THE IMMUNE SYSTEM

The Immune System - The immune system is involved in guarding our bodies from internal and external threats, including cancer.  Because of the important role of immune cells in preventing and possibly contributing to cancer, as well as the use of immune cells and products in treating cancer, the subject is treated here in detail.

Introduction to the Immune System

The immune system consists of a large number of different types of cells and proteins that function to distinguish between normal and abnormal cellular components and between 'self' and 'non-self'. As an example, when a thorn gets stuck in the body, the immune cells are able to recognized the thorn as a foreign object (i.e. 'non-self') and attack it. The same is true for bacteria, viruses or other organisms that can invade our bodies. A more subtle distinction between self and non-self occurs in the recognition of cancer cells by the forces of the immune system. The cancer cells are recognized and attacked because they differ from the normal 'self' from which they arose.

The cells and proteins of the immune system participate in two broad and somewhat overlapping types of immunity-Non-specific and Specific⁽¹⁾

The Innate Immune System

The innate immune system gets its name from that fact that we are all born with it already in place, and it changes little throughout our lives. This division of the immune system provides protection by recognizing general features of possible pathogens. For instance, barriers such as the skin block entry of many kinds of organisms. Similarly, cells of the innate immune response recognize general features of pathogens, such as the cell walls of bacteria. These cells do not distinguish within the various classes of pathogens. To use a military analogy, it would be like using the same type of missile to shoot at many different kinds of targets instead of having different missiles for different types of target. Macrophages, for instance, are cells that participate in the innate immune response by finding, eating, and killing many different types of bacteria. Natural killer cells (NK cells) are another type of immune cell that functions to eliminate cells that have become infected with viruses and cancer cells.⁽¹⁾

 There are several different components of the innate immune system.  While is it sometimes called 'non-specific' immunity, that is not really accurate.  The defenses presented below are geared toward specific kinds of living and non-living 'invaders'.  When an organisma or particle attempts to enter the body, there are several physical and chemical barriers that must be bypassed.  Our skin is a tough flexible shield that blocks many types of invaders.  The entry points to our body are protected by sticky mucus (i.e. mouth, nose,  anus, vagina) or wax (ears) that traps bacteria, dust and other particles.     Body secretions like the acid in our stomachs and proteins in saliva and tears also work to prevent entry.  Our hair keeps larger organisms from reaching our skin.  If an invading organism or particle (i.e. a thorn) do make it past these defenses, cells (produced in the bone marrow) like macrophages and neutrophils are waiting to attack the foreign object.

Roll your mouse over the graphic below to see some components of the innate immune system in humans.

The Acquired Immune Response

Specific or adaptive immunity is the second line of defense because it is initiated if the non-specific, innate immune response is unable to completely combat the invading pathogen. The two systems really overlap somewhat. As an example, proteins produced by cells of the adaptive immune system are present in secretions like tears that also contain proteins that are part of the innate immune system.

The adaptive response develops and changes over the course of our lifetimes and is thus also called acquired immunity. The cells and proteins of the adaptive immune response are highly specific for invading pathogens or abnormal cells within the body. This is in contrast to the broad spectrum activities of the components of the innate immune system.

Like our innate immune system, the specific immune response is composed of several different types of cells and the proteins that they produce. The main cells of the adaptive immune response originate in our bone marrow and mature at different locations in the body. The cells may float around in the blood stream or lymphatic system or take up residence in an organ or tissue. Two of the main cell types spend a significant amount of time in the lymphatic system and are known as lymphocytes. These two types of immune cells are called T cells and B cells. A major proteincomponent of the acquired immune system is the antibodies produced by B cells.⁽¹⁾

The specific immune response is an active system with four defining characteristics:

• Antigen Specificity-The cells and proteins of this system only recognize very particular protein fragments (peptides) on other cells or dissolved in body fluids
• Diversity in the number of peptides that can be recognized. The acquired immune system is capable of responding to an astounding number of different foreign proteins. The number of different proteins and organisms we encounter in our lifetime is enormous and the acquired immune system is able to generate a specific response against each one!
• Memory-A hallmark of the acquired immune response is that if the same foreign object is encountered again, the response is both more rapid and more intense. The system remembers the things it has encountered. This is accomplished by the generation of 'memory' cells that live for a long time, waiting for their chance to re-activate and lead the charge.
• Self:Non-Self Discrimination-The acquired immune system is able to recognize cells that have been altered in very minor ways and respond appropriately. An example of self:non-self discrimination is the rejection of an organ following transplantation. A kidney from one person may be recognized as 'non-self' by the recipient and destroyed. For this reason, transplant patients receive medications that lower their immune response.⁽¹⁾

Of importance to us: The genetic changes that make normal cells into cancer cells can also alter them in ways that can be detected by the immune system. 

The Lymphatic System

Once they are formed in the bone marrow, lymphocytes circulate in the body and reside in lymphatic tissue including lymph nodes and the spleen, where they search for and await contact with their target proteins. The lymphatic system is a system of vessels (tubes) that is present all throughout the body. Like the more familiar circulatory system, the lymphatic system carries fluid, proteins and cells of the immune system. Red blood cells are not found in the lymphatic system. The two systems (lymphatic and circulatory) are connected. The lymphatic system picks up fluid and cells from around the body and returns them to the circulatory system via ducts located in the neck/shoulder area. The fluid within the vessels is known as lymph.

Like smaller streams merging into rivers that ultimately flow into an ocean, small lymphatic vessels empty their contents into larger ones. The flow leads to collections of grape-like structures knowns as lymph nodes. Many cells in the immune system reside in the lymphatic system for much of their existence.

The lymphatic system is of great importance in cancer for several reasons:

• Cancer cells can spread (metastasize) by getting into the lymphatic system.
• Many cancer types are classified or staged by whether or not cancer cells can be found in lymph nodes close to the site of the original tumor. The logic is this: The lymphatic system is found all over the body so if cancer cells from a tumor have made it that far, they may also have traveled to distant locations.

Cells of the Acquired Immune Response

The main cells of the specific immune response are lymphocytes - B cells and T cells. All lymphocyte precursors originate in the bone marrow. The pre-B cells stay in the bone marrow to undergo further development, while the T cell precursors migrate to an immune organ located in the neck (the thymus) to further develop. In fact, T cells get their name from the thymus. For trivia buffs: B cells are named after an organ found in chickens (the bursa of Fabricius) where they were first studied. Humans do not have an equivalent organ.

Early in T cell and B cell development, developing cells that strongly react with normal cell proteins are removed from the system. In this way, the immune system ensures that the B cells and T cells do not kill normal body cells. If self-reactive T cells and B cells are not removed from the lymphocyte population, autoimmune diseases like lupus or rheumatoid arthritis may develop.

There are two classes of mature T cells:

• Helper T cells- These cells help other immune cells, including CTLs, macrophages and B cells, carry out their functions more efficiently.
• Cytotoxic T Lymphocytes (CTL)-(cyto=cell and toxic because they can kill) These are cells that are able to kill other cells, they are cellular assasins. They directly kill any cell that they recognize as abnormal, such as cells infected with viruses or cancer cells.

The immature T cells residing in the lymph nodes and spleen do not mature into full effector cells until an APC comes to them and shows them, or presents to them, a particular protein antigen. Once the T cell is notified by the APC that there are cells in the body expressing these abnormal proteins, the T cells mature and leave the lymph nodes and the spleen to circulate in the body and find the abnormal cells. When the T cells find the abnormal cells they are able to kill them. In the case of virus infection, killing the infected cell is a harsh but effective way to limit the production of the viruses within. Cancer cells may also be recognized and eliminated by cytotoxic cells of the immune system.

B cells are another critical component of the acquired immune response.  Like T cells, B cells are formed in the bone marrow.  The cells move out into the body to mature.  B cells are responsible for producing antibodies, proteins that recognize foreign objects that enter the body (viruses,bacteria, other proteins, etc.).  Different B cells can recognize different targets.  There are millions of different kinds of B cells in our bodies and our immune system can respond to a very large number of different 'foreign' targets.

The immune system functions as an effective surveillance system to eliminate abnormal cells and invading organisms from our bodies.

How the Immune System Sees the World

Our immune system constantly surveys our body checking for invaders, like bacteria and viruses. The system is also able to recognize when normal cells become altered such as cancer cells. Recognition of invaders or altered 'self' involves cooperation between different cells and is tightly controlled.

The exact steps involved in the generation of an immune response are slightly different depending on the type of threat (virus, bacteria, etc.) but in general, our cells recognize small parts of the target, usually protein fragments that are created by the digestion of a larger protein. For example, a bacterium that invades the skin via a wound may be recognized by the proteins on its surface.
A protein or other product (sugar, lipid, etc.) that can be recognized by the immune system and lead to the production of an immune response is known as an antigen.

Some immune cells, including macrophages and dendritic cells, are able to carry these proteins on their surface, like waving a flag! The fragments of proteins (antigens) are 'presented' to the B and T cells and cause those cells to become active. The cells that are able to present antigens are known, understandably enough, as Antigen Presenting Cells or APC.

Individual B cells and T cells each express a single type of receptor molecule on their cell membrane. They do have many copies of that receptor on their surface. These receptors are called B-cell receptors (BCR, or immunoglobulins) and T-cell receptors (TCR). Each of these receptors binds to just one very specific peptide (antigen) from an abnormal cell or foreign object. The expression of a single type of receptor ensures that each lymphocyte is specific for just one antigen. Unlike the cells of the innate immune response, lymphocytes can distinguish between very similar target molecules. There are enought different lymphocytes in the body to recognize more than one billion different peptides! This amazing diversity assures that there are cells that are able to recognize just about any target encountered in our lifetimes.

The specific immune response is divided into two parts, humoral and cellular immunity. Humoral immunity is dependent on the production of specific proteins known as antibodies. Antibodies are produced by B cells. These protein interceptors are are small Y-shaped molecules that circulate in blood and other body fluids. When an antibody bumps into its specific target (antigen) it binds tightly allowing the target to be destroyed or inactivated. Antibodies can

• Neutralize toxins
• Bind to viruses to prevent their entry into cells
• Bind molecules in the bloodstream leading to their clearance
• Mark the target for consumption by of the non-specific immune system
• Work with other proteins in the body to directly kill bacteria and parasites