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Introduction
• How can the body identify and eliminate foreign invaders. especially
since microorganisms are constantly evolving ways to avoid
detection?
• The trick is to be able to distinguish between “self” and “non-self”: to
recognize molecules in the body that don’t belong there.
• Foreign molecules (often on the surface of foreign organisms) raise an
immune response in the body.
• The primary defense is a set of antibody molecules (also called
immunoglobulins, Ig). The human body produces over 1,000,000
different antibodies for this purpose.
• Antibody molecules bind to antigens, which are molecules that are
non-self. Each antibody is specific for a particular antigen.
• Some antibodies are present in the blood and other body spaces as
soluble molecules. The antibodies cause antigens to clump up and
form precipitates that scavenger cells pick up and digest.
• Some soluble antibodies mark foreign cells for attack by the
complement system, a series of proteins that punches holes in the cell
membranes.
• Other antibodies are on the surface of immune system cells
(lymphocytes), which are stimulated to engulf and digest foreign cells
by phagocytosis.
Complement
• The complement system is a way of
rupturing the membrane of invading
cells.
• Antigens on the surface of the invader
bind to soluble antibodies.
• Then a series of other proteins
(already circulating in the blood) is
activated: the complement cascade.
• These proteins bind to the complex in
a specific sequence, creating a large
hole, which usually kills the cell.
This is a compliment.
The Immune System
• The lymphocytes, or white blood cells,
mostly travel through the body in the
lymph vessels, a separate circulatory
system that is connected to the blood
system. The cells collect in lymph nodes,
where large numbers of lymphocytes can
attack foreign invaders.
• There are two main branches of immune
system: T cells and B cells. Both originate
in the bone marrow, from the same stem
cells as the red blood cells.
– T cells then move to the thymus gland to
mature.
– B cells were originally named for their site
of maturation in birds: the Bursa of
Fabricius. This organ doesn’t exist in
humans. B cells probably mature in the
bone marrow.
• B cells secrete soluble antibodies:
humoral immunity.
• T cells interact directly with their targets:
cellular immunity
• In the early 1900’s, there are a major
debate as to whether the immune
response was humoral or cellular. Turned
out they were both right.
Antibody Molecules
• Basic structure: 2 heavy chains
plus 2 light chains, joined together
by disulfide bridges between
cysteine amino acids.
• The molecule has a "Y" shape,
with the two ends of the fork being
composed of both heavy and light
chain regions.
• These ends are the regions that
bind the antigens (Ag). Each Ab
molecule has two identical Ag
binding regions, and thus the Ab
molecules can bind together large
groups of Ag's. This makes an
insoluble complex that is easy for
other cells in the immune system
to find and eat.
More Antibody Molecules
• Each light (L) chain has 2 domains, a
variable (V) region and a constant (C)
region. There are only a small number of C
regions in each person, but there are very
many different V regions. Note that the V
and C regions are together on the same
polypeptide chain!
• Each heavy (H) chain has 4 domains, a V
domain followed by 3 C domains. The C
domains determine the class (IgG, IgM, etc)
of the antibody.
• Ig's come in 5 classes: IgM (early
response), IgG (main blood Ig), IgA (in body
secretions), IgE (allergic response), and IgD
(mostly a cell surface molecule in the early
response).
– IgM comes in both membrane-bound and
soluble forms. The soluble form is 5 Ig’s
connected together in a star shape.
– IgA is two Ig’s connected together tail to tail.
• In many cases, the constant class-specific
regions of the H chains bind to receptors on
the surface of specific cells. For instance,
IgA binds to secretory cells so it gets
secreted into tears, mucus, etc. Also, IgE
binds to mast cells that trigger histamine
release and other rapid responses to
invasion.
Generation of Antibody Diversity
• There isn't room in the genome for 1,000,000
different antibodies.
• Coding is done in pieces, with a unique DNA
splicing mechanism used to assemble the L and
H chains. Each immune system cell splices the
DNA differently.
• Thus, the DNA in the region of the H and L chain
genes in B and T cells is not identical to the DNA
in other body cells.
Light Chain Splicing
• There are two different L chain genes, called kappa
and lambda. Immunoglobulins use one or the
other.
• At the kappa L chain gene, there is a single region
of DNA that codes for the C domain. Upstream from
the C domain is a group of about 250 V domains
and another group of 5 J (for "joining") regions.
– Each V region has a 5’UTR segment, a separate exon,
attached to it: the leader.
• During the development of the B cell, a randomly
chosen V domain joins with a randomly chosen J
domain to form a VJ domain. This occurs by
splicing out the DNA between them.
– Note that this is a very different mechanism from intron
spicing that occurs in the RNA of most genes!
• Once the VJ domain is formed, it can be
transcribed into RNA along with the C domain and
any DNA that lies between the VJ and C. All the
intervening RNA is spliced out as an intron, so the
final messenger RNA has VJC all together; this is
then translated into a L chain protein.