Concepts of Biology (BIOL116) - Dr. S.G. Saupe; Biology Department, College of St. Benedict/St. John's University, Collegeville, MN 56321; ssaupe@csbsju.edu; http://www.employees.csbsju.edu/ssaupe/

The War Within:  A Look at the Immune System

I. The First Line of Defense - "the moat around the castle"

A. General characteristics.
    This provides a barrier to the entry of an invader; like a moat around a castle. There are two major features: (1) it is non-specific. In other words, it doesn’t respond to a specific pathogen, rather, it is a generalized response; and (2) it is an external defense mechanism, that is, one that deters the entry of the invader into body.  Characteristic of all animals; in some, it is their only line of defense against pathogens.

B. Examples.  There are a variety of mechanism that prevent pathogen entry into the body.  These include:

1. Intact skin and mucous membranes
2. Lysozyme - enzyme in secretions like tears and saliva; digests microbial cell walls. This is somewhat analogous to filling the moat with acid.
3. Ciliated cells - sweep away invaders, block entry
4. Gastric juices - harsh, acidic environment - more acid in the moat
5. Normal microflora out-competes invader - putting microbes to work for us.
6. Lactic acid - sebaceous glands in skin
7. Desquamation of skin cells - in other words, skin cells slough off, "washing off" pathogens
8. Hairs - block entry
9. Saliva, tears, sneezing - wash out invaders
10. Anaerobic bacteria - reduce oxygen levels, produce lactic acid

C. Back-up system.
    Pathogens that make it past the "first line" are confronted by additional lines of defense (some are general and others specific to the type of the invader)

II. The Second Line of Defense - responds to internal threats; more specific

A. Cellular defenses - occur in blood and lymph. These are derived from stem cells in bone marrow.

1. Neutrophils.
       Make up 60-70% of white blood cells, amoeboid, follow chemical signals, short-lived, self-destruct upon contact with invader ("kamikazes").
   
   
2. Macrophages.
       Large, long-lived, amoeboid with distinct pseudopodia, many "loiter" in organs where invaders come to them; they develop from monocytes.  These are antigen presenting cells - which essentially "advertises the kill" to other components of the immune to get ready for possible attack.
   
   
3. Neutrophils and macrophages together comprise the phagocytes
   
   
4. Eosinophils.
       Approx. 1.5% of white cells; limited phagocytic activity; these cells are granulated contain grains with digestive enzymes which are released on contact with an invader. Especially involved in fighting large parasites.
   
   
5. Natural Killer Cells.
       Destroy the bodies own infected cells

B. Antimicrobial Proteins.

1. Interferon.
       Secreted from virus-infected cells; there are three types alpha, beta and gamma; interferons ultimately interfere with the further spread of virus. Interferon stimulates other cells to produce proteins to inhibit viral replication. Interferon also activates natural killer cells that destroy viral-containing cells.
   
   
2. Interkeukin.
       Regulates various cells of the immus system.  Secreted by macrophages and leucocytes.
   
   
3. Tumor Necrosis Factor (TNF)
       Kills tumor cells, stimulates inflammatory response
   
   
4. Complement system.
       Group of about 20 blood proteins; inactive initially, become activated when bind to antibody bound to antigen. Once activated, this system is responsible for: (a) releasing chemicals to attract phagocytes; (b) bind to surface of invader to target for removal by phagocytosis (macrophages); and (c) induce lysis of invader.
   

C. Inflammatory Response.
    Triggered by tissue damage. Injured cells (basophils) release histamine which: (1) dilates blood vessels � increases blood flow � heat, redness, increased numbers of phagocytic cells; and (2) increases capillary permeability � release of fluid and white blood cells into interstitial fluid � swelling (edema), phagocytosis, clotting

D.  Fever.
    Interleukin-1 released by macrophages and other cells.  Rests temperature in hypothalamus.  

III. The Third Line of Defense - Cells of the Immune System

A. Immunology is the study of disease resistance.
    The job of the immune system is to: (1) recognize self vs. non-self (an invader); and then (2) inactivate, remove or destroy the invaders. This is an example of a very specific defense.

B.  Immunity is acquired by: 

1. previous exposure (by accident or vaccination) to a particular antigen (active immunity); or 
2. mother to child transfer through milk or placenta (passive immunity); or 
3. receiving antibodies from others (i.e., rabies; passive).

C.  MHC (major histocompatibility complex).
    Marker proteins occur on the surface of cells. These are unique for each individual. The Class I MHC are located on all nucleated cells, important in self vs. non-self recognition; class II MHC are on immune system cells; class III MCH - involved in complement system.  The immune system ignores cells with these markers.

D. Two main components to the immune system:

1. Humoral response - circulation of free antibodies; destroys free (not inside a cell) pathogens; extracellular. Named because it is associated with the "humors" (blood); and
   
2. Cell-mediated immunity - destroys cells containing intracellular pathogens (and transplanted tissues, cancer cells).

E. Antigens
    These are large molecules that initiate an immune response. Most are proteins (or large polysaccharides). They are called antigens because they are "antibody-generating"

F. Antibodies

1. Chemistry. 
       Antibodies are proteins (actually glycoproteins). Specifically, they are examples of immunoglobulins (Ig). All are basically Y-shaped molecules made of four polypeptide chains, 2 light and 2 heavy, that are held together by disulfide bonds. There are variable (V region) and constant (C region) regions in both chains. The constant regions are the same for all antibodies in a particular class. The variable region differs for every different antibody, of which there are countless numbers. The ends of the arms of the "Y" are sites for binding antigen. The base of the Y binds to B cells.
   
   
2. Types.
       There are 5 different classes based on their general molecular structure: IgG, IgM, IgA, IgD, IgE. They differ in the C region and have slightly different functions (i.e., IgA - is involved in allergic responses and IgE with histamine-secreting cells).
   
   
3. Action.
       Antibodies recognize specific antigens. They can: (1) neutralize the antigen directly (i.e., when bind to a toxin or flu virus); or (2) target an antigen for elimination by complement system or phagocytes.
   
   
4. Antibodies are produced by B cells.
   
   
5. B cells make about 10¹⁵ different antibodies. These are coded by a limited number of genes which randomly make different polypeptide chains resulting in many (billions) kinds of antibodies.

G. Lymphocytes.
    Main cell of the immune system; develop in bone marrow. They are concentrated in lymph nodes and other organs. They have cell surface receptors to detect antigens. There are two types of lymphocytes:

1. B lymphocytes.
       Mature in the BONE marrow, involved in humoral immunity (antibody-mediated), antibody producing. Antibodies stick out from cell surface. Types: 
   
   virgin B cells - not yet activated to produce antibodies;
   plasma cells - B cells activated to produce antibody; 
   memory B cells (continue to produce antibody long after exposure).  These are antigen presenting cells (APC)
   
   
   
2. T lymphocytes.
       Mature in the THYMUS, involved in cell-mediated immunity. Functioning in recognizing between self and no-self. They have a R cell antigen receptor (TCR).  Types:

• helper T's - master switch, the "commanders" of the immune system; CD4 receptor; they stimulate division of B cells and cytotoxic T cells;
• cytotoxic T's - destroy infected cells, cancer cells; CD8 receptors; and 
• suppressor T's - controls/slows immune response.
  

IV. The immune system in action.
    Scenario - let's imagine that the hepatitis A virus has breached our first wall of defense and is intent on attacking our liver.  

1. Macrophages engulf virus. However, some virus makes it to the liver and infects the liver cells.
   
   
2. Macrophages that have phagocytized the virus, transport pieces of the virus (antigens) to the cell surface where they bind to MHC II markers. This results in an antigen-MHC complex which advertises the kill to other immune system cells. This macrophage is now considered to be an "antigen presenting cell".
   
   
3. Antibodies sticking out from the surface of virgin B cells (those not previously exposed to antigen) bind to some of the virus. Binding of the virus antigens to the surface of the B cell "activates" the B cell. The B cell responds by transporting virus antigen that it has engulfed to the cell surface where it combines with the MHC II complex. Thus, the B cell is now an "antigen presenting cell" and it will respond to stimuli from helper T cells
   
   
4. The "antigen-presenting" macrophages activate helper T cells by: (a) secreting interleukin-1 (cytokines); and (b) binding with helper T cells. The helper T cells bind to the antigen-MHC II complex on the macrophage cell surface. The interaction between the MHC II - antigen complex and the T helper cells is facilitated by another surface marker protein, CD4.
   
   
5. In response to activation, the helper T cell begins to: (a) proliferate; and (b) secrete its own cytokines (interleukin-2).
   
   
6. Interleukin-2 secreted by activated helper T cells causes "previously activated" B cells to start dividing to yield a populations of B cells that (a) produces more antibodies (plasma cell; antibody factories) and (b) remember the invader for subsequent action (B memory cells).
   
   
7. Interleukin-2 secreted by activated helper T cells stimulates other helper T cells to grow and divide more rapidly (positive feedback).
   
   
8. The activated helper T cells:  (a) divide to produce other T cells (including memory T cells and cytotoxic T cells; and (b) activate cytotoxic T cells (using interleukin and other cytokines). The cytotoxic T cells then bind with an antigen-MHC I complex. Thus, this targets the bodies own cells which are infected with antigen for disposal (like infected liver cells, which move the virus antigen to the cell surface). Cytotoxic T cells release perforins (proteins that punch holes in cells causing them to lyse). Another cell surface molecule, CD8, helps the T cell in its interaction with the MHC I-antigen complex on the target cell.

V. Secondary response - much quicker because of memory cells

VI. Immunization

• Introduce killed or weakened (attenuated) pathogen (i.e., anthrax)
• Introduce closely related pathogen with same antigens (i.e., cowpox/small pox)
• Move the antigen-encoding genes into an innocuous virus and introduce that
• Purify antibody from other source and inject them; doesn't last. Tetanus and rabies are good examples, hence regular boosters. Another source of antibody is mother to offspring transfer thru milk or placenta.

VII Immune system problems

• Allergies - recognize antigens on pollen, etc., stimulates production of histamines, etc.
• Autoimmune disorders - attack your own cells (i.e., rheumatoid arthritis, SCID)
• Immunodeficiency - cell mediated response is weakened (i.e., HIV/AIDS)