Transcript The Specific Immune Response....continue

The Specific Immune
Response....continue...
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 macrophages
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 function is to capture , concentrate and present antigens
to lymphocytes (APC)
• Origin : stem cells in bone marrow
• Several Type
Langerhans (LC) found in skin
Circulating 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 II 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 II
(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 (GM-SF)
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.
Antibodies
Blympho
cytes
•
+
=
Humoral
immunity
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: B- Lymphocytes
• 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
mIg
Resting B lymphocyte
+
Blymphocyte
Antigens
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 1-2 weeks).
• Some dividing B- lymphocytes change into memory cells where they
display same mIg as parent B- cell and change rapidly into plasma 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 convert
immediately 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 (variable 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 specificty 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
IgA
IgD
IgE
Structure
Monomer Pentamer Dimer
Monomer Monomer
Serum %
80%
0.2%
Location
Blood,lymph, Blood,lymph, Secretions( Blood,
intestine
B cells as
tears, milk), lymph,
monomer
blood,
B cells
5-10%
10-15%
0.002%
Mast cells ,
basophils,
blood
lymph
Placenta
transfer
Yes
No
No
No
No
Complement
fixation
Yes
Yes
No
No
No
Function
1ry immune
Neutralize
viruses and response
toxins,
enhance
phagocytosi
s, protect
fetus
Localized
protection
on mucous
surfaces
Serum
function
not
known,initi
ation of
immune
response
on B cells
Allergic
reaction and
lysis of
parasitic
worms
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
Mast
cell
+
IgE
Antigens
Antibody (Immunoglobulin) functions
5. Antibody dependent-cellular cytotoxicity (ADCC)
- Classically mediated by NK, but also by eosinophils and
neutrophils
- Part of the adaptive immune response (depend on antibodies)
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
Blymphocyte
Single clone from
single B lymphocyte
recognizes single
specific epitope on
antigen