Unit 17 -  Body Defense

 

A.  Introduction ‑ The body has evolved a number of mechanisms to

    defend itself against infection and disease.  Historically these

    mechanisms  have been viewed as protection against microorganisms. We now know that these mechanisms also play major roles in other areas such as allergy, autoimmune disease, cancer, and organ transplant rejection.   In this section we will survey the major defense mechanisms and see how they function in the above mentioned areas.

 

B.  Non‑specific defense ‑ Defense mechanisms are usually considered

    to be  either specific (aimed at a specific organism or substance) and non‑specific (triggered by a large number of different agents). The non‑specific mechanisms constitute the first two lines of body defense.

 

   l.  First line of defense ‑ Skin and mucous membranes ‑ These

        form a physical barrier between the internal body and the external environment.  The skin guards the external body while the mucous membranes line and protect the openings to the body. In addition to the barrier function, the skin produces antimicrobial substances and generally provides an environment which is not conducive to the growth of microorganisms. The stomach produces large quantities of HCL which also serves as an antimicrobial agent.

 

    2.  Second line of defense ‑ These are mechanisms which are

        triggered  when the first line as not proved effective.  These include the following.

 

        a.  Phagocytosis ‑ This is the ingestion and destruction of 

            organisms, foreign material, and diseased and dying

            tissues by the phagocytic cells of the body.  As previously discussed there are two principal classes of phagocytic cells.

 

            (l) Granulocytes ‑ These are the white cells that are

               found principally in the blood.  PMN's can leave the blood and move into the tissues. Mast cells, which are found throughout the connective tissues and usually associated with allergic responses have also been shown to ingest and destroy a wide range of bacteria.

 

            (2) Agranulocytes (Mononuclear cells) ‑ These are the    monocytes and macrophages.  They are found throughout the connective tissues of the body and lining various lymph and vascular channels.  Collectively these cells constitute a cleansing and surveillance system referred to as the Reticuloendothelial system or RE system. More recently this system has been renamed the Mononuclear phagocytic system (MPS).

 

        b.  Inflammation ‑ This is a response of the body to any 

            irritating agent.  The overall function is to remove the 

            source of irritation, prevent the spread of infection if a microbe is present,  and repair the damage which has been

            done.  The components of the process are as follows.

 

            (l) Hyperemia ‑ This is increased blood flow to the

               point of irritation.  It is brought about by the dilation of the blood vessels supplying the irritated area.  This dilation is brought about by chemical substances released by damaged tissues, Mast cells (cells found in connective tissues which have chemical contents similar to basophils), and basophils.  If the inflammatory response is occurring near the surface of the body the hyperemia will result in redness (rubor) and warmth (calor) two of the cardinal signs of inflammation.  Increased blood flow to the area permits the mobilization of white cells and other defensive agents carried by the blood.

 

            (2) Swelling (tumor) ‑ This is the third cardinal sign

               of inflammation and is due to the accumulation of

               tissue fluid (edema).  This increased tissue fluid is due to increased permeability of the capillary blood vessels.  The increased permeability is brought about by the chemical mediators released by the same cells that caused hyperemia.  Increased fluid in the area brings additional nutrients and other vital defense substances.  Swelling causes compression of the nerve endings which results in pain (dolor) the fourth cardinal sign of inflammation.

 

            (3) Pus formation ‑  Injured cells release substances

               that attract phagocytic cells, especially neutrophils. These cells congregate at the site of infection where they ingest microorganisms, dead and dying cells, and

               other debris.  The combination of tissue fluid, white

               cells, and cellular debris constitute pus.

 

            (4) Defensive fibrin ‑ The excess fluid from the

               circulation brings with it the clotting protein fibrinogen.  It forms  a fibrin meshwork around the infected area.  This prevents the spread of the infection from the immediate area.  If the inflammatory response fails to fully clear the area of debris, then fiber forming cells contribute collagenous fibers which form a capsule that walls off the distressed  area.  A closed fibrous sac such as this is termed an

               abscess.

 

            (5) Repair ‑ Eventually all of the distress is removed

               and the dead cells phagocytized.  Abscesses located at the surface of the body rupture and drain to the

               outside.  Abscessed deep in the body must be reabsorbed by the body.  The cavity left fills up with scar tissue and the process is complete.

 

            (6) Chemical mediators of inflammation ‑ As has been       discussed, the processes involved in inflammation are mediated by chemicalsubstances.  These substances  include the following. 

              

               (a) Histamine ‑ Released by many cells, especially mast cells, basophils, and platelets.  It causes        vasodilation and increased capillary permeability. 

                (b) Kinins ‑ These polypeptides dilate arterioles,     increase vascular permeability, act as chemotactic agents (attract white cells), and induce pain.

 

                (c) Complement system ‑  This is a series of 11

                   plasma proteins that plays a number of roles in

                   defense including specific immunity.  Active complement components can mediate virtually every aspect of the  inflammatory response.  The activation of complement can be a part of specific immunity or it can be specific.  The non‑specific activation usually begins with a protein called properdin which can attach to molecules found on many bacteria (but not body cells).

 

                (d) Prostaglandins ‑ These are local hormones which are related to fatty acids.  They can cause            vasodilation, pain, and fever.                 

 

(e) Leukotrienes ‑  These are substances produced by      leukocytes.  They are chemically similar to           prostaglandins.  They can cause increased             permeability, adherence of leukocytes to the          lining of small vessels, and they are chemotactic     for neutrophils.

 

               (f) B-defensins – These are broad-spectrum antibiotic                      like substances epithelial mucosal cells that line                     the hollow organs.  At inflammatory sites where                        these epithelium has been breached, large amounts                      of these are released to control bacteria and                          fungi.

       

        c.  Natural Killer (NK) cells ‑ These are large granular 

            lymphocytes.  They are non‑specific and kill both tumor cells  and virus invaded cells.  Such cells usually have altered membranes antigens that NK cells recognize.  NK contact the target cells and destroy their membranes by releasing substances known as perforins.  NK cells may be our primary defense against cancer, especially in the early stages before an immune response against the tumor cells has developed. The constant monitoring of body cells by NK cells is termed immunological surveillance.

           

        d.  Interferon ‑ This is a protein produced by cells when invaded by viruses.  It does not protect the invaded cell, but is absorbed by adjacent cells where it stimulates the synthesis of an antiviral protein which protects those cells. In addition, interferons stimulate the activity of macrophages and NK cells.

 

            (l) There are three different kinds of interferon.

 

               (a) alpha interferon (leukocyte interferon). Attracts and stimulates NK cells.

 

               (b) beta interferon (fibroblast interferon).  Slows inflammation in damaged areas.

 

               (c) gamma interferon (immune interferon ‑ produced

                   by lymphocytes ). This interferon functions in specific immunity and will be discussed more completely later.

 

            (2) Interferon also has anti‑cancer activity.  During

               recent  years interferon genes have been cloned into

               bacteria so that large quantities are now available.  Interferon has been used as an anticancer agent. It has not show activity against the  more common cancers such as breast, lung, and colon, but  it does have good affect on rarer forms. Recently, new subtypes of interferon have been discovered and there is hope that some of these may have more powerful anticancer properties.

 

            (3) There is also hope that interferon may prove to be a

               good  antiviral drug.  The results are mixed, and many side effects have been found.   

 

      

        e.  Complement - This is a series of plasma proteins that circulate in an inactive state  Complement when activated becomes a major mechanism for destroying foreign substances in the body.  Complement functions in both non-specific defense as well as in specific immunity.  It will be considered in more detail along with specific immunity.

 

        f.  Fever - This is an increase in body temperature that usually accompanies infection.  Current evidence indicates that fever is a protective response of the body to infection, and many infectious organisms cannot grow well at elevated body temperatures. Many bacteria require large amounts of iron and zinc to multiply.  Fever causes the liver and spleen to sequester these elements, reducing the supply available to the bacteria.  Substances called pyrogens are responsible for fever.  Pyrogens are substances produced  by leukocytes and macrophages which have been exposed to microgoranisms.

 

C.  Specific resistance ‑ Third line of defense ‑ This is immunity,

    and  as the  name implies is specifically targeted.   It is composed of cells and molecules which recognize and destroy the offending agent. The principal cells of the immune response are the lymphocytes and macrophages.

 

    l.  Types of immunity ‑ There are two basic types of immunity.

 

        a.  Humoral  (antibody) mediated immunity (HMI)    This 

            depends primarily upon  protein  molecules termed  antibodies or immunoglobulins to attack and neutralize   the foreign substance.

 

        b.  Cell mediate immunity (CMI) ‑ Cells are the effectors in 

            this type  of immunity,  directly attacking the foreign 

            substance. In  the case of CMI,  the foreign substance is always another cell.

 

    2.  Antigens ‑ Antigens by definition are substances which

        provoke  an immune response,  either HMI or CMI or both.  It is antigens to which the immune system responds. Chemically,  antigens are usually either  proteins  or complex carbohydrates. In order to be antigenic, a molecule must possess a large degree of complexity.

 

        a.  Haptens - These are small molecules which are ordinarily not antigenic.  However, sometime in the body they may combine with proteins and the combination then does become antigenic.  After this occurs, the hapten by itself is capable of provoking an immune response.  This is the basis for many drug allergies.

 

    3.  Antigen receptors -  Every lymphocyte has a unique molecule on its membrane surface that functions as the antigen receptor.  These receptors have a three dimensional shape that will allow them to combine with only one particular antigen, and it is the recognition of this antigen that is the basis of the immune response.  At there are literally millions of different shaped antigens there must also be millions of different lymphocytes each with its own antigen receptor.  How all of these different antigen receptors originate will be discussed in more detail later.

   

    4.  Cellular basis  of immunity ‑ There are three functional cell

        categories which play a role in specific immunity.  They are as follows.

 

        a.  Antigen presenting cells - These are macrophages, B lymphocytes, and certain skin cells known as dendritic cells.  These cells encounter the antigen for the 

            first time.   They process the antigen and display components of the antigen on their own cell membrane so that other key cells in the immune response can recognize it and respond accordingly.

 

        b.  T ‑ lymphocytes (T‑cells) ‑ These are lymphocytes which 

            have been processed by the thymus gland.   There is a hormone (or a  series  of hormones) termed thymosin which is produced by the thymus gland.  This hormone induces the maturation of immature lymphocytes from the bone marrow  into  mature T‑cells.   Fully  80% of the circulating  lymphocytes are T‑cells.   T‑cells all appear identical  but  can  be  show to  fall  into  several  different functional  categories.   Each subclass can be identified by  the  receptors  (molecules)  found  on  the  surface  of its membrane.  Two of the major receptors are designated CD4 and CD8.   The major subclasses of T‑cells are as follows.

 

            (l) Helper T cells (T4 or TH) ‑ This is the primary regulatory cell of the immune system.  It is ultimately responsible for recognizing the antigen displayed by the macrophage and then signaling for an appropriate immune response.  It may be thought of as the commander and chief of the immune system.  This is the cell that the AIDS virus destroys.  There are two subpopulations of helper T cells.

 

               (a) TH1 - This subpopulation of helper T-cells release a variety of chemical substances which recruit macrophages and stimulate TC cells to proliferate. They function in cell mediated responses.

 

(b)    TH2 – These direct migration of eosinophils and basophils to the site of distress. They also fight parasitic infections of the gut.

 

               Both populations “help” B cells to initiate antibody                   responses.

 

            (2) Cytotoxic T cells (T8) ‑ These cells have the ability to make contact with other cells and destroy them.  They seem to be especially effective against virus infected cells and cancer cells.

            

(3)    T suppressor cells (T8) ‑ These cells also have a regulatory  role but it is directed toward suppression of an immune response.  These cells  play a role in    terminating immune responses that have run their course. They also may play a role in self tolerance.

 

            (4) TDH – These are delayed hypersensitivity cells.  They                  exhibit both CD4 and CD8 markers and play a role in                    certain allergic responses.

           

 

        c.  B‑lymphocytes (B‑cells) ‑ These are cells that produce antibody. They are recruited by T‑helper cells.  They have receptors on their membrane that interact with antigen.  When stimulated by antigen and helper T‑cells, they undergo rapid mitosis to form a clone of large lymphocytes termed plasma cells.  These are active antibody producing cells.  They produce antibody which is specific for the antigen which stimulated the B‑cell, that is, antibody which has the same shape as does the antigen receptor on the B-cell. B‑cells appear identical to T‑cells and can only be separated  based upon their membrane receptors.

 

        d.  Memory cells ‑ Both T and B lymphocytes produce memory cells that exist for long periods of time and remember the antigen.  If the antigen makes a subsequent appearance, these memory cells immediately initiate an immune response. Consequently an intense immune response can be mounted immediately, destroying the antigen carrying organisms before they can establish an infection.  This is why we are usually immune of a disease that we have had previously.

 

        e.  Summary ‑ The following is a summary of the cellular events and interactions that occur during the immune response.

 

            (l) Antigen reacts with receptors found on the surface of B lymphocytes and/or cytotoxic T lymphocytes.  The antigen must also be processed by an APC and presented to a T‑helper cell.

 

            (2) The now activated T‑helper cell divides to form a colony of cells which are sensitive to that particular antigen. The helper cells now release chemical agents which activate B‑cells and/or cytotoxic T‑cells.  These cells now proliferate and initiate an immune response against the antigen. The activated helper T cells only interact with B-cells and cytotoxic T-cells which have been activated by the same antigen.

 

            (3) The B‑cells which have been activated produce antibody which binds with the antigen thereby altering it in some fashion.  If the antigen is attached to cells, or inside of cells, cytotoxic T cells can attach to these cells and destroy them.

 

            (4) Once the immune response has run its course and the antigen has been cleared, T‑suppressor cells will bring a halt to the various immune reactions and thereby prevent an over reaction which could harm the body.

 

            (5) A population of memory cells, both B and T, will      continue to circulate.  When an antigen is seen for the first time, there may be only four or five lymphocytes which have receptors that will fit it and become activated.  These cells must proliferate to reach sufficient numbers to be effective.  For this reason, initially an immune response may take 5 to 10 days to become powerful enough to clear the antigen.  However, following antigen clearing, thousands of memory cells for that antigen will remain.  If they ever meet the antigen   again they will be present in sufficient numbers to provoke an immediate response thereby destroying the antigen before disease can result.

 

            (6) The cellular interactions of the immune response are  presented in figure 17.1.

 



 

    5.  Intercellular  recognition  and  communication    The 

        cellular interactions described previously rely on precise recognition and communication  between the various cells of the immune response system. 

 

        a.  Antigen recognition ‑ The cells of the immune response system must be able to recognize foreign antigen and each other. as all other body cells.  The basis of this recognition is a set of self antigens found on the surface of the cells.   These are referred to as the MHC (major histocompatibility complex) antigens or the HLA (human leukocyte antigens).   These surface antigens are all genetically controlled and serve as identification markers for antigen presentation and recognition.  Only identical twins will have absolutely identical MHCs. There are two major classes.

 

            (l) Class  I  ‑ These antigens are found  on  all 

               nucleated  cells in the body.

 

            (2) Class  II    These are found only  on antigen presenting cells.

 

            Both classes are involved in antigen presentation. Antigen must be combined with these MHC self antigens in order to be recognized.  The origin of the antigen determines which class of MHC will be involved.

 

            (1) Exogenous (outside) antigens - These must be combined with class II cell antigens.  The APC processes the exogenous antigen and then combines parts of it with its own MHC II antigens which are then read by the helper T cell.  This type of presentation can turn on both HMI and CMI.

 

            (2) Endogenous (inside) antigen - This antigen comes from inside the body cell, usually from a virus infection or a cancer.  This can be combined with MHC I proteins found on the surface of any nucleated cell and presented to cytotoxic T cells.  This type of presentation can affect only CMI. It is primarily a defense against our own body cells that have become diseased and potentially threaten the other cells.  Therefore, any cell can call in the defense of cytotoxic T cells.  Note that for the cytotoxic T cells to become activate and proliferate, they must receive a second signal from a helper T cell.  This means that the antigen in question must also be processed by an APC.

 

        b.  Costimulation -  In order for a T cell to become activated and respond to an antigen requires more than the presence and recognition of the antigen itself.  There must always be a second signal or a costimulator.  This costimulator represents a second binding site on the presenting cell that must attach to the T cell.  The costimulator serves as a fail safe mechanism to prevent T cells from attacking normal cells.   A good analogy for antigen and costimulation is the activation of a car.  The first signal is the key in the ignition (antigen), but in order to have the car to move it must be put into gear (costimulation). Sometimes the costimulator is found on the APC, a protein molecule that is produced during the initial ingestion of antigen.  At other times it is a polypeptide released by a macrophage or T cell known as a cytokine.

 

            (1) Anergy - This represents a prolonged state of inactivity that an immune cell undergoes once it has combined with antigen but not received proper costimulation.  Anergy can result in the loss of ability to respond to the bound antigen by the immune system.

       

        c.  Communication ‑ cytokines ‑ The cells of the immune

            system have receptors on their surfaces that respond to antigen and other  receptors  that respond to  chemical  signals.  These  signals  are  proteins  released by various white cells  and  are termed cytokines.   Those released from macrophages are known as monokines while those released from lymphocytes are termed lymphokines.  At  this point over 30 have been discovered.  Some of the better known  cytokines and their functions  are  listed 

            below.

                                                                     

                           

Cytokine

Origin

Target

Action

Interleukin-l (Il-1)

monocytes and macrophages

TH cell, B cell:

activation and proliferation: promotes fever and inflammation

Interleukin-2 (Il-2)

TH cells

TH and TC cells and B cells

growth and proliferation: activates NK cells

Interleukin-3 (Il-3)

TH cells

hematopoietic stem cells and mast cells

growth and proliferation

Interleukin-4 (Il-4)

TH cells

B cells

Costimulates activated B cells: stimulates secretion of IgE

Interleukin-5 (Il-5)

TH cells

B cells

Costimulates B activated B cells: IgA secretion

Interleukin-6

(Il-6)

TH cells

B cells

Converts B cells into plasma cells

Gamma interferon

TH cells

many

many

 

Colony stimulating factors (CSF)

TH cells and macrophages

hemopoietic tissue

proliferation of granulocytes

Tumor necrosis factor (TNF)

monocytes and macrophages

tumor cells

destruction

 

Macrophage chemotactic factor (MCF)

TH cells

macrophages

attracts to site of CMI reactions

Macrophage inhibiting factor (MIF)

TH cells

macrophages

inhibits movement from area of CMI reactions

Perforin

TC cells and

NK cells       

infected body cells

destruction of

target cell

membrane

 

 

 

 

 

        d.  An example of the recognition and communication that goes

            on among the immune cells would be as follows.

 

            (l) A macrophage engulfs an invading organism.  The        macrophage digests the antigen and combines fragments of it with its MHC II self antigen.

  

            (2) A helper T cell with an appropriately shaped antigen receptor attaches to the macrophage by recognizing the MHC II-antigen combination on the macrophage's membrane.  After costimulation has occurred, the macrophage releases Il-1 which stimulates division of the helper T cell.

              

            (3) The activated helper T‑cell produces Il‑2 which        is self stimulatory and causes the helper T cell to grow and divide.  Il-2 can also cause proliferation and cytotoxic T cells that have been presented antigen.

           

            (4) Type 2 helper T cells release Il-4, Il-5, and Il-6 which cause proliferation of B cells and their conversion into active antibody secreting plasma cells.

 

            (5) Type 1 helper T‑cells produce gamma interferon which hasmany  effects.

 

               (a) Like Il‑2, it activates cytotoxic T‑cells.

 

               (b) It increases the ability of B‑cells to produce     antibody.

 

                (c) It attracts and activates macrophages at the

                   site of infection.

 

               (d) It activates NK cells.  It also has antiviral effects.

 

            (6) The cytokine cascade amplifies the immune

               response until the invading organism is overwhelmed by sheer strength of numbers.

 

    6.  Humoral mediated immunity ‑   This is immunity which is

        mediated by antibodies produced by B‑cells.  A more recent term for antibody is immunoglobulin.  

 

        a.  Immunoglobulins ‑ These are large complex protein

            molecules that belong to that class of plasma proteins known as gamma globulins.  Gamma globulin, antibody, and immunoglobulin all mean the same thing.  Immunoglobulins are synthesized by B‑cells after stimulation by an antigen, and are specific for that antigen.

 

        b.  Structure of immunoglobulins ‑ Each immunoglobulin is 

            composed of four polypeptide chains.

 

            (l) Two of the chains are large and termed heavy (H)

               chains.

 

            (2) Two of the chains are small and termed light (L)

               chains.

 

            (3) Both the heavy and light chains have a constant

               region and a variable region.  The constant regions are the same for all heavy chains within a given

               immunoglobulin class, and the same is true for light chains.  The variable regions are unique for each immunoglobulin type and give them their specificity.

       

        c.  Classification of immunoglobulins ‑  Immunoglobulins are 

            divided into five classes based upon the constant region

            of the heavy chain.  Within each class, the constant region of every heavy chain is identical.  The classes are as follows.

 

            (l) IgG (Immunoglobulin G) ‑ The most abundant in the

               body.  It circulates in the blood and can cross the

               placenta.

 

            (2) IgM ‑ This is another circulating immunoglobulin,

               but it is present in much lower quantities than IgG.

               IgM also serves as an antigen receptor on the surface                of B cells.

 

            (3) IgA ‑ Secreted on the surfaces of the body that open

               to the outside.   Found in tears, saliva, and other

               surface secretions.

 

            (4) IgD ‑ Found attached to the surface of B‑cells where

               it serves as an antigen receptor.

 

            (5) IgE ‑ A non‑circulating antibody.   It attaches to

               Mast cells in the tissues and mediates allergic

               responses.

 

        d.  Antibody diversity - Clonal selection - It was pointed out earlier that each lymphocyte had a unique antigen receptor. As noted above the antigen receptor for B cells are IgD and IgM antibodies attached the surface of the cell membrane.  How is it possible for each lymphocyte to have a uniquely shaped antigen receptor and be able to produce an antibody that is exactly the same shape? 

 

            (1) During development of a lymphocyte there are about 200 or so gene segments that code for antibody and antigen receptors.  During the maturation of the lymphocyte, the variable regions are assembled randomly by "mixing and matching" various gene segments.  With several hundred fragments to choose from, right away it becomes obvious that millions of possible amino acid sequences in the final antibody are possible.

 

            (2) The different variable regions for both light chains and heavy chains are not attached randomly to the different constant regions which also increases variability.

 

            (3) The genes for B-cell receptors and antibodies show hypermutability.  They mutate very rapidly during development increasing the  possible receptor types even further.

 

            (4) Once an antigen finds a receptor it fits, the lymphocyte which bears that receptor has been "selected."  With appropriate costimulation it will rapidly divide forming a clone of identical cells which are also sensitive to the same antigen.  In the case of B-cells this clone becomes a clone of antibody secreting cells all of which produce antibody specific for the antigen which did the selecting.

 

        e.  Functions of immunoglobulins - Ig usually does not destroy antigen directly.  Usually they mark antigen for destruction by other agents of the defense system such as phagocytic cells or complement.  The principal functions that immunoglobulins are involved in are as follows.

 

(l)     Precipitation – Soluble molecules (mostly proteins) such as bacterial toxins are precipitated out of solution into masses which can then be phagocytized.  Such molecules are sometimes called anti-toxins and preciptins.  IgG

           

            (2) Agglutinins  ‑ These react with antigens on the 

               surface of  the  cells  causing  the  cells  to  clump together (agglutinate).  IgG, IgA, and IgM (the best). Agglutinated cells are easily phagocytized.

 

            (4) Opsonins ‑ These react with surface antigens to form

               a coat  on  cells.   This facilitates phagocytosis.  

               IgG.

            

            (5) Neutralization  ‑ These react with viruses and  bacterial exotoxins by destroying their ability to infect cells.  IgG and IgA.

 

            (6) Lysins    These immunoglobulins cause  the  breakup

               of cells.   They do  this  by  targeting  the  cells  with complement proteins.  The complement proteins then react on  the surface of the cell causing holes to  appear in the membrane.  The complement proteins may be thought of as a bomb.   The bomb is placed on the target cell and then activated by immunoglobulin.

               IgG and IgM.

 

        f.  Complement ‑   This is a major mediator of HMI.  It

            consists a number of   different  plasma proteins.   When immunoglobulin reacts with antigen it often initiates a  series  of complement reactions.  These reactions are usually termed the "fixation" of complement.   Once the complement begins to react it can mediate a number of different processes.  These include:

 

            (l) Lysis or destruction of cells by destroying 

               their membranes.

 

            (2) Toxin inactivation.

 

            (3) Initiation of inflammation.

 

            (4) Opsonization

 

            (5) Enhancement of immunoglobulin formation.

 

            (6) Stimulation of B‑cell lymphokine production.

 

    7.  Cell mediated immunity ‑ In CMI, not only is the effector

        always a  cell,  but the target is also a cell.   The target cell may be one of the following.

 

        a.  A host cell that contains an intercellular parasite (TB

            is an example.

 

        b.  A transformed cell (one with new antigens) due either 

            to  a virus infection or the cell has become cancerous.

 

        c.  A foreign tissue graft.

 

        The target cell is always killed by either contact with a 

        T‑cell, macrophage, or NK cell.   The sequence of events in a CMI response is as follows.

 

        a.  An APC recognizes the target cell antigen and processes it. This information is communicated to a helper T-cell combined with the MHC class II protein of the APC.  The antigen is also presented directly to a cytotoxic T cell by the target cell itself combined with its MHC class I protein.  

 

        b.  The helper T‑cells then release a series  of lymphokines

            that  have the following effects.

 

            (l) Macrophages are attracted to the antigen bearing 

               cells, inhibited  from leaving the area,  and then

               activated so that they become more phagocytic. These activated macrophages destroy the target cells.

 

            (2) The cytotoxic T‑cells which were directly activated by the antigen are stimulated to proliferate (by 

               Il‑2).  These then attach to the antigen bearing cells which they destroy.

 

            (3) NK cells are activated.

 

        c.  Memory T cells remain following the immune response. 

 

        d.  Because  the entire CMI response is mediated by white

            cells, all CMI responses have an inflammatory appearance about them.

 

    8.  Tolerance ‑ The immune system normally recognizes self  and does not attack its own body.   This is known as tolerance.  The following mechanisms seem to play a role in inducing tolerance.

 

        a.  Negative selection - During differentiation, any lymphocyte which has an antigen receptor that will react with body antigens is destroyed.  This appears to be the major mechanism of tolerance.

 

        b.  T suppressor cells seem to play some type of role in tolerance, but exactly what that role is and how important it may be are not known.

 

        c.  Anergy may also play a role in inducing tolerance.  Whenever an antigen combines with a lymphocyte and there is not costimulation, the lymphocyte may permanently lose its ability to respond, thereby inducing tolerance to that antigen.

 

         d. Besides  normal  self  tolerance,  there is  a  special 

            case whereby  the  body tolerates foreign antigens.   This is the case  of the mother's immune system accepting a  fetus which bears some of its father's antigens.

  

D.  Immunity against disease ‑ Immunity against disease causing

    organisms is obtained by exposure to these organisms, or at least some of their antigens.   Once an immune response has been mounted against a particular antigen, memory cells will remain, and if that antigen is again encountered, and immediate and overwhelming immune response will  be  launched,  preventing  the organism  from  establishing an infection.  Immunity can be of two types.

 

    l.  Natural ‑ Here immunity is developed by exposure to organisms

        by natural means.  Sometimes the actual disease will be seen but low level exposure can provide immunity with no overt symptoms.

 

    2.  Artificial ‑ This is vaccination.   Deliberate injection of 

        small amounts of antigen stimulate the immune system and  provide for immunity  which  will protect against exposure  to the organism under normal conditions.

 

E.  Organ transplantation ‑ During the last thirty years the idea of 

    replacing defective organs surgically with healthy ones taken

    from a donor has become a viable means of treatment.  Most failure is due to rejection by the immune system.

 

    1. Tissues from donors and recipients will have different HLA (MHC) and consequently the CMI division will mount an attack.

 

    2.  In a mismatched graft, normally the graft will take and grow

        for the first few days.  Vascularization of the graft will begin.  On days 5 through 7 a massive cellular infiltration of the graft tissues begins.  The majority of the infiltrating cells are cytotoxic T cells and macrophages.  Following this

        infiltration, necrosis of the grafted tissues begins and within a few days the graft is completely rejected.

 

    3.  Prevention of graft rejection involves tissue matching such

        that the HLA's of both donor and recipient and as similar as

        possible.  An antigen match up of about 75% is considered minimum.

 

    4.  Even with the best tissue matching usually some suppression

        of the recipient's immune system is necessary.  Various drugs

        and anti‑lymphocyte sera are used for this purpose. 

 

F.  Autoimmune disease ‑ This is where the immune system begins

    reactions against self antigens.  The cells involved are usually cytotoxic T cells.  There are several different causes for these reactions.

 

    l.  New or altered antigens may appear on the surface of body

        cells.  These will be treated as foreign by the immune system.

   

    2.  Foreign antigens which are very similar to self antigens may       stimulate an immune response (HMI or CMI).  The immune

        effectors then cross react with the similar self antigens.  By way of example streptococcal species can induce antibodies that will cross react with antigen on the heart producing rheumatic heart  disease.

 

    3.  Certain body antigens (such as those in the lens of the eye)

        are sequestered from the immune system since before birth.  If exposed at a later date they will stimulate an immune

        response.  Cataracts of the eye are thought to be such a response.

 

    4.  It is also possible that a deficiency of T suppressor cells

        may lead to immune responses against self antigens.

 

G.  Allergic responses (hypersensitivities)  These can be thought of     as over reactions of the immune system.   There are two types          of responses based upon the two types of immunity.

 

    l.  Immediate   hypersensitivity    This  is  allergy  mediated 

        by immunoglobulin.  The sequence of events is as follows.

 

        a.  Exposure to antigen causes the synthesis of IgE.

 

        b.  IgE does not circulate but rather attaches to Mast cells

            and basophils.

 

        c.  A subsequent exposure to the antigen results in an

            antigen‑antibody response occurring on the surface of these cells.  This causes them to release chemical substances such as histamine and heparin which affect the circulatory system and the excitable tissues.

 

        d.  The manifestations of the allergic response depend upon

            which part of the body the reaction occurs in. These types of reactions are often referred to as anaphylaxis.

 

        e.  Anaphylactic shock ‑ This is a highly acute and generalized

            allergic response that affects most of the tissues of the body.  There is massive vasodilation and loss of fluid from the circulatory system.  The edema that results can block the respiratory passages causing rapid death.  If this does not occur, cardiac shock can result and this too will result in death.  Anaphylaxis is life threatening and must be treated immediately.  It is usually countered by giving vasoconstrictive agents such as epinephrine which will also open the respiratory passages.

 

    2.  Delayed hypersensitivity ‑  Although this is classically referred to as a "hypersensitivity" is really just a CMI response.  As it is mediated by T cells known as T delayed  hypersensitivity cells (TD).  These cells may display either the CD4 or CD8 markers.  The sensitized cells release cytokines such as gamma interferon that attract and activate macrophages. Macrophages then clear the antigen.  The reactions require 24 to 72 hours to appear following exposure.  This is because it takes this period of time for the appropriate cells to congregate in large enough numbers to form a visible response. Poison ivy is a classic example as is the tuberculin test.

 

H.  Tumor immunology - Cancer cells frequently have changed surface components (antigens).  This is the basis of recognition by the immune system.  Once recognized both antibody reactions and cellular reactions can destroy the tumor cells.

 

    1.  Antibody mediated reactions include the following.

 

        a.  Lysis by antibody and complement.

 

        b.  Phagocytosis of opsonisized cells.

 

        c.  Antibody mediated loss of adhesive properties of tumor cells.  Many kind of tumor cells must adhere to one another or to two other tissues in order to metastatic.  Antibodies which prevent this prevent metastasis.

 

    2.  Cellular mediated reactions include the following.

 

        a.  Destruction of tumor cells by cytotoxic T cells.

 

        b.  Destruction of tumor cells by activated macrophages.

 

        c.  Destruction of tumor cells by NK cells.