cells, release substances that attract other immune cells to the trouble spot, thus mobilizing defenses. The invader itself may release substances that attract immune cells.

Regulation: The immune response must be regulated to prevent extensive damage to the body, as occurs in autoimmune disorders. Regulatory (suppressor) T cells help control the response by secreting cytokines (chemical messengers of the immune system) that inhibit immune responses. These cells prevent the immune response from continuing indefinitely.

Resolution: Resolution involves confining the invader and eliminating it from the body. After the invader is eliminated, most white blood cells self-destruct and are ingested. Those that are spared are called memory cells. The body retains memory cells, which are part of acquired immunity, to remember specific invaders and respond more vigorously to them at the next encounter.

Last full review/revision March 2013 by Peter J. Delves, PhD