Download Specific Defenses of the Host

Specific Defenses of the Host
The Immune response
The Immune System
Innate (Nonspecific) Immunity
Acquired
(Specific)
Immunity
First line of defense Second line
(barriers at the body
defense
Third line of
defense
•Skin
•Mucous
membranes
•Secretions
•Reflexes
•Normal microbiota
•T cell
lymphocytes
•B cell
lymphocytes
•Antibodies
surface)
•Inflammation
•Phagocytes
•Fever
•Complement
system
•Interferon
Acquired (specific) immunity
• The Acquired immune system recognizes
foreign substances and develops a specific
immune response against them.
• Substances that provoke an immune response
are called Antigens (Ag).
– Bacteria, viruses, fungi, protozoa, helminthes, and
cancerous cells are examples.
• The main type of cells of the Acquired immune
system are lymphocytes.
Acquired (specific) immunity
• Humoral immunity
– B-cells (B- lymphocytes)
– Carried out by
Antibodies
– Effective against
Extracellular antigens
(antigens outside our
cells like bacteria)
– MHC independant
• Cell mediated
– T-cells (T-lymphocytes)
– Carried out by Perforin
– Effective against
Intracellular antigens
(antigens inside cells
i.e.… viruses)
– Cancer
– Tissue transplant
rejection.
– MHC dependant
Cell Mediated Response
T cytotoxic (Tc ) cells
T- cells
• Thymocyte (immature Tcells) are produced by the
bone marrow.
– Thymocytes are immature
and are unable to react
with antigen
– They travel to the thymus
where they are screened
and mature into T-cells.
• Mature T cells must be
able to distinguish
between self and nonself.
Distinguishing self from non-self
Question
• How do T-cells recognize self cells (The
cells that make up your body) from foreign
cells?
• Answer: They bind to and analyze a
protein marker found on all of your cells
called the Major Histocompatability
complex (MHC).
Major Histocompatability complex
(MHC)
The MHC is a marker found
on all of your cells.
– It identifies your cells as
“self” to your immune
system.
– The MHC also randomly
picks up proteins from
inside your cell and
displays them on the
outside to your immune
system
• T-cells must be able to
differentiate your MHC
markers from others
Positive selection of Thymocytes in
the thymus.
• Thymocytes that enter the thymus are self
programed to die.
• The thymoctyes that are able to recognize
the MHC and bind to it receive a signal
that allows them to live.
• All thymocytes that are unable to bind to
your MHC die.
Question
• How do your T-cells recognize unhealthy
body cells harboring intercellular parasites
from your normal healthy cells?
Answer:
• The bone marrow generates T- cells that collectively are
able to recognize any possible protein in the context of
your MHCs.
• The T-cells that bind to healthy normal self-proteins in
the context of an MHC die in the thymus.
• Only T-cells that are able to bind to an MHC coupled with
a foreign protein are released out to the body.
• This is called Negative selection
• The MHC constantly
samples proteins in the
cytoplasm.
• The MHC displays these
proteins to the immune
system outside the cell.
• If the protein displayed is
normal and are regularly
found in the cell, the Tcells will not attack.
• If the protein in the MHC
is foreign, (ie…viral
protein) the T-cells will
attack the cell.
Screening of T-cells
• In the thymus, Thymocytes undergo a double
screening process.
– Positive selection: Selects for thymoctes that have
receptors capable of binding self-MHC. These cells
are given a positive stimulus which allow them to live.
• Thymocytes that fail positive selection die.
– Negative selection: selects against thymocytes that
are able to bind self proteins presented by self-MHC.
• Thymocytes that have high affinity receptors for self proteins
receive a negative stimulus that causes them to die.
Results of Positve and Negative
Screening
• The T-cell repertoire in the body consists
of T-cells which are only able to recognize
foreign proteins in the context of self MHC.
• The Cell mediated response is MHC
restricted
Turning on the Specific
Immune Response
A job left to the Innate Immune
system
Overview of Cell Mediated
Response
• Antigen presenting cells (APC) ingest microbes
and present the Antigens to a type of T-cell
called a T-Helper cell (TH-cell).
• The TH-cell becomes activated and secretes a
cytokine called interleukin 2.
• Interleukin 2 from the TH-cell, binds to T Tc-cell
and has 2 effects.
– 1. Activates Tc-cells causing them to produce
perforin molecules. These cells are now able to kill
infected host cells.
– 2. Causes activated Tc-cells to proliferated and go
through clonal expansion.
The non-specific or innate immune response
turns on the specific immune response.
• APC (macrophages,
dendritic cells and B cells)
ingests a microbe.
• The microbe is processed
into short antigenic
fragments
• These fragments are
combined with a MHC
molecule inside the APC.
• The MHC /Ag complex is
presented on the surface
of the APC
MHC II /AG complex
Antigen Presenting Cell (APC)
T Helper cells
• The APC travels to the lymph
node where it meets T-helper
cells (TH-cells)
• A TH-cell with an appropriate
receptor binds to the MHC II
/Ag complex.
V
– This is called the primary
signal
• The Primary signal causes
receptors for interleukin 2 to be
expressed on the surface of
the TH-cell.
Interleukin 2 receptors (IL-2)
Co-stimulatory signal
• B7 protein on the APC
binds to a CD28 receptor
on the TH-cell.
– This is called the
Costimulatory signal
• The costimulatroy signal
induces the TH-cell to
produce and secrete IL-2.
Interleukin 2
• The costimulatroy
signal induces the THcell to produce and
secrete IL-2.
• The IL-2 binds to IL-2
receptors on the THcell.
Clonal Expansion
• IL-2 causes the THcell to clone itself over
and over.
• The TH-cell is now
ready to activate a Tcytotoxic cell.
Activating Tc-cells
• T cytotoxic cells (Tc-cells)
migrate into an area of
infection by chemotaxis.
Infected Cell
• A Tc-cell with an
appropriate T-cell receptor
binds to an MHC I /Ag
complex.
MHC I /Ag
TCR
• This binding stimulates the
Tc-cell to produce
receptors for IL-2
IL-2R
C
Differentiation of Tc-cells
• After the IL-2Rs are expressed on the
outside of the Tc-cell the Tc-cell lets go of
the infected body cell and migrates into
lymph-nodes or other lymphatic tissues.
• If the Tc-cells in the lymphatic tissue finds
an activated TH-cell and receives IL-2 it will
proliferate into active T cytotoxic
lymphocytes and memory cells.
Cell Mediated Cytolysis
IL-2
The MHC Question
• Why doesn’t activated Tc-cells bind to the
APCs and kill them?
Answer to MHC Problem
• There are two different types or classes of
MHCs: MHC I and MHC II
MHC I.
• This class is found on every nucleated cell
of the body.
• Proteins and antigens bound to MHC I are
always taken up from the pool of free
floating proteins in the cytoplasm.
• Only T-cytotoxic cells are able to bind to
this class of MHC.
– Tc cells can only kill cells with MHC I.
MHC II
• This class is only found on the surface of APCs.
• Antigens that are bound to this class of MHC are
always taken from phagolysomes.
– This means that the cell is healthy
• Only T-Helper cells can bind to this class of MHC
– TH-cells activate Tc- cells but never kill cells that they
interact with. Thus APCs are perserved.