1. Animals have physical barriers to invasion by foreign materials and organisms.

• For us, the first line of defense is the skin, which is fatty and of low pH and mucous membranes which are sometimes flushed by cilia and have lysozyme.

2. Animals have innate immune systems that attack foreign objects that get into the cell.

• For example, we have phagocytotic cells, including macrophages, that attack and engulf foreign organisms. (Macrophages also cooperate with the adaptive immune system, which we will consider next.) Important in the innate immune system are "toll-like receptors" (TLRs). These are transmembrane proteins that were first discovered in Drosophilia, the fruit fly, and are named for the German word "Toll", for amazing! TLRs are also important in the adaptive immune system of vertebrates.

3. Most animals do just fine with just physical barriers and an innate immune system. Homeotherms have the physical barriers and an innate immune systems but add an adaptive immune system that includes B and T lymphocytes. B-lymphocytes are lymphocytes which mature in the bursal tissues - the bursa of Fabricus in birds and bone marrow in humans.

• B-lymphocytes produce immunoglobulins (antibodies). Look here for a collection of images of immunoglobulin structures. The Fc portion is constant within a class of antibody and is involved in the complement pathway, binding to phagocytes, to mast cells, etc. The major classes of antibodies are:
  • IgG - 80 - 85% of circulating antibody. Bacterial invasion. Involved in the complement pathway for immune cytolysis, and is the only antibody to be able to cross the placenta.

  • IgA - two IgG-like units bound together. Major antibody in tears, saliva, mucous, colostrum and milk.

  • IgM - five IgG-like units in a sort of ring. Often for large antigens, used with complement for immune cytolysis. Found as the only antibody in some lower vertebrates.

  • IgD

  • IgE Allergy and hypersensitivity reactions. The Fc portion binds to Mast cells which produce vasoactive amines (histamines). An anti-helmintic (against worms!! - parasites!).

  • (Do you know what each of the classes of immunoglobulins acts on? Do you know how many IgG units each has? Did you look carefully at the diagrams of immunoglobulins and read the associated text?)

• During maturation, each B-lymphocyte shuffles gene segments to produce billions of variants which make unique Fab fragments. And, these genes mutate at a rate of about 100,000 times that of most other genes. When a lymphocyte encounters an antigen which fits the Fab fragment produced by that particular cell, it is stimulated to divide and produce a large clone of that cell line, producing a particular antibody. During fetal development, however, cells which find an antigen which fits die. And so, the fetus doesn't develop immunity to itself but the mature organism can make antibodies to any foreign substance.

• The classical complement pathway uses IgG or IgM to assemble a group of complement proteins which can cause immune cytolysis through the membrane attack complex which causes cell lysis. And, components of the complement pathway serve as attractants for phagocytes or cause histamine release from mast cells and basophils, which causes inflammation, which increases the permeability of the capillaries to blood cells, including white blood cells.

4. T-lymphocytes are lymphocytes which mature in the thymus. These cells are involved in inactivating antigens by direct contact (no antibodies) and produce cytokines.

• T-lymphocytes are involved in attacking virus infected cells. A CD4 (formerly T4) lymphocyte, a "helper T-cell", interacts with a macrophage or dendritic cell (both APC, antigen presenting cells). The APC has phagocytosed virus and presents pieces of the virus proteins on its cell surface. These virus proteins help binding of the APC to the CD4 cell in conjunction with the CD28 receptor of the CD4 cell. As a result of this interaction, the APC is activated. Look here for a nice figure illustrating this process. Notice the binding between the T-cell receptor (TCR) and the Major Histocompatibility Complex (MHC) on the APC.

Macrophages are derived from white blood cells called monocytes. After becoming macrophages, they migrate through the body, 'seeking' foreign substances. Dendritic cells are so named because they have dendrites, sharp projections of the cell membrane, similar in appearance (but not function) to the dendrites of nerve cells. Dendritic cells are concentrated right below the surface of the skin. Thus, immunity can be gained by injecting a foreign substance intradermally (right below the skin). With the 2004 shortage of flu vaccine, some physicians suggested that intradermal injection be considered since it uses less vaccine than the traditional intramuscular injection. Less vaccine is required since APCs are concentrated right below the skin

• The TCR looks a bit like an immunoglobulin, but the B-cell receptor IS a membrane bound version of an antibody. Here is a close up cartoon of the TCR and BCR.
• Now, the APC can bind to and activate a CD8 (formerly T8). These cells are known as "cytotoxic T-cells" because they can kill foreign or virus infected cells.
• The activated cytotoxic T cells produce perforin which causes holes to appear in the infected target cells, the infected cell lyses and is killed. Perforin was discovered by Dr. Eckard Podack, the chairman of the UM Department of Microbiology and Immunology.

5. The humoral immune system has an extensive set of interactions between helper cells and B-lymphocytes, much like described for the cellular immune system. And the cellular immune system has many more facets that the examples presented above.

All text and images, not attributed to others, including course examinations and sample questions, are Copyright, 2009, Thomas J. Herbert and may not be used for any commercial purpose without the express written permission of Thomas J. Herbert.