The Body's Defenses

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Summary

The First Line of Defense (nonspecific)

  • Skin
  • Mucous Membranes and their Secretions
    • Stomach acid
    • Mucous
    • Tears
    • Urine

The Second Line of Defense (nonspecific)

  • Phagocytic White Cells
    • neutrophils
    • monocytes / macrophages
    • eosinophils
  • Antimicrobial Proteins
    • complement
    • cytokines (interleukins)?
    • interferon
  • The Inflammatory Response and Fever
    • histamines
    • cytokines (interleukins)
    • pyrogens

The Third Line of Defense: The Immune system (specific mechanisms)

  • Lymphocytes (Cellular response - a 2 prong attack on invaders)
    • B-cells - antibodies
    • T-cells - help stimulate B-cells, other T-cells directly attack infected cells or are involved in self-regulation of the immune system.
  • Antibodies (Humoral response)

 

Basic Features of the Immune System

The Immune system's primary role is to protect the body against damage from any source that proves dangerous including viruses, bacteria, fungi, and other microorganisms as well as internal threats such as cancer. Evolution continues to improve the countermeasures parasites use to invade our bodies. Although our immune system is also capable of evolving to meet this challenge medical and technological advances so far have kept the legions of invaders at bay. How long will the uneasy peace last against constant new threats such as AIDS and E. Bola.

 

How does the immune system identify and respond to pathogens?

The first step involves the preparation of a molecule of foreign protein, referred to as an antigen, for identification. Macrophages such as the interdigitating dendritic cells and other so-called antigen-presenting cells, APCs, such as macrophages scavenge materials from the blood and tissues and digest them. Once inside these cells, small pieces of the antigens (peptides) enter a special processing center, a vacuole called the compartment for peptide loading or CPL, where they are bound to a special class of membrane proteins called major histocompatibility complex (MHC) molecules. The CPL somehow attaches the antigen to a class II MHC molecule and embeds it into the plasma membrane for all passing immune cells to see. It is this antigenic flag around which various lymphocytes rally.

MHC molecules are organized into 3 classes. (Class I molecules are found on all nucleated cells, class II are found on B-cells and macrophages, and class III are the various soluble proteins that make up complement.) Class I MHC molecules act as a badge identifying all nucleated cells as "self". T-cells have molecules called T-cell receptors which fit like lock and key to the Class I or Class II MHC molecules on normal healthy cells. But these T-cell receptors are actually a dual site, capable of recognizing a specific antigen which is attached to the MHC molecule. T-cells can only be activated when the antigen-MHC site is occupied (first signal), and a second, less understood, site is also involved (second signal). Conversely, anytime a T-cell gets the first signal but not the second it will be inactivated - perhaps by apoptosis. (A receptor protein coded CD28 is implicated)

The body's third and perhaps the ultimate line of defense is its immune system. It is distinguished from the nonspecific defenses by four features: specificity, diversity, self/non-self recognition, and memory.

  1. Specificity - the immune system's ability to recognize and eliminate particular microorganisms and foreign molecules called antigens.
  2. Diversity - the ability of the immune system to respond to millions of kinds of invaders, each recognized by its antigenic markers by a unique antibody producing lymphocyte.
  3. Self/Non-Self recognition. Why doesn't the immune system attack our own cells? The standard explanation is that the immune system is "trained" during its early development to recognize the difference between self and non-self. This is called self-tolerance. It is presumed that any lymphocytes with receptors for molecules present in the body (self) before birth (and perhaps after) are somehow destroyed. Thus there are no antigen receptors for an animal's own molecules. However it may be that the immune system responds to danger, actual damage detected as a special chemical signature caused by the rupture of injured or dying cells.
  4. Memory - refers to the immune system's ability to remember antigens it has encountered and to react quickly and effectively against them a second time around. This is known as acquired immunity. Acquired immunity may be active; conferred by recovery from a particular infectious disease; or passive&emdash;transferred from one individual to another&emdash;often obtained through vaccination. It the case of infants mom's antibodies can pass through the placental barrier.

When a lymphocyte first encounters an antigen it recognizes and is stimulated to divide it initiates the Primary Immune Response. The process involves clonal selection, the rapid development of a single line or lines of T- and B- lymphocytes from a vast and diverse army.

But before this occurs all pathogens must slip by the:

I. The First Line of Defense

  1. The skin is an effective physical barrier by being both tough (keratin resists the digestive enzymes of invading bacteria) and poisonous (certain fatty acids are toxic to bacteria as are secretions from sweat and oil glands which lower the pH of the skin somewhere between 3 and 5&emdash;a hostile environment for most pathogens).
  2. The secretions of the mucous membranes in the respiratory system effectively trap invading bacteria which can then be swept away by the ciliate lining.
  3. The nasal passages and sinuses are now known to make nitrous oxide and other nitrogen compounds which are toxic to a wide range of infectious microorganisms. "Unlike the nose, which harbors many types of bacteria, the sinuses...remain curiously free of intruders." The reason, recently discovered, is that the sinuses produce nitric oxide, NO, a gas considered a pollutant in the atmosphere is lethal even in small doses to bacterial and viruses, binding strongly to their vital enzymes. NO is made by the sinus' epithelial cells. (July '96, Discover)
  4. Most invaders cannot withstand the strong acid (HCl) found in the stomach.
  5. Anti-bacterial enzymes known as lysozymes are found in tears and other body secretions. Lysozymes (digestive enzymes) found in the respiratory tract and around the eyes attack the cell walls of many bacteria.
  6. Urinary passages are protected by the flushing action of urine.
  7. The vagina and lower intestine are protected by the symbiotic association of mutualistic bacteria which help crowd out dangerous species by using up available resources, out-competing the invaders or by creating a hostile environment.
  8. The inflammatory response and fever. Certain white blood cells release molecules called pyrogens which set the body's thermostat at a higher temperature. While a high fever is dangerous a moderate one inhibits the growth of some microorganisms (possibly by decreasing availability of iron) and can facilitate phagocytosis.

II. Secondary /Tertiary Defenses: Nonspecific and Specific

 

1A. Nonspecific, Chemical Secondary Defenses

 

  1. Histamine - speeds release of other agents both chemical and cellular and initiates the inflammatory response. Histamines (which are blocked by antihistamines) initiate the redness and swelling associated with inflammation and infection. Histamine is released by injured basophils and mast cells that are found in connective tissue. Histamine triggers local vasodilation and makes the capillaries leakier. Prostaglandins which are also released promote blood flow to the injury.
  2. Cytokinins (kinins or lymphokines)- attract phagocytes, increase inflammatory response. Released by injured cells, these short polypeptides increase circulation and capillary permeability; attract white blood cells to the injury or infection; and increase sensitivity of nerve endings. There are at present 16 known interleukins.

     

    1. interleukin 1 - (IL1) Discovered first, it stimulates cell division in T-cells when the proper combination of receptor proteins are linked between itself and the antigen presenting cell (APC) usually one of the macrophages.

      interleukin 2 - (IL2) Released by Helper T-cells when stimulated by interleukin 1. This actually stimulates the T-cells to grow and divide and release a messenger - interferon gamma

      interleukin 12 - appears to pack a double punch against tumors - shuts off new blood vessel growth and recruits natural killer cells (II,1B,3)

      interleukin 16 - made by the CD8 lymphocyte - this lymphokine attacks CD4 (T-helper) lymphocytes (the cells infected by the aids virus. It attaches to the surface of the CD4 cell, sending a message to its nucleus to stop HIV replication.

     

  3. Complement (Class III MHC molecules) are Antimicrobial proteins which speed phagocytosis and kill bacteria by lysis. Complement is a group of at least 20 proteins, named for their cooperation with other defense mechanisms. It helps indirectly by recruiting phagocytes or directly by lysing invading bacteria. Complement is essential in rapid clotting of blood, which begins the repair process and helps block the spread of pathogenic microbes to the rest of the body. Complement proteins act together in a precise cascade of activation steps (each one activating the next in the series) that culminates in the lysis of an invading bacteria. They assemble into ring like formations that penetrate the lipid bilayer of the bacterial membrane forming pores that allow water into the bacteria. Complement proteins can bridge the gap between 2 adjacent antibodies. This association of antibodies and complement activates the complement protein to form a membrane attack complex. Some are responsible for chemotaxis and recruitment of phagocytes to the infected site. The complement coats the surface of a bacterium. Because phagocytes have specific complement recognition sites, C3b receptors, they can lock on to the bacteria in a process called opsonization.
  4. Interferon - antimicrobial proteins which block viral protein synthesis and viral entry (activated by interleukins)

    Several varieties of interferon are known, and some are now mass produced by recombinant DNA technology. They are known to enhance both inflammatory and immune responses.

    Interferons are secreted by an infected cell, diffuse to neighboring cells, where they stimulate the production of other proteins that inhibit synthesis of viral coat protein and viral replication. The defense is not virus specific.

    One type of interferon activates phagocytes enhancing their ability to ingest an kill microorganisms.

 

 
1B. Non-specific Cellular Secondary Defenses

The leukocytes (white blood cells) are mobilized to attack invaders. They are produced continually by stem cells in regions of red bone marrow.

 

  1. Phagocytes - engulf bacteria (eosinophils, neutrophils, and monocytes. They are attracted to the site of infection by kinins and complement.
    1. Neutrophils make up about 60-70% of all white blood cells. These expendable front-line "foot soldiers" are attracted by various chemical signals (chemotaxis). They can leave the blood and enter infected tissue by amoeboid motion. They tend to self destruct as they destroy foreign invaders. About 100 billion are made every day of your life.
    2. Monocytes while only about 5% of the WBCs create a very effective defense. Once at the site of infection, they develop into macrophages, the largest phagocyte, and readily engulf microbes by extending pseudopods around them. Some macrophages are permanent residents of, and are given different names depending on, the tissue or organ they are found in. For instance microglia are special macrophages found only in the brain, and dendritic cells are located primarily in the skin. Macrophages have both class I and class II MHC molecules on their surfaces. These phagocytes are the voracious eaters at infection sites, readily engulfing invading organisms, cellular debris, and even free antigens, all of which are dealt with by the potent lysosomal enzymes&emdash;well not quite all. The macrophage can also become involved in "intelligence gathering" collecting various bits and pieces of the enemy and displaying their remains like some gruesome trophy of war. A newly discovered organelle has been found called the CPL (compartment for peptide loading) which processes the bits of ingested foreign protein and adds them to class II MHC molecules for presentation on the outer surface of the plasma membrane of macrophages (or B-lymphocytes?). Discover, 1-95
    3. Only about 1.5% of white blood cells are eosinophils. Although they have limited phagocytic activity they can destroy larger parasites such as worm larvae. This is accomplished by latching onto the surface of the parasite then releasing destructive enzymes stored within the cytoplasmic granules of the eosinophil.

     

  2. Basophils, release histamines, part of the inflammatory response.
  3. Natural Killer (NK) cells attack the body's own cells; either cells infected by a virus or cancerous cells.The NKs mode of destruction is not phagocytosis but an attack on the membrane of the target cell, which causes that cell to lyse (break open). This is similar to the cytotoxic T-cell but non-specific. They are recruited by IL-12 plus interferon gamma and suppress proliferation of antibodies by TH2 cells.

2A. Specific Chemical Tertiary Defenses (Humoral responses - antibodies)

When a virgin B-cell encounters an appropriately displayed antigen and a secondary signal (usually found on a Helper T-cell) it is prompted to divide, giving rise to a population of effectors called plasma cells.

 

  1. Specific antibodies secreted by plasma (B-cells) aid phagocytes. The circulating antibodies defend mainly against toxins, free bacteria, and viruses present in body fluids (humors). B-cells originate in the red bone marrow and in the fetal liver. Virgin B-cells mature to become plasma cells or memory B-cells by presenting a processed antigen to a corresponding helper T-cell which releases interleukin 1. When activated B-cells form an unmistakably extensive rough endoplasmic reticulum used to manufacture up to 2000 identical antibody proteins per second for the 4-5 day life span of these cells.
  2. Antibodies are large proteins composed of four polypeptides joined in the shape of a Y. Two chains are small and two large. All four polypeptides have constant regions that are the same for every antibody (of a class) and variable regions tailored to a specific foreign particle (antigen) Special proteins secreted by B-cells in response to and capable of combining with foreign substances are called antibodies. Also called immunoglobins (Igs). Every antibody has at least two identical sites that can reversibly bind to its antigen (epitope).

    Antigens are usually large organic molecules (>5000 daltons) such as proteins, carbohydrates, nucleic acids, and even some lipids.

    Relatively small localized region to which the antibody chemically bonds is called the antigenic determinant or epitope.

    Be able to draw and label a typical antibody:

    Antibody Links:

  3. Mammalian antibodies are placed into 5 classes according to the nature of their constant region. Each class has a different function in the humoral response. (IgM, IgG, IgA, IgD, IgE)

    Of the millions of different antibodies produced by B-cells only a few will ever be needed.

     

  4. Antigen / Antibody Interactions. How antibodies Work. Neutralization, agglutination, precipitation, activation of complement.
    1. Neutralization occurs when antibodies block viral binding sites or coat a toxin.
    2. Agglutination (gluing together) in which antibodies with multiple binding sites stick large groups of particulate antigens (such as bacteria) together making the whole mess easier to dispose of, by macrophages, and other phagocytes. Agglutination is possible because each antibody molecule has 2 antigen binding sites and can cross link adjacent antigens.
    3. Precipitation of soluble antigens by a similar process makes these numerous molecules easier for phagocytes to find and engulf.
    4. Certain interactions between antibody and antigen activates the complement system.

     

    1. Opsonization. various antibodies can cover the surface of a multi-antigenic invader such as a bacterium. The constant regions bristle out of the bacterial surface, exposing special sites (Fc region) which bind to Fc receptors on the surface of phagocytes.

     

  5. Memory B-cells act as "reserve army" fully prepared to respond quickly to reoccurrence of infection by the same pathogen.

    Some cells in the B-cell population acquire a lasting memory and remain for many years after the primary response is over to provide immunity to the same pathogen. However, some microbes like the flu virus mutate so rapidly that the immune system eventually will not recognize it, thus necessitating a new primary response.

 
2B. Specific Cellular (Tertiary) Defenses

Lymphocytes of the cell-mediated system defend against bacteria and viruses inside the host's cells, and against fungi, protozoans, and worms. T-Cells

Some stem cells originating in the red bone marrow, migrate to and mature in the thymus gland to become virgin T-cells each with its own unique T-cell Receptor protein. When a Virgin T-cell encounters an antigen that it recognizes plus the appropriate secondary signal it divides to give rise to a population of effector cells.

Each T-cell is equipped with antigen-specific receptor molecules (Similar to, but not exactly antibodies) that enable it to recognize just one type of antigen fragment attached to an MHC molecule. If a T-cell finds a matching antigen on a presenting cell and if that presenting cell offers the appropriate signals, the T-lymphocyte responds in two major ways. One is to enlarge and repeatedly divide, thereby increasing the number of cells that react to the antigen. The other is to secrete lymphokines (cytokines such as interleukin), proteins that directly inhibit the pathogen or that recruit other cells to join in the immune response.

  1. Helper T-cells which activate B-cells (and therefore antibody production). Helper T-cells recognize Class II MHC molecules, which are only found on macrophages and B-cells.
  2. Cytotoxic T-cells that kill virus-infected cells. Cytotoxic T-cells only recognize Class I MHC molecules cradling a specific antigen. These cells are stimulated to reproduce by specific Helper T-cells.

    Cytotoxic T-cells by recognizing specific antigens in association with class I MHC molecules, can bind to any cell of the body infected by that particular antigenic invader. If docking is successful the cytotoxic T-cell releases a protein called perforin which creates lesions in the infected cell's membrane leading to the cells lysis - spilling out the invader and other chemicals which quickly attract other lymphocytes and macrophages.

  3. Suppresser T-cells which somehow suppresses the positive feedback characteristic of the immune response.
  4. Memory T-cells act as a "reserve army"

2C Regulation of the immune system.

"We are constantly acquiring tolerance to our own proteins." The self in other words is constantly being defined anew.

T-cell anergy - When cells of the immune system "see" antigens in the absence of the right cosignals, they shut themselves down instead of attacking. (Scientific American, Aug. 1993)

Because some of the molecules to which the system can react are part of the bodies normal tissues the immune system must go through a series of modifications that prevent self-destruction. This process is known as tolerance induction (self vs. non-self recognition)

Mechanisms to induce tolerance

  1. physical elimination of lymphocytes that recognize the body's molecules during early development which is referred to as a clonal deletion.
  2. immuno-regulation, involves the generation of regulatory cells that weaken harmful or inappropriate lymphocyte responses
  3. Anergy: the process of turning off reactive cells. The (CD28)/(B7/BB1) complex is the cosignal postulated by Lafferty and Cunningham and in 1993 confirmed by Ronald H. Schwartz. The (CD28)/(B7/BB1) cosignal may be induced as a consequence of the interaction of the antigen specific T cell receptor with the MHC molecule on the presenting cell. It is also induced by other stimuli &emdash; perhaps a signal prompted by the evidence of cell death which is absorbed by a dendritic cell. If only the antigen induced signal is present T-cells are suppressed. They increase in size and release small amounts of lymphokine but interlukin 2 is missing (This is the most critical element needed for cell division)
  4. Highly specific immune suppression is created by any cell expressing a receptor called FAS ligand. Cells possessing the FAS ligand are granted immune privilege. Those without may commit apoptosis or suicide.