Transcript AdaptiveImmuneFuncti..

Immune System Function:
Adaptive Immune Response
Review Concept:
Purpose of the Immune system is to protect from damage caused by pathogenic microorganisms such as:
- Bacteria
- Viruses
- Fungi
- Parasites
Review Concept:
Innate Inflammatory Response is the first line of defense:
Recruitment and activation of inflammatory cells which then kill whatever doesn’t
belong...
Adaptive Immune Response can be initiated by the non-specific innate inflammatory response
Adaptive response is highly specific to antigens
Greatly enhances neutrophil/macrophage/NK-cell activation
“Remembers” antigens
When macrophages recognize pathogens as foreign entities they are stimulated to engulf
the pathogen and then digest them, in effect, destroying them. In this way invading
pathogenic organisms are prevented from causing us harm. (At least we hope they are all
killed before we are harmed.)
With really virulent pathogens (such as the ebola virus) the “killing the pathogen” process
doesn’t happen fast enough; the pathogen multiplies very fast and damages our cells far
faster than we can repair them so the cells end up dying in large numbers (and we die
along with them due to multiple organ failure) before we can kill all of the pathogens.
With pathogens that are not too virulent, our adaptive immune response has time to
respond, and produce lots of antibody-producing B-lymphocytes. The antibodies bind to
the specific pathogens and then trigger a very aggressive activation of neutrophils and
macrophages and NK cells and compliment and CTL’s to effectively kill off the invading
pathogen (ie. kill it faster than it reproduces and kills our cells).
Adaptive Immune Response
Major Functional Cells Include:
Lymphocytes
- T-Lymphocytes
- Natural Killer Cells
- B-Lymphocytes
- Macrophages
All lymphocytes originate from precursor cells in the bone marrow
- B LYMPHOCYTES: mature in marrow then circulate in blood/spleen/lymph
those with “antigen receptors” which recognize “self antigens” are destroyed before they reach
maturity
- T LYMPHOCYTES: mature in the thymus then circulate in blood/spleen/lymph
only MHC-recognizing Tcells are allowed to mature and of these, only those which do not
recognize both MHC and self-antigens are allowed to fully mature
White Blood Cells
- Neutrophils
- Mast Cells
- Basophils
- Monocytes
- Eosinophils
- Platelets
Major Functional Tissues Include:
- Bone Marrow
- Lymph Nodes
- Spleen
- Thymus
Thymus
Spleen
T-cells are “born” in the bone marrow by the hundreds of millions every day. They migrate to the thymus where
they mature into antigen-responsive (but still naïve) T-cells and then circulate throughout the lymph, spleen,
and blood. The process of maturing in the thymus is actually a two-step selection process. First, only those Tcells that recognize MHC protein complexes are allowed to mature. Then, of these maturing cells, those that do
not react strongly with both MHC and self-antigens are allowed to complete the maturation process. This
produces a population of naïve T-cells that do not react with “self ” antigens but are still able to interact with
the antigen-presenting cells that express both MHC and antigens. Approximately 2% of the original T
Lymphocytes that are “born” in the marrow survive this process. Each individual naïve T-cell has a T-cell
receptor on its surface that is capable of binding to a specific antigen (an antigen that could have come from a
digested bacterium that was then bound to the surface of an antigen-presenting cell) and each T-cell receptor
on different T-cells will recognize different antigens. Thus, in total, our T-cells are born with the ability to
recognize millions and millions of different antigens before we are actually exposed to the pathogens that they
are derived from.
An interesting concept is that if we do not have the appropriate array of genes to produce the specific T-cell
(and B-cell) receptors that recognize antigens, from a particular strain of virus for example, we will not be able
to develop an immune response to that particular virus and we may die from the resulting viral infection. From
a historical perspective, Europeans who could not make antibodies against influenza and measles (and a pile of
other diseases) had long-since died of these diseases so that by the time they “invaded” N. America in the late
1400’s, the Europeans simply got sick for a week or so if they were exposed to the pathogens that caused the flu
or measles. The N. American natives were not so lucky. They had never been exposed to such diseases and
there had been no “selection” for those who had the genetic ability to develop immunity against these
“European” diseases. Within a decade, almost 90% or more of the native population had been wiped out by the
common diseases. Only those who already had naïve T-cells with T-cell receptors that recognized antigens from
the new pathogens could survive. In a very short time the unbelievable power of viruses to almost completely
wipe out humans was demonstrated very clearly. Of course “hind-sight is 20:20”, viruses were unknown then
and no one could have recognized this at the time.
Bone Marrow
Lymph Nodes
The other lymphocytes directly involved in the adaptive response are the B-lymphocytes. B-lymphocytes also
are “born” in the bone marrow but unlike the T-cells the B-cells mature in the marrow before circulating
throughout the lymph, spleen, and blood. The maturation process weeds out those B-cells that have antigen
receptors that recognize self-antigens so that only about 10% of the new T-cells actually survive the maturation
process. B-cells also express antigen receptors on their cell-surface which interact with the antigen-presenting
cells
Antigens
Molecular shapes made from just about any biological components that can be recognized by
“immune cells” as “not self ”.
Soluble and Cell Surface Antigens can include the following:
Antigen
Proteins (native)
Peptides (digested proteins)
Nucleic Acids
Polysaccharides
Lipids
Small Chemicals
Recognized by
B Lymphocytes
B & T Lymphocytes
B Lymphocytes
B Lymphocytes
B Lymphocytes
B Lymphocytes
T Lymphocytes
Antigen presenting cells
(macrophages, dendritic cells, B
lymphocytes) process original
antigen and express it on their cell
surface in conjunction with MHC.
T lymphocytes with receptors for
the displayed peptide interact with
APC and are stimulated to
proliferate and differentiate into
helper T lymphocytes, cytolytic T
lymphocytes, and memory T
lymphocytes.
Helper T lymphocytes secrete
cytokines to stimulate other cells,
especially the B Lymphocytes
Cytolytic T lymphocytes lyse
antigen-bearing target cells
Memory T lymphocytes remain in
circulation for many years to
stimulate a swift response to a
subsequent infection
Macrophages which engulf invading pathogens, bacteria for example, will digest them and small pieces of
proteins (peptides - short amino acid chains of 5 to 12 amino acids long) or lipids from the bacteria’s cell
membranes, or lipopolysaccharides from the bacteria’s cell membrane are displayed on the macrophage’s cell
surface in conjunction with the MHC (major histocompatability complex). These small pieces of the bacteria
(or some other pathogen) proteins are called antigens and other antigen-presenting cells (dendritic cells, Blymphocytes) also can stimulate T-cells as described next.
The dendritic cells happen to be the major antigen-presenting cell but because we started with macrophages in
the inflammatory section, we will continue with that concept. After digesting the foreign pathogen and building
the antigen-MHC complexes on the cell membrane, the macrophage (actually, a whole whack of them) migrates
into the lymph and then moves through the lymph to (hopefully) come in contact with a T-lymphocyte (T-cell)
which has a cell surface receptor capable of recognizing the displayed shape (antigen).
Once an antigen presenting cell with an expressed antigen migrates through the lymph and comes in contact
with a naïve T-cell with a receptor that recognizes the same antigen, the T-cell will be stimulated to differentiate
into different types of specialized T-cells: helper T-cells, cytolytic T-cells (CTC’s), and memory T-cells. These
specialized T-cells then proliferate to produce many thousands of clones of the helper and cytolytic cells and
memory cells. The helper T-cells and CTC’s will live for several days to a few weeks while the memory cells can
live in the lymph for many decades. The CTC’s will kill any cell which displays the same antigen that stimulated
the original T-cell to divide and proliferate while the helper T-cell is necessary to help stimulate the production
of antibody-producing B-cells. The memory cells stay circulating in the lymph and when they bump into the
original pathogen again (many weeks, months, or years later) they are immediately stimulated to proliferate and
differentiate into many thousands of helper cells and CTC’s. These cells then initiate an extremely aggressive
attack against the pathogen and it is often completely destroyed before any symptoms of disease can start.
B Lymphocytes
Express Ig M and D receptors on cellsurface
Antigen-presenting cells such as
macrophages digest invading
pathogens and express specific
antigens on their cell surface
Macrophages present antigens to
naïve B-lymphcytes and the
lymphocytes, with the co-stimulation
by helper T lymphocytes, are then
stimulated to proliferate and
differentiate into antibody producing
B lymphocytes and memory B
lymphocytes
Antibody producing B lymphocytes
secrete large amounts of IgG
antibodies which bind to the specific
antigenic sites of the invading
pathogen
Memory B lymphocytes remain in
circulation for many years to provide
a swift response to a subsequent
infection
Antibodies (IgG)
produced by B-lymphocytes
bind to the antigenic sites on the
pathogen
B-cells also express antigen receptors on their cell-surface which interact with the antigen-presenting cells and are
stimulated to differentiate into antibody producing B-cells and memory B-cells. The catch to this process is that it
won’t happen without the participation of the helper T-cells that recognize the exact same antigen. The helper Tcells must interact with a APC-stimulated B-cell before the newly stimulated B-cell can differentiate into antibodyproducing B-cells and memory B-cells and proliferate through clonal expansion.
The resulting antibody-producing B-cells release huge numbers of antibodies but only live for several days to a few
weeks. Each antibody is identical and binds only to the antigen on the original pathogen that stimulated the B-cell
in the first place. When antibodies bind to pathogens they greatly stimulate any neutrophils, NK cells, and
macrophages to destroy them. The antibody-activated neutrophils, NK cells, and macrophages also produce large
amounts of inflammatory signals to attract more killer cells to the region to enhance the killing response. A fullblown immune response usually can occur within one to three weeks of the first exposure to an antigen resulting in
an adaptive immune response for the (hopefully) elimination of pathogens before they can cause mortal damage
The way the pathogen is destroyed often involves compliment proteins and the antibodies. The antibodies bind to
the antigens and then the compliment proteins bind to any membrane coated with antibodies and destroy the
membrane. Complement is actually a group of proteins produced (in part) by the liver. When they come in contact
with foreign cells which are incapable of inhibiting them, they will assemble into complex tube-like structures which
penetrate the membrane of these foreign cells and open up a large pore. Thus the pathogens are destroyed by
complement through the process of membrane rupture; leading to cellular necrosis. The process of complement
binding and assembly into membrane-destroying proteins is greatly enhanced when they bind to those antibodies
which are already bound to the pathogen.
The memory B-cells and memory T-cells stay circulating in the lymph and when they bump into the original
pathogen again (many weeks, months, or years later) they are immediately stimulated to proliferate and differentiate
into many thousands of cytolytic T-cells and antibody-producing B-cells and even more memory cells. Stimulation
of memory cells can initiate a full-blown response within hours. In this way a sub-clinical infection with a previously
“seen” pathogen will be wiped out long before any symptoms of infection can occur.
Pathogens which cause disease are, of course, very numerous. They range from viruses and bacteria to various
yeasts, fungi and parasites. As already mentioned, viruses are often the cause of many seriously deadly diseases.
In essence, the adaptive immune response leads to the production of antigen-specific (pathogen-specific)
antibodies which greatly enhances the ability of neutrophils, macrophages, NK cells, and compliment to do
their job of removing pathogens from the body.