The Immune System
Leukocytes or white blood cells arise from stem cells in the bone marrow. The traditional classification system is based on their appearance and staining properties.

Granulocytes -- are grainy cells. These include the eosinophylls which stain red with eosin, basophylls which stain with basic stains and neutrophylls that don't stain very well. Neutrophylls are the domininat white cell and respond to early stages of infection.  When they mature they develop a multilobed nucleus and are called polymorphonuclear leukocytes.

Agranular leukocytes include phagocytotic monocytes and lymphocytes.  Lymphocytes include the B cells which produce antibodies and are central to the humoral response to infection; T cells that are responsible to the tissue level response and NK or natural killer cells.

The body has a number of defense mechanisms that prevent the entry of foreign organisms.  The skin and mucous membranes form a barrier that is also protected by secretions of tears, mucus, and digestive fluid.  When the barrier is broken and foreign organisms invade the body, there are two phases of the immune response: the non-specific phase and the specific phase.

Non-Specific Immunity

 

A. Phagocytosis

Neutrophylls, monocytes and tissue specific phaocytotic cells are capable of engulfing foreign organisms and digesting them. Cell wall components of bacteria attract these phagocytes.  Monocytes develop into macrophages under this stimulation. Tissue specific cells of the liver, spleen and lymph nodes also clear the tissue fluid of invaders.

B. Fever

    Activated macrophages release cytokines (interleukin 1, interleukin 6) that act as pyrogens to reset the hypothalamic thermostat. The body temp rises and plasma iron falls, bacteria are inhibited and neutrophylls are stimulated.

C. When infected with a virus, cells produce chemical messengers, the interferons which block viral reproduction in neighboring cells and help to curb the spread of infection. Alpha and beta interferon are produced by most cells of the body; gamma interferon is produced by NK cells and lymphocytes.
 

Specific Immunity
 
Molecules on the surface of foreign invaders, particularly proteins and glycoproteins are recognized by the immune system as non-self. These molecules, called antigens, trigger the body's specific defense system.
Most antigens are large molecules, but small molecles attached to a large molecule can also trigger a reaction.  The small molecules are called haptens.
Complications may arrise when foreign haptens attach to the body's own proteins.  This can trigger a reaction agains that body protein.

In specific immunity, the body produces antibodies that bind specifically to antigens.  There are two phases of this response  1) the humoral response mediated by antibody production of B cells and 2) the cell-mediated immunity produced by T cells.

These cells are produced from stem cells in the bone marrow and travel to the spleen, lymph glands and thymus for further maturation.

 A. The humoral response

  When B cells mature, they display a specific antibody on their sturface.  When they come in contact with a complementary antigen, they are stimulated to grow and divide.  The B cell becomes a very active protein producing factory. The cells enlarge and are known as plasma cells.  Anitibodies with the same specificity are produced, and now they are released from the cell into circulation.  Most plasma cells die within a week, but a few undergo a transformation to memory cells.  Memory cells remain in circulation for months to years.  They have the same specificity as the original B cell. If the body is infected again with that antigen, memory cells can mobilize very quickly to minimize the infection. Vaccines induce the production of memory cells so that the body can defend against specific infections.

B. Antibodies

    The proteins produced by B cells are called antibodies. An antibody consists of one or more Y shaped peptides. Each Y unit contains 4 peptides, 2 long chains and 2 short chains held together with disulfide bonds.  Each of the chains contains a constant region where amino acid sequences are the same for all antibodies and a variable region in the arms of the y where the sequences are variable and specific to a given B cell.  Antigens are bound to the variable region of the antibody.

 

There are several antibody types, also called immunoglobulins.
Ig M is a pentamer -- 5 y shaped units.  It is the first antibody produced by a B cell and remains attached to the cell surface.  This antibody is active in agglutination reactions where many antigens are clumped.
IgA is a dimer and it is secreted in tears and milk.
IgG is the most common of the antibodies, and it is a monomer.  After a B cell with IgM antibodies is stimulated, it will produce IgG antibodies with the same specificity for release.
IgD -- were are not completely sure about, but it seems to have a helper function.
IgE is the antibody produced in allergic reactions.

The genetics of antibody production is complex and unique.  Antibody peptides are coded by several gene for separate regions.  There are clusters of these genes that are assembled by splicing for specific antibody production.  Its estimated that a give person has 1020 different antibody molecules each specific for a given antigen.

C. Complement

There are two basic ways that an antigen antibody complex destroys a foreign invader.  The first is by creating a "tastier morsel".  When an invader is surrounded by antibodies, it is a more likely target for the phagocytosing neutrophylls and macrophages. This process is called opsonization.

The second pathway is the activation of the complement system.
There are 11 complement proteins that circulate in the serum in an inactive state.  When antibodies and antigens are bound a cascade of activation is triggered. The reactions recognize, react and attack a foreign organism.  In the attach phase, coplement proteins C5 through C9 form a ring shaped pore that is inserted into the wall of the invader and causes it to lyse.

D. Monoclonal antibodies

Antibodies against a specific antigen can be attached to other molecules -- radioactive isotopes, chemo agents,and  fluorescent tags. This provides a means of counting or killing cells that display a given unique antigen such as cancer cells.  Antibodies are produced by injecting an experimental animal with a given antigen and harvesting the B cells it produces in response.  These cells generall represent a range of antibodies against various regions of the antigen.  A given cell is hybridized with a cancerous B cell to "immortalize" it. The resulting hybridoma is grown to produce a source of a monoclonal antibody.

E. Allergies.
Some antigens, termed allergens trigger the release of IgE antibodies from specialized B cells.  The antibodies are inserted into the membrane of leucocytes called mast cells.  If the allergen is again presented to an activated mast cell, it binds to the cell surface of the mast cell.  This triggers the cell to release histamine and leucotrines that cause allergic reactions

F. Functions of T cells

    T cells produced in the bone marrow, mature in the thymus and seen the lymph nodes.  There are three recognized types of Ts.  Killer Ts, Helper Ts and Supressor Ts.  The killer or cytotoxic Ts attach the body's cells that have been infected with a foreign virus.  They produce a group of polypeptides called perforins that perforate the target cell's membrane.

Helper T's and Suppressor T's interact with B cells to stimulate and to shut down the immune response.

When a foreign antigen is presented, the inflammatory response is triggered.  Macrophages engulf the invaders and cytokines are released.  One of the cytokines released by macrophages, interleukin I actives T cells. Other cytokines are released by T cells and macrophages to stimulate granulocytes, B cells and T cells.  When macorphages digest the foreing organism, they encorporate some of the foreign protein in their plasma membrane.  These cells are termed antigen presenting cells.  Dendritic cells are also antigen presenting cells.  These cells originate in the bone marrow and reside in lymph tissue, the lungs and skin.

When the foreign protein is displayed by the APC, its recognized because it is in combination with the protein pattern normally on that cells's surface.  These proteins are part of the major histocompatibility complex.  These proteins are found on the surface of all body cells; Class I patterns are found on all body cells except blood cells and Class I are found on APC's and B cells. MHC molecules are produced by a set of 4 genes on chromosome 6. They are mixed and matched to produce patterns that are common to a species, common to an individual and common to a type of cell.

T cells do not produce antibodies, but they do have antibody like receptors on their surfaces that recognize antigens when they are presented on another cell's surface.  Killer T's recognize MHC I + foreign antigen and Helper T's recognize MHC II + foreign antigen.

When presented with foreign protein by an APC cell, a Helper T binds to it. A CD4 cofactor binds to tyhe MHC II complex and the T cell receptor binds to the foreign antigen+ MHC complex.  The Helper T is activated and produces interleukin I to stimulate other T cells and other factors which stimulate macrophage activity.

The activated T helper cell then may bind to a B cell recognizing it by the presence of MHC II molecules and foreign antigen bound by the antibodies on its surface.  This interaction stimulates the B cells to grow, proliferate and mature to plasma cells.