Download The Specific Immune Response

The Specific Immune Response
Overview of the specific (adaptive)
immune response - continue
1. Cell Mediated Immunity ( T cell mediated immunty)
Key players : T lymphocytes. Two types:
Cytotoxic T cells (CTL) or (CD8+)
T helpers ( TH) cells (CD4+)
- Cytotoxic T cell directly attack and destroy antigen-bearing cells especialy
virally infected cells and tumours
- Helper T cells act indirectly by secreting proteins called cytokines that
activate other cells such as macrophages to destroy the antigen-bearing
cells
Cellular immune response by TH cells
(CD4+)
- Particularly useful in eradicating pathogenic bacteria especially
intracellular bacteria
Can you give some examples for intracellular bacteria????
- Act indirectly by secreting chemical mediators called cytokines that
Activate other cells such as macrophages to destroy the antigen-bearing cells
- Activated macrophages can then kill intracellular pathogens that would
normally divide in a non-activated macrophage
- Activated macrophages also kill foreign mammalian cells
(tissue transplantation) and in some cases tumor cells (have
Specific antigens that are not found on normal cells)
Mechanism of cellular immune
response by TH cells (CD4+)
• 1st step : foreign antigen will be captured and
engulfed by the phagocytes (macrophages) and
another cell type called dendritic cells at the site
of infection
(internalization)
- What are dendritic cells?
Dendritic Cells
• Named so because they resemble dendrites of neurons
(THEY ARE NOT NEURONS!!!)
• Their main fucntion is to capture , concentrate and present
antigens to lympnocytes ( APC)
• Origin : stem cells in bone marrow
• Several Type
Langerhans (LC) found in skin
Circuilating DCs
Myeloid (MDC1 and MDC2)
Plasmacytoid
Interstitial DCs
Heart, lungs, liver, intestines
Interdigitating DCs, T-cell areas of lymph nodes and Thymic
medulla
Mechanism of cellular immune response by
TH cells (CD4+)
• Next , internalized antigen is processed
inside the macrophages and dendritic cells
where the antigen is degraded and fragment
of it binds to MHC class II molecule
(Major Histocompatibility Class I I
molecule)
Major Histocompatibility complex proteins are
found on the surface of cells:: T cells cannot recognize
foreign antigens unless they are associated with these MHC proteins
Class I MHC proteins are
found on the surface of ALL
nucleated cells
Class II MHC proteins are only
found on the surface of
B lymphocytes, macrophages
and other antigen presenting cells
ALL MHC proteins are imbedded in the cytoplasmic membrane of
cells and project outward from the cell surface
Mechanism of cellular immune
response by TH cells (CD4+)
• THEN , the processed antigens bind to Class I I
(Ag-MHC class II complex ) are transported to
the cell surface where they expressed.
- The macrophages and dendritic cells now
move toward regional lymph nodes under
the influence of certain chemical substances
(chemotaxis)
Mechanism of cellular immune
response by TH cells (CD4+)
• In the regional lymph nodes the phagocytes
and dendritic cells present the antigen in
association with MHC class II molecule to
CD4+lymphocytes.
• That is why macrophages and dendritic
cells are called antigen presenting cells
(APC).
Class II MHC
proteins and helper T
cells (TH)
The Class II proteins and antigen
are expressed on B cells, APCs
and macrophages
1. The APC takes up an external foreign
protein via phagocytosis or endocytosis
2. Class II proteins are produced in the
endoplasmic reticulum and assembled
with a blocking protein (Ii) or invarient
chain
3. The Class II proteins enter the
phagolysosome where the Ii is degraded
and the partially processed antigen
binds to the class II molecule
4. The complex is translocated to the
surface of the APC where it interacts
with the TCR of a T helper cell
Mechanism of cellular immune
response by TH cells (CD4+)
• The part of the CD4+ that comes in contact with the
antigen - MHC class II complex is called TCR (T Cell
Receptor).
• Cell- cell interaction mediated by TCR (from CD4+ T
lymphocytes) and antigen - MHC class II complex (from
macrophages or dendritic cells) will activate TH CD4 + to
produce chemical mediators called cytokines (hormones
of the immune system) :
Interferon - gamma ( IFN- gamma)
Tumour necrosis factor - alpha (TNF-alpha)
Granulocyte monocyte- colony stimulating factor
Mechanism of cellular immune response by
TH cells (CD4+)
• These cytokines further stimulate macrophages to increase
phagocytic activity and to in turn produce cytokines that
promote inflammation
Class II MHC proteins and helper T cells
(TH)
Specialized TH cell involved in
the inflammatory response
Cell-cell interaction mediated
by the TCR and the class II
MHC-antigen complex activates
The TH cell which produces
cytokines
TNF-alpha (tumor necrosis factor)
IFN-gamma (interferon)
GM-CSF (granulocyte-monocyte
colony stimulating factor)
These cytokines further stimulate
macrophages to increase phagocytic
activity and to in turn produce cytokines
that promote inflammation
Types of Specific
(adaptive) immunity
Humoral
immunity
Cellular immunity
Specific immune response - humoral
immunity
• B cell mediated immunity through the
production of antibodies.
Antibod
ies
Blympho
cytes
•
+
=
Humora
l
immuni
ty
Particularly effective against pathogens such as viruses
and extracellular bacteria in the blood or lymph and also
against soluble pathogen products such toxins
Humoral immunity: BLymphocytes
• Origin and Maturation: Bone marrow
- B- lymphocytes from the bone marrow are released into
circulation in a resting state and they do not secrete antibodies
- Instead, resting B-lymphocytes display membrane bound
antibodies (immunoglobulins) usually in the form of mIgD or
mIgM
- After activation by antigen, B- lymphocyte divides ( clonal
expansion)
. Some differentiated into plasma cells which secrete
antibodies, die within 1- 2 weeks.
. Some change into memory cells- display same
membrane bound antibodies as parent cell.
Phases of B-lymphocyte activation
Antig
en
Mechanism of humoral immune
response by B - lymphocytes
• Resting B - lymphocyte is coated with membrane bound
antibodies or immunoglobulin (mIg) on the surface of the
lymphocytes
• The first step in the initiation of the humoral immune
response is the binding of the antigen to the mIg
mI
g
Resting
Blympho
cyte
+
Antigen
s
Blympho
cyte
Mechanism of humoral immune
response by B - lymphocytes
• The mIg- antigen complex is then endocytosed and
complexed with MHC class II molecule and then surface
expressed
• Here , B - lymphocyte acts as APC where it presents the
antigen-MHC class II complex to TH cells
• Now, TH cells start to secrete cytokines ( IL-4 and IL-5)
that stimulate B-lymphocyte to divide (clonal expansion)
and differentiate into plasma cells
(1 B cell --> 4,000 Ab-secreting cells --> ~1012
antibody molecules/hour)
Mechanism of humoral immune
response by B - lymphocytes
• Plasma cells start to secrete antibodies (short half life, die in 12 weeks).
• Some dividing B- lymphocytes change into memory cells
where they display same mIg as parent B- cell and change
rapidly into plsama cells when encountering same antigen for
second time (secondary immune response.
• Primary immune response is usually mediated by IgM while
the secondary immune response is stronger and mediated by
IgG.
• Note : In secondary immune response , memory cells conver
timmediately to plasma cells and produce IgG in high amounts
without the aid of helper T cells
Class II MHC
proteins, helper T
cells that stimulate
antibody
producing cells—
the B cells
B cells are coated with
antibodies that react with
specific antigens
When the antigen binds to the
antibody, the B cell first acts
as an APC.
The bound antigen is endo
cytosed and complexed with
MHC II and then surface
expressed
The surface
expressed complex
interacts with and
activates TH cells that produce
the cytokines interleukin 4 & 5
IL4 and 5 stimulates the B cells to produce
identical memory B cells and antibody
secreting plasma cells that secrete the
same antibody
Secific immune response-Summary
Antibody (Immunoglobulin) Structure
• 5 classes: IgG, IgM,IgA, IgD and IgE
• Common structure , four polypeptide
chains:
- Two identical heavy (H) chains,
each carrying covalently attached
oligosaccharide groups (50-70 kDa)
- Two identical, non-glycosylated
light
(L) chains (23kDa)
• Within the immunoglobulin,
disulphide bonds join together:
- Two heavy chains
- Heavy chains to the light chains
• The disulphide bonds joining the
antibody heavy chains are located in a
flexible region of the heavy chain
known as the hinge region.
Heavy chain determines the Ig class:
IgG : gamma HC
IgA: alpha HC
IgD: delta HC
IgM: mu HC
IgE:epsilon HC
Light chain either kappa or lambda
irrespetive of Ig class
Antibody (Immunoglobulin) Structure
•
Based on variability of amino acid
sequences, both H and L chains can be
divided into:
- VH and CH domains(variable and
constant)
- VL and CL domains (vaiable and
constant)
• The variable domains are attached to the
constant domains.
• As the name implies, the variable domains
vary in their amino acid sequence from one
antibody molecule to another, providing the
vast diversity the immune system needs to
fight foreign invaders.
• The antigen binding site is formed where a
heavy chain variable domain (VH) and a light
chain variable domain (VL) come close
together. These parts show the biggest
difference among different antibodies.
Antigen
binding
site
Proteolytic treatment of Ig with
protease enzymes
• When the immunoglobulin is treated
with proteolytic enzymes (proteases),
such as pepsin or papain, it is broken at
the hinge region into two fragments
known as Fab
(Fragment for antigen binding) and Fc
(Fragment Crystalizable).
• The immunoglobulin specifity is
determined by the Fab fragment, as well
as its capability to react with the antigen.
• (Fc) cannot bind with antigens, but is
responsible for biological effector
functions like complement fixation,
binding to macrophages, natural killer
cells and neutrophils.
IgG
IgM
Structure Monomer
Pentamer
Serum %
80%
Location
Blood,lymp
h,intestine
5-10%
IgA
IgD
IgE
Dimer Monomer Monomer
10-15%
Blood,lymp Secretions(
h,B cells as
tears,
monomer
milk),
0.2%
0.002%
Blood, Mast cells ,
lymph, B basophils,
cells
blood
blood,lym
ph
Placenta
transfer
Yes
No
No
No
No
Complemen
t fixation
Yes
Yes
No
No
No
Function
Neutralize
viruses
and toxins,
enhance
phagocyto
sis, protect
fetus
1ry
Localized
immune protection
response on mucous
Serum
function
not
known,init
iation of
immune
response
on B cells
Allergic
reaction
and lysis of
parasitic
worms
surfaces
Antibody (Immunoglobulin) functions
1. mIgs activate Blymphocytes when
comes in contact with
antigen
2. Secreted Ig
neutralizes the effect
of viruses ,
extracellular bacteria
and toxins
Antibody (Immunoglobulin) functions
3. Opsonization: bind
pathogens for
recognition by other
immune cells (e.g.
phagocytes)
Opsonins- are the
tagging proteins that
make unrecognizable
particles into “food” for
phagocytes.
Antibody (Immunoglobulin) functions
4. Mast cell degranulation:
• Mast cells contain histamine in intracellular granules
• Binding of IgE to cell surface receptors on a mast cell
primes the cell to respond to allergen
• Introduction of allergen and its subsequent binding to IgE
stimulates the mast cell to degranulate and release of
histamine
Mast cell
Mast
cell
+
IgE
Mast
cell
Antigens
Antibody (Immunoglobulin) functions
5- Antibody dependant-cellular cytotoxicity (ADCC)
- Classically mediated by NK, but also by eosinophils and
neutrophils
- Part of the adaptive immune response (depend on antibodies)
Antibodi
es bind
antigen
on the
surface of
target
cells
NK ells
express
CD16, a
receptor for
Fc ,
recognize
cell bound
antibodies
Relese of
perofrins
and
granzymes
by NK ells
Cell
death
Antibody (Immunoglobulin) functions
6. Complement activation
Will be discussed in details in next lecture
Monoclonal Vs polyclonal antibodies
Blymph
ocyte
Polyclonal
antibody
Antigen
Blymphoc
yte
Blymphoc
yte
Multiple clones from
multiple B lymphocytes each of
which recognizes
different epitope on
same antigen
Monoclonal Vs polyclonal antibodies
Antigen
Monoclonal
antibody
Blymphoc
yte
Single clone from
single B lymphocyte
recognizes single
specific epitope on
antigen