The Body's Defenses
- Mucous Membranes and their Secretions
- Stomach acid
- Phagocytic White Cells
- monocytes / macrophages
- Antimicrobial Proteins
- cytokines (interleukins)?
- The Inflammatory Response and Fever
- cytokines (interleukins)
- 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
- 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
The first step involves the preparation of a molecule of foreign
protein, referred to as an antigen, for identification.
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
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
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
(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
- Specificity - the immune system's ability to
recognize and eliminate particular microorganisms and foreign
molecules called antigens.
- 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.
- 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
- 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
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
But before this occurs all pathogens must slip by the:
I. The First Line of Defense
- 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
- The secretions of the mucous membranes in the
respiratory system effectively trap invading bacteria which can
then be swept away by the ciliate lining.
- 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)
- Most invaders cannot withstand the strong acid (HCl) found
in the stomach.
- 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.
- Urinary passages are protected by the flushing action of
- 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.
- 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
Chemical Secondary Defenses
- 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.
- 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.
- 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
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
- 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.
- 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
The leukocytes (white blood cells) are mobilized to attack
invaders. They are produced continually by stem cells in regions of
red bone marrow.
- Phagocytes - engulf bacteria (eosinophils, neutrophils,
and monocytes. They are attracted to the site of infection by
kinins and complement.
- 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.
- 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
- 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.
- Basophils, release histamines, part of the inflammatory
- 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
- 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.
- 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
Relatively small localized region to which the antibody
chemically bonds is called the antigenic determinant or
Be able to draw and label a typical antibody:
- 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.
- Antigen / Antibody Interactions. How antibodies Work.
Neutralization, agglutination, precipitation, activation of
- Neutralization occurs when antibodies block viral
binding sites or coat a toxin.
- 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
- Precipitation of soluble antigens by a similar process
makes these numerous molecules easier for phagocytes to find
- Certain interactions between antibody and antigen activates
the complement system.
- 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
- 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
2B. Specific Cellular (Tertiary)
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.
- 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.
- 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
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
- Suppresser T-cells which somehow suppresses the positive
feedback characteristic of the immune response.
- 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
- physical elimination of lymphocytes that recognize
the body's molecules during early development which is referred to
as a clonal deletion.
- immuno-regulation, involves the generation of regulatory cells
that weaken harmful or inappropriate lymphocyte responses
- 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
- 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.