4th SEMINARTHE ADAPTIVE IMMUNE RESPONSE:
ANTIGENS AND ANTIGEN-SPECIFIC RECEPTORS
SENSING
RECOGNITION
SIGNALING
RESPONSE
INNATE IMMUNITY
Cells
Receptors
Signaling pathways
Cell-Cell collaboration
Effector functions
DEFENSE SYSTEMS
ADAPTIVE IMMUNITY
SENSING
RECOGNITION
SIGNALING
RESPONSE
RECOGNITION BY CELLS OF THE ADAPTIVE IMMUNE SYSTEM
Antigen-specific receptors: B cell receptor (BCR) and T cell receptor (TCR)
• The basic structure (90%) of the receptors (BCR or TCR) is common
• Each cell expresses a receptor that is unique in specificity (the 10% difference means different specificity)
• These differences in antigen-specificity are achieved during maturation in the central lymphoid organs (bone marrow and thymus)
ANTIGEN
Any structure that can be recognized by the adaptive immune system (BCR, TCR).
Antigenicity: ability of a chemical structure to bind specifically to a TCR or a BCR/antibody
According to the results of the specific binding an antigen may be either:• Immunogenic: recognition induces an immune response• Tolerogenic: recognition induces tolerance (specific immune non-
responsiveness)
FACTORS INFLUENCING IMMUNOGENICITY
• Size (the bigger the better)
• haptens: antigens that can not provoke an
immune response because of their small
size unless they are attached to a carrier
molecule (e.g. a self peptide)
• Genetics• Species (evolutionary the farther the better)
• Individual (e.g. transplantation antigens)
• Age (young: immature, old: decreasing number of
lymphocytes)
• Dose
• Route (vaccination)subcutaneous > intravenous > oral / intranasal
Not true for live vaccines (e.g. oral polio vaccine)
• Adjuvant (vaccination)• substances that enhance the immune response
to an antigen (aluminum salts, LPS, Freund’s adjuvant, TLR ligands)
• depot effect – slower biodegradation, prolonged antigen intake by antigen presenting cells
• activation of innate immunity
• Physical status• corpuscle (cell, colloid) or soluble• denatured or native
• Degradabilityantigen presentation by APCs
ANTIGENIC DETERMINANT (EPITOPE)
Part of the antigen that directly interacts with the antigen binding site of the TCR or BCR/antibody.
B CELL EPITOPE T CELL EPITOPE
Recognized by B cells
proteinspolysaccharideslipidsDNAsteroidsetc. (many artificial molecules)
cell- or matrix-associated or soluble
Recognized by T cells
proteins mainly (8-23 amino acids)
requires processing and presentation by APCs
ANTIGEN RECOGNITION ≠ CELL ACTIVATION
H HL L
H H
L L
Secreted IgAntigen-specificsoluble protein
EFFECTOR MOLECULE
Membrane-bound IgAntigen-specificReceptor (BCR)RECOGNIZING
MOLECULE ba
signaling
B CELL PLASMA CELL
Antigen binding
BCR AND ANTIBODY
IMMUNOGLOBULINS
Definition: Glycoprotein molecules that are present on B cells as part of the BCR or produced by plasma cells as antibodies in response to an immunogenic antigen.
Membrane-bound immunoglobulin (mIg) - BCR
Secreted immunoglobulin (sIg) – antibody
serum antibodies = gamma globulin fraction
STRUCTURE
• 2x Heavy chain (light blue)
• 2x light chain (dark blue)
• Variable regions antigen binding
• Constant regionshinge region
carbohydrate
disulfide bond
CH1
VL
CL
VH
CH2 CH3
Epitope
CDR1 CDR2CDR3
CDR1CDR2
CDR3
Light chain
Heavy chain
CDR3
FR1 FR2 FR3 FR4
CDR1CDR2
varia
bili
ty in
de
x
25 7550 100aminoacid sequence N – C terminal
150
100
50
0
HYPERVARIABLE REGIONS
CDR = Complementarity Determining Region – those amino acids of the variable regions that directly interact with the epitope
FR = frame – those amino acids of the variable regions that do not interact directly with the epitope (stabilizer function)
DIFFERENT VARIABLE REGIONS DIFFERENT ANTIGEN-BINDING SITE
DIFFERENT SPECIFICITY
(Classes/subclasses)
Sequence variability of H/L-chain constant regions
Sequence variability of H and L-chain variable regions
(individual, clone- specific)
Allelic variants
isotype idiotypeallotype
• IgG - gamma (γ) heavy chains• IgM - mu (μ) heavy chains• IgA - alpha (α) heavy chains• IgD - delta (δ) heavy chains• IgE - epsilon (ε) heavy chains
light chain types• kappa (κ)• lambda (λ)
HUMAN IMMUNOGLOBULIN CLASSESencoded by different structural gene segments (isotypes)
Ig isotype Serum concentration
Characteristics, functions
12-14 mg/ml
Major isotype of secondary (memory) immune response
Complexed with antigen activates effector functions (Fc-receptor binding, complement activation
Trace
amounts
The first isotype in B-lymphocyte membrane
Function in serum is not known
Trace amounts
Major isotype in protection against parasites
Mediator of allergic reactions (binds to basophils and mast cells)
3-3,5 mg/ml
Major isotype of secretions (saliva, tear, milk)
Protection of mucosal surfaces
1-2 mg/ml
Major isotype of primary immune responses
Complexed with antigen activates complement
Agglutinates microbes The monomeric form is expressed in
B-lymphocyte membrane as antigen binding receptor
• Fab• antigen binding• valence = 1• specificity determined
by VH and VL
• Fc• effector functions
IMMUNOGLOBULIN FRAGMENTS STRUCTURE/FUNCTION RELATIONSHIPS
papain
Fc
Fab
VH
VL
• F(ab’)2
- Bivalent!
IMMUNOGLOBULIN FRAGMENTS STRUCTURE/FUNCTION RELATIONSHIPS
pepsin
Fc peptides
F(ab’)2
ANTIBODY FUNCTION
• Role of the Fab part:
• Binds the antigen
• May form crosslinks between antigens (precipitation / agglutination – see later)
• Neutralization: binding can block the enzyme or toxin or other virulence factors of pathogens and can avoid damage to host cells
• Role of the Fc part:
• Activate cells carrying Fc-receptors on their surfaces:
• Phagocytic cells – opsonized phagocytosis
• NK cells – antibody-dependent cellular cytotoxicity (ADCC)
• Activates the complement system via the classical pathway
NEUTRALIZATION OPSONIZATION
ADCC
(A) High-affinity FcRs on the surface of the cell bind monomeric Ig before it binds to antigen. (mast cell)
(B) Low-affinity FcRs bind multiple Igs that have already bound to a multivalent antigen. (macrophage, NK cell)
COMPLEMENT ACTIVATION
IgG
IgM
IgA
A F T E R B IR T H
breas t milkIgA
0
1 0 0 %( a d u l t )
3 3y e a r
2 546 a d u l t9 1m o n t h
maternal IgG
B E F O R E B IR T H
PRODUCTION OF IMMUNOGLOBULINS
Epithelialcell
JC C
SS
SS
C
C
SS
SS
CC
ss
JC C
SS
SS
CC
SS
SS
CCss
JC C
SS
SS
C
C
SS
SS
CC
ss
pIgR and IgA areinternalised
‘Stalk’ of the pIgR is degraded to release IgA containing part of the pIgR (the secretory component)
JC C
SS
SS
C
C
SS
SS
CC
ss
IgA and pIgR are transported to the apical surface in vesicles
B cells located in the submucosa produce dimeric IgA
B
Polymeric Ig receptors are expressed on the basolateral surface of epithelial cells to capture IgA produced in the mucosa
SECRETORY IgA AND TRANSCYTOSIS
MUCUS
JC C
SS
SS
C
C
SS
SS
CC
ss
JC C
SS
SS
C
C
SS
SS
CC
ss
JC C
SS
SS
C
C
SS
SS
CC
ss
TCR• Alpha and beta chains instead of light and heavy (innate
subgroup of T cells express gamma-delta chains as TCR)
• Both chains are membrane-bound
• Monovalent interaction with the antigen
• Antigen recognition requires presentation by antigen presenting cells via MHC molecules
• Recognize peptide antigens (mainly)
• No secreted form
ANTIGEN PRESENTATION• T cells that express CD8 as co-receptor (cytotoxic T cells) recognize peptides presented via MHC class I molecules
• T cells that express CD4 as co-receptor (helper T cells) recognize peptides presented via MHC class II molecules
• For activation both cell types require the help of APCs
• Antigen presentations that lead to T cell activation take place in the secondary lymphoid tissues (e.g. lymph nodes)
• MHC I is expressed by every nucleated cell RBCs don’t express them
• Professional antigen presenting cells express MHC class I and class II molecules:
» macrophage (innate)» DC (innate)» B cell (adaptive)
TCR
APC
MHC
TCR TCR
APC
MHC
APC
MHC
MHC RESTRICTION OF T CELL RECOGNITION
1. A given TCR recognizes a defined MHC – peptide complex
2. The same peptide presented by another MHC is not recognized by the same TCR
3. Another peptide bound to the same MHC is not recognized by the same TCR
1. 2. 3.
MHC
TCR
CD3
APC
s s
ss
ss
s
ss
V V
C C
s
α β
ss
ss
ss
ss
CD3
s s
ε δ ε γ
ζ ζ
ITAMImmunoreceptor Tyrosine-based
Activation Motif
ACTIVATION
ACTIVATION OF TCR AND BCR
Antigen
BCR
Antigen
SUPERANTIGENS
Microbial proteins that bind to and activate all the T cells that express a particular set or family of TCR molecules.
The activation is independent from the presented antigen.
Leads to polyclonal T cell activation that causes life threatening inflammatory responses.
conventional antigen
monoclonal/oligoclonal
T cell response
1:104 - 1:105
superantigen
polyclonal
T cell response
1:4 - 1:10
107 – 108 / 1011 1010 / 1011activated T cells
SUPERANTIGENS
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