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ACQUIRED IMMUNITY
RECOGNITION
ORGANIZATION OF IMMUNE CELLS UNDER EPITHELIAL
SURFACES
Epithelial cells
Stroma cells
NK cell
B
Th2
Eosinophil granulocyte
DC
NKT cell
Ag-specific B-cell
Neutrofil granulocyte
Th17
Granulocyte
Macrophage activation
Th1
Macrophage
Cellular killing
Treg
CTL
CELL – TO – CELL COMMUNICATION NETWORKS
PERIPHERAL
TISSUES
PERIPHERAL
LYMPHOID TISSUES
DEFENCE SYSTEMS
INNATE IMMUNITY
ACQUIRED IMMUNITY
SENSING
Cells
RECOGNITION
Receptors
SIGNAL
TRANSDUCTION
RESPONSE
Signaling
pathways
Cell-to-cell
collaboration
Effector
mechanisms
SENSING
RECOGNITION
SIGNAL
TRANSDUCTION
RESPONSE
ADAPTIVE (ACQUIRED) IMMUNITY
Antigen recognizing receptors
Helper T cell
Cytotoxic T cell
B cell
LYMPHOCYTES
Fishes 450 millon years
Lamprey
WHAT IS RECOGNIZED BY INNATE AND ACQUIRED
IMMUNITY?
HOW DO THEY RECOGNIZE PATHOGENS?
RECEPTORS
Common pattern of groups of pathogens
Pathogen Associated Molecular Pattern
PAMP
Recognition by receptors
Pattern Recognition Receptor
PRR
9-13 various Toll-receptors
TLR family
Innate immunity
Ancient
Unique structural elements
Antigenic determinant
Recognition by highly specific
antigen receptors
B cell receptor BCR (sIg)
T cell receptor TCR
Several millions antigen receptors
Acquired immunity
450 million years
WHAT CELL TYPES MEDIATE ACQUIRED IMMUNITY
INNATE/NATURAL IMMUNITY
ACQUIRED/ADAPTIVE
IMMUNITY
Phagocytes
(monocyte/macrophage,
neutrophil, dendritic cell)
B lymphocytes (B2)
T lymphocytes
Killer cells (NK cell, δ T cell)
B1 lymphocytes (CD5+)
helper T cell
CELLS
cytotoxic T cell
Enzymes
(lysozyme,transferrin,
lactoferrin, spermin, trypsin)
Antibacterial peptides
Complement system
Cytokines, chemokines
HUMORAL
FACTORS
Antibodies
Produced by B-cell
derived plasma cells
ADAPTIV IMMUNITY IS TRANSFERABLE
Antibodies, antibody specificity, diversity
Antibodies were discovered in the late 1800s (Emil Behting, Shibasaburo
Kitasato) SERUM THERAPY antibodies specific to toxins
Discovery of blood group antigens (Landsteiner)
QUESTION: How can so many different pathogens and other structures be
recognized by antibodies? What drives and How the production of antibodies
occurs?
Niels Jerne
Ehrlich Paul
Macferlene Burnet
Macfarlane Burnet (1956 - 1960)
CLONAL SELECTION THEORY
Antibodies are natural products that appear on
the cell surface as receptors and selectively react
with the antigen
Lymphocyte receptors are variable and carry
various antigen-recognizing receptors
‘Non-self’ antigens/pathogens encounter the
existing lymphocyte pool (repertoire)
Antigens select their matching receptors from
the available lymphocyte pool, induce clonal
proliferation of specific clones and these clones
differentiate to antibody secreting plasma cells
The clonally distributed antigen-recognizing
receptors represent about ~107 – 109 distinct
antigenic specificities
DIVERSITY OF LYMPHOCYTES
1012 lymphocytes in our body ( B and T lymphocytes)
Assumption 1
All lymphocytes have
a different receptor
How many
SPECIFICITIES
?
Assumption 2
The receptor can be
activated by many
different antigens
Cc. (minimum) 10 million various (107) B lymphocyte clones with
different antigen-recognizing receptors
Cc. (minimum) 10 – 1000 million various (107 - 9) T lymphocyte
clones with different antigen-recognizing receptors
BINDING OF ANTIGEN TO THE SELECTED
B-LYMPHOCYTES RESULTS IN CLONAL EXPANSION
B cell
B Cell Receptor
(BCR)
A nti g e n
Ag
Plasma cell
ACTIVATION
Clonal expansion
Differentiation
Antibody
(immunoglobulin Ig)
secretion
MEMORY B CELLS
A nti g e n
A nti g e n
Clonal selection induces proliferation
and increases effector cell frequency
No. of
cells with
useful
specificity
Threshold of
protective effector
function
No. of cell divisions
POSSIBLE FATES OF B-LIMPHOCYTE CLONES
Transient, not final
differentiation state
Activation
Clonal expansion/proliferation
Differentiation
Memory cell
Circulation
Restricted life span
Homeostasis
Apoptosis
Plasma cell
Antibody production
THE B-CELL RECEPTOR AND ANTIBODIES PRODUCED
BY PLASMA CELLS HAVE THE SAME PROTEIN
STRUCTURE = IMMUNOGLOBULIN
B CELL
Antigen recognizing
receptor
BCR
Immunoglobulin (Ig)
Antibody
TWO FORMS OF IMMUNOGLOBULINS
Membrane-bound Ig
Antigen-specific
receptor
Antigen binding
L
L
L
H
H
Secreted Ig
Antigen-specific
soluble protein
EFFECTOR MOLECULE
L
H
H
ab
signalling
PLASMA CELL
B CELL
IMMUNOGLOBULIN IgG
VH
FV= VH+ VL
VL
Antigen binding
site
Induced fit model
Are antigens able to shape antibody binding?
RESTRICTED FLEXIBILIY
HIGH SPECIFICITY
Bacteria are not well informed how to
display Ag determinants for proper binding
by host-antibodies
Antibodies have to be flexible
ANTIBODIES WITH DIFFERENT
STRUCTURES AND PROPERTIES
Display of antigenic determinants is independent on the antibody repertoire
TIME COURSE OF THE ADAPTIVE IMMUNE
RESPONSE
Antibody
Primary response
Secondary response
g/ml serum
Lag
Cell interactions
CENTRAL
Recognition
Activation
AFFERENT
MEMORY
Antigen A
Effector/execution
Regulation
EFFECTOR
Response to
antigen A
Primary
Response to
antigen B
Antigen A
Days
AAntigen
antigénB
CHARACTERISTICS OF INNATE AND ACQUIRED IMMUNITY
•
•
•
•
•
•
•
NATURAL/INNATE
Rapid, prompt
response (hours)
No variable receptors
Limited number of
specificities
No improvement
during the response
No memory
Not transferable
Can be exhausted,
saturated
•
•
•
•
•
•
•
•
ADAPTIVE/ACQUIRED
Time consuming
Variable antigen receptors
Many very selective
specificities
Efficacy is improving
during the response
Memory
Can be transferred
Regulated, limited
Protects self tissues
COMMON EFFECTOR MECHANISMS FOR THE
ELIMINATION OF PATHOGENS
TWO LINES OF DEFENSE IN THE IMMUNE SYSTEM
INNATE/NATIVE IMMUNITY
ADAPTIVE/ACQUIRED IMMUNITY
Protects against pathogens without
clonal expansion
Protects from pathogens after clonal
expansion
Receptor code is fixed in the germ line Receptor code requires somatic gene
rearrangements
FIRST LINE OF DEFENSE
SECOND LINE OF DEFENSE
Inherited
Acquired
Always present
Slow response
Promt/rapid response
Specific for both self and non-self
No self specificity
Confers long term protection
Confers short term protection
Is able to establishe memory
TWO LINES OF DEFENSE
ACQUIRED PROTECTION BASED ON EXPERIENCE
INHERITED CAPABILITY – FIRST LINE