Download antigen presentation clonal selection induction of antibody synthesis

11/28/12
MICROBIOLOGY LECTURE 8
IMMUNOLOGY 2
PROF T.J. FOSTER
ANTIGEN PRESENTATION
CLONAL SELECTION
INDUCTION OF ANTIBODY
SYNTHESIS
Lymphatic
System
Antigens
brought by
macrophages
from site of
infection to
lymph nodes
Bone marrow &
thymus.
Generate white
blood cells
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Antigenic Determinants.
Epitopes
A single protein has many different epitopes on its surface
[slide from lecture 7]
Antigen presentation
by macrophages &
other antigen
presenting cells
Clonal selection
Cell division
Immature cells
Lymphoid tissue
Differentiation
Long lived.
In lymphoid
tissue
Short-lived
Y
2
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
3
Y
Y Y
Y
YY
Y
Y
Y
Y
Y
Y
Y
Y
Y Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
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THE PRIMARY RESPONSE
LYMPHOID TISSUE
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
CLONAL SELECTION
Y Y
Y
Y
Y
Y
Y
Y
Y
Y
differentiation
Y
Y
ANTIGEN
PRESENTATION
Memory cells
Y
Y Y
YY
Y
PLASMA
CELLS
short-lived
B LYMPHOCYTES
Retained in lymphoid
tissue
Y
Y
Antibody synthesis
ANTIGEN PRESENTATION
CLONAL SELECTION
THE IMMATURE B LYMPHOCYTE WITH THE
APPROPRIATE ANTIGEN-BINDING DETERMINANT
DISPLAYED ON ITS SURFACE IS SELECTED
ACTIVATED TO DIVIDE AND DIFFERENTIATE
PLASMA CELLS THAT SYNTHESIZE ANTIBODIES ARE
SHORT-LIVED
MEMORY CELLS REMAIN IN LYMPHOID TISSUE
THERE ARE MANY DUPLICATE COPIES OF THE
ORIGINAL B CELL
PRIMARY & SECONDARY
RESPONSES
SECONDARY
PRIMARY
Antibody
concentration
in blood
First exposure
Second exposure
Months, years
later
7
14
21
28
Time (days)
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THE SECONDARY RESPONSE
B cells
Y
Y
Y
Y
CLONAL SELECTION
• quicker
• more B cells for
specific antigens
Y
Y
Y
Y
Y Y
Y Y
Y
Y
Y
Y
Y
Y
Y
Y
Y Y Y
PLASMA
CELLS
Y
Y
differentiation
Y
ANTIGEN
PRESENTATION
B LYMPHOCYTES
Y
LYMPHOID TISSUE
Y
Memory cells
Y
Y Y
YY
Y
Y
Y
Antibody synthesis
IMMUNOLOGICAL MEMORY
•  LONG-LIVED, PROTECTIVE
•  VACCINATION
–  PRIMARY RESPONSE WITHOUT
SUFFERING SYMPTOMS OF DISEASE
–  FIRST EXPOSURE TO DISEASE GIVES
SECONDARY RESPONSE
T CELLS
T Helper Cells TH
Antigen Presentation to B cells
Cytotoxic T Cells TC
Kill host cells that are infected with
viruses and intracellular bacteria.
Kill some cancer cells
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ANTIGEN PRESENTATION
Humoral Immunity
MHC II-Antigen complex
recognized by one subset
of T cell
Many types with
different specificities.
ANTIGEN PRESENTATION
Requires CD4 on TH to
promote binding
TH
Intermediate between
presenting cell and
B cell
ANTIGEN PRESENTATION
Antigen binding
determinant on
surface.
Internalized by
endocytosis
Presented on
surface by MHC II
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HUMORAL IMMUNE RESPONSE
Proliferation &
differentiation
triggered by cytokines
Secreted Ig binds same antigen epitope as the receptor on the
Immature B cell
ACTIVATION OF B CELL
summary of key points in previous diagrams
B cells carry surface-located antibody that recognizes
specific antigen
Antigen is endocytosed and presented on surface in MHCII
TH cell carries a TCR that recognizes MHCII-antigen
complex
TH secretes IL-2 which stimulates B cell division and
differentiation into PLASMA cells and MEMORY cells
Plasma cells secrete antibody specific for antigen
Cell-Mediated Immunity
A dendritic cell is another type of antigen-presenting cell
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ANTIGEN PRESENTATION
MHCI - on all cell types.
Presents fragment of
intracellular pathogen
(bacteria or virus)
CD8+ T Cell
CYTOTOXIC T CELLS
T cell population with TCR that
recognizes MHCI-antigen complex
amplified
CD4
Activated cytotoxic T
cell seeks infected cells.
Secretes perforin protein
Membrane damage. Lysis
Recognizes MHC-I antigen
complex on surface
ACTIVE IMMUNITY
Stimulation of body’s immune system
NATURAL
•  INFECTION
ARTIFICIAL
•  VACCINATION
– Stimulates immune response &
immunological memory without
symptoms
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Passive Immunity
Transfer or administration of antibodies
NATURAL
–  FOETUS
–  MILK
receives maternal IgG
contains IgA
ARTIFICIAL
–  TETANUS ANTITOXIN (horse)
–  RABIES ANTIBODIES (human)
–  POOLED IgG (human non-enriched/
enriched with anti-Hepatitis B)
Active Immunization
Vaccines
•  Toxoid
–  Inactivated toxin
•  Chemical
•  Genetic
(formaldehyde)
(non-toxic mutant / fragment)
•  Killed Whole cell / inactivated virus
•  Subunit
–  Purified component of cell / virus
•  Live-attenuated
–  Bacteria or virus
CURRENTLY USED VACCINES : BACTERIA
PATHOGENIC BACTERIUM
DISEASE
VACCINE
Mycobacterium
tuberculosis
Tuberculosis
Live BCG. Non-
Corynebacterium
diphtheria
Diphtheria
Clostridium tetani
Tetanus
pathogenic mutant of
M.bovis
Toxoid
chemically inactivated
toxin. Loss of toxicity
retains antigenicity
Toxoid
Bordetella pertussis
Whooping cough Toxoid +
Surface proteins
Neisseria menigitidis C Meningitis
MenC polysaccharide capsule
Haemophilus influenzae Meningitis
Hib polysaccharide capsule
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Vaccine for Cholera.
Killed whole cells + enterotoxin B subunit
Y Y
Stimulates
secreted IgA
antibody on
mucosal intestinal
surface
YY
Lumen of
intestine
microvilli
Columnar
epithelial
cells
Immunity in Vaccinated Individual or Convalescent
microvilli
Columnar
epithelial
cells
Enterotoxin
5 B, 1 A subunits
Y
Lumen of
intestine
Y
Antibodies to pilus &
outer membrane protein
block bacterial attachment
Anti CtxB blocks toxin
Binding to GM1
A
A
Specific receptor
on surface of cell
for B subunit
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This lecture covers the induction of the immune response. Fragments of antigens are processed after destruction of
the pathogen by a macrophage or dendritic cells. A fragment binds to the MHCII receptor which migrates to the cell
surface. The MHCII-peptide complex is recognized by a specific T cell receptor (of which there are many). Binding is
facilitated by the surface protein CD4 ( the HIV receptor). The macrophage secretes a chemical messenger called
interleukin 1 which stimulates the T cell to divide and form two populations: memory T cells that remain until the next
infection and active T helper cells that engage a B cell that bears a surface-located antibody molecule that reacts with
the antigen. It becomes internalized and is then presented on the surface in the MHCII complex. This is recognized by
the T cell receptor which originally bound to the MHCII-antigen complex on the macrophage. The T cell secretes
interleukin 2 which stimulates the B cell to divide and differentiate into antibody-secreting plasma cells. Many
undifferentiated B cells remain in the lymphoid tissue as Memory Cells. This process is termed CLONAL SELECTION
and results in IMMUNOLOGICAL MEMORY. Upon a subsequent exposure, antigen presentation and clonal selection
occur more efficiently. This allows the immune response to develop before symptoms of disease occur. Vaccination
generates a primary response without development of symptoms of illness.
Another aspect of cell-mediated immunity are killer T cells. These are stimulated by exposure to host cells infected
with intracellular viruses and bacteria (eg Salmonella typhi). The intracellular microbes/viruses cannot be recognized
by immunoglobulin. The Tc cell recognizes an infected cell because the latter displays protein fragments of the
replicating virus in its MHCI receptor which are recognized by the Tc cell’s TCRs. This stimulates the release of the
membrane damaging protein perforin which kills the infected cell.
There are several different types of vaccine currently used in Ireland to combat infectious disease caused by bacteria
and viruses.
Toxoids are chemically modified forms of a toxin. Toxoid vaccines are effective when the symptoms of disease
are caused by a toxin. (Diphtheria & tetanus vaccines are toxoids & the whooping cough vaccine contains a toxoid).
Live-attenuated vaccines have been weakened by multiple rounds of culture in the laboratory. The tuberculosis
vaccine BCG is a live-attenuated form of Mycobacterium bovis that is sufficiently closely related to M. tuberculosis to
give immunity. Several virus vaccines are live-attenuated variants.
Subunit vaccines comprise components of the bacterial (or viral) surface. They have a protective antigen but lack
toxic components such as lipopolysaccharide endotoxin of Gram negative bacteria. The new improved Whooping
Cough vaccine comprises purified surface protein antigens (and a toxoid). Another type of subunit vaccine comprises
capsular polysaccharides (Haemophilus influenzae b, Streptococcus pneumoniae and Nessieria menigitidis C)
coupled to a protein to make them more immunogenic.
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