The Immune System

Introduction

Immuno-oncology is an evolving field of study on the role of the immune system in cancer initiation and growth. This introductory module describes the purpose of the human immune system, components of the immune system, and innate and adaptive immune responses.

The immune system is the body’s biological defense system. The main purpose of the immune system is to identify self from non-self. The immune system identifies and defends the body from non-self proteins, viruses, bacteria, fungi, parasites and other pathogens. Occasionally, the immune system can make a mistake and attack itself, resulting in autoimmune disorders.

The immune system comprises many different cells, organs, and tissues that work together to combat infection, cellular damage and disease. Cells of the immune system include white blood cells, such as macrophages, as well as T and B lymphocytes. The main lymphoid tissues of the immune system are the thymus and the bone marrow.

Components of the Immune System

Organs and Tissues

The immune system consists of many parts that work together to defend the body against invaders. The primary parts of the immune system include the bone marrow and thymus. The bone marrow is extremely important to the immune system because all the body’s blood cells (including T and B lymphocytes) originate in the bone marrow. B lymphocytes remain in the marrow to mature, while T lymphocytes travel to the thymus.

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The thymus is a bi-lobed gland located above the heart, behind the sternum and between the lungs. The thymus is only active through puberty, then it slowly shrinks and is replaced by fat and connective tissue. The thymus is responsible for producing the hormone thymosin, which in turn aids in the production of T cells. While in the thymus, T cells multiply, acquire different antigen receptors, and differentiate into helper T cells and cytotoxic T cells. Various proteins (e.g., CD4, CD8) are expressed on the T cell surface. The thymus will have produced all the T cells an individual needs by puberty.

After the T and B lymphocytes have matured in the thymus and bone marrow, they then travel to the lymph nodes and spleen where they remain until the immune system is activated. Lymph nodes are located throughout the body. The spleen is located in the upper left area of the abdomen, behind the stomach, and under the diaphragm. The main function of the spleen is to filter the blood. Healthy red blood cells easily pass through the spleen; however, damaged red blood cells are broken down by macrophages (large white blood cells specialized in engulfing and digesting cellular debris, pathogens and other foreign substances in the body) in the spleen. The spleen serves as a storage unit for platelets and white blood cells. The spleen aids the immune system by identifying microorganisms that may cause infection.

In addition to the lymph nodes and spleen, mucosal associated lymphoid tissues (MALTs) and gut associated lymphoid tissues (GALTs) play a vital role in the immune system, although they are considered to be part of the lymphatic system. MALTs are lymphoid tissues found in parts of the body where mucosa is present, such as the intestines, eyes, nose, skin and mouth. They contain lymphocytes and macrophages that defend against pathogens attempting to enter from outside the body. GALTs are lymphoid tissues found in the mucosa and submucosa of the gastrointestinal tract, tonsils, appendix and Peyer’s patches in the small intestine.

Immune Cells

Many cells work together as part of the innate (non-specific) and adaptive (specific) immune system. See the module “Innate vs. Adaptive Immune Response” for more information on innate and adaptive immune response. Immune cells are sometimes called white blood cells or leukocytes.

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Granulocytes are a type of leukocyte that contain granules in their cytoplasm containing enzymes. Neutrophils, basophils and eosinophils are types of granulocytes. Neutrophils are considered the first responders of the innate immune system. Neutrophils and macrophages circulate though the blood and reside in tissues watching for potential problems. Both cells can “eat” bacteria, as well as communicate with other immune cells if an issue arises.

Cells of the adaptive immune system (also called immune effector cells) carry out an immune function in response to a stimulus. Natural killer T lymphocytes and B lymphocytes are examples of effector cells. For example, activated T lymphocytes destroy pathogens via cell-mediated response. Activated B cells secrete antibodies that aid in mounting an immune response. Effector cells are involved in the destruction of cancer.

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 Non-effector cells are antigen-presenting cells (APCs), such as dendritic cells, regulatory T cells, tumor-associated macrophages and myeloid-derived suppressor cells. Non-effector cells cannot cause tumor death on their own. Non-effector cells prevent the immune action of the effector cells. In cancer, non-effector cells allow tumors to grow.

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The Innate vs. Adaptive Immune Response

The first line of defense against non-self pathogens is the innate, or non-specific, immune response. The innate immune response consists of physical, chemical and cellular defenses against pathogens. The main purpose of the innate immune response is to immediately prevent the spread and movement of foreign pathogens throughout the body.

The second line of defense against non-self pathogens is called adaptive immune response. Adaptive immunity is also referred to as acquired immunity or specific immunity and is only found in vertebrates. The adaptive immune response is specific to the pathogen presented. The adaptive immune response is meant to attack non-self pathogens but can sometimes make errors and attack itself. When this happens, autoimmune diseases can develop (e.g., lupus, rheumatoid arthritis).

The hallmark of the adaptive immune system is clonal expansion of lymphocytes. Clonal expansion is the rapid increase of T and B lymphocytes from one or a few cells to millions. Each clone that originates from the original T or B lymphocyte has the same antigen receptor as the original and fights the same pathogen.

While the innate immune response is immediate, the adaptive immune response is not. However, the effect of the adaptive immune response is long-lasting, highly specific, and is sustained long-term by memory T cells.

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Inflammation

Inflammatory response plays a critical role in immunity. When tissues are damaged, the inflammatory response is initiated, and the immune system becomes mobilized. The immune cells of the innate immune system (i.e., neutrophils and eosinophils) are the first recruited to the site of tissue injury or damage via blood vessels and lymphatic system, followed by macrophages.

If the damage occurs near the surface of the skin, redness and swelling may be visible. Pain and warmth are also symptoms of inflammation.

The goals of the inflammatory response are to:

1. Prevent initial establishment of infection or remove damaged tissue.
2. Prevent the spread of infection or repair damaged tissue.
3. Recruit effector cells if the immune cells of the innate immune system cannot control infection or repair damaged tissue.
4. Mobilize effector cells (T and B lymphocytes).

Adaptive Immunity – Humoral and Cellular Immunity

There are two main mechanisms of immunity within the adaptive immune system – humoral and cellular.

Humoral immunity is also called antibody-mediated immunity. With assistance from helper T cells, B cells will differentiate into plasma B cells that can produce antibodies against a specific antigen. The humoral immune system deals with antigens from pathogens that are freely circulating, or outside the infected cells. Antibodies produced by the B cells will bind to antigens, neutralizing them, or causing lysis (dissolution or destruction of cells by a lysin) or phagocytosis.

Cellular immunity occurs inside infected cells and is mediated by T lymphocytes. The pathogen's antigens are expressed on the cell surface or on an antigen-presenting cell. Helper T cells release cytokines that help activated T cells bind to the infected cells’ MHC-antigen complex and differentiate the T cell into a cytotoxic T cell. The infected cell then undergoes lysis.

Activated vs. Anergic Immune Functionality

The activated immune system is one in which the white blood cells are actively mounting a response to an antigen or pathogen.

Anergy, or immune intolerance, occurs when the there is a failure to mount a complete immune response to an antigen. Anergy can occur in both T and B lymphocytes.