Download Immunoglobulins structure and function

IMMUNOGLOBULINS
STRUCTURE AND FUNCTION
IMMUNOGLOBULINS
Definition
Glycoprotein molecules that are
present on B cells (BCR) or
produced by plasma cells (usually
referred to as antibodies) in
response to an immunogen
 Antibodies production is the sole function
of the B cells
 Not toxic or destructive, bind the
pathogen tightly and target destructive
components of the immune system
 Antibodies are useful in the defense
against extracellular pathogens
 Antibodies are secreted in the secondary
lymphoid organs and in bone marrow and
find their way to the extracellular spaces
 During the course of an infection
antibody effectiveness improves steadily
PHASES OF B CELL RESPONSE
!
!
IMMUNOGLOBULIN STRUCTURE
• 2x Heavy chain (light blue)
• 2x light chain (dark blue)
• Variable regions  antigen binding
disulfide bond
• Constant regions
carbohydrate
CL
VL
CH
VH
CH2
1
hinge region
CH3
Ribbon structure of IgG
BCR (B cell receptor)
Associated chains
for signaling
Antibody
!!
Transmembrane
domain
Cytoplasmic
domain
MEMBRANE BOUND!
Antigen recognition and B cell
activation
SOLUBLE (freely circulating)
Antigen recognition and effector
functions.
Produced by plasma cells
ANTIBODY DOMAINS AND THEIR FUNCTIONS
!!
Antigen recognition
antigénkötés
s
s
s
s
s
s
VH
s
s
CH1
s
s
s
s
Variable
domain
va riábilis
d om ének
s
s
VL
s
ss
ss
s
konsta ns dom ének CH2 s
effektor funkc iók
Effector functions
CH3 ss
s
s
s
s
s
s
s
Constant domain
s
s
CL
mIg = BCR
Associated chains providing
signaling capacity
!
B CELL ACTIVATION
B cell
BCR oligomerization results in B cell
activation, proliferation and differentiation
!
FLEXIBILITY OF ANTIBODIES
FEATURES OF ANTIBODY-ANTIGEN INTERACTION
Valency: numbers of antigen
epitopes an antibody binds
Affinity: the strength of
interaction between a specific
antigen and one binding site
of the antibody
Avidity: The overall strength
of binding at multiple sites in
an antibody
ANTIGEN BINDING
Antigen Binding
Fragment (Fab)
Complement binding site
Constant fragment (Fc)
Binding to Fc receptors
on phagocytic cells
Placental transfer
VARIABILITY IN DIFFERENT REGIONS OF THE Ig
DETERMINES Ig SPECIFICITY OR CLASS
isotype
Idiotype
Sequence variability of H/Lchain constant regions
Sequence variability of H/Lchain variable regions
DIFFERENT VARIABLE REGIONS 
DIFFERENT ANTIGEN-BINDING SITES 
DIFFERENT SPECIFICITIES
ANTIGEN BINDING FRAGMENT (Fab)
CONTAINS HYPERVARIABLE REGIONS
DNA recombination of gene
segments encoding these
regions (variable heavy and
light polypeptide chains) gives
a huge number of variability
during B cell development in
the bone marrow.
Aka. Somatic recombination
COMPLEMENTARY DETERMINING REGIONS (CDR)
CDR2
CDR1
Light
chain
CDR3
Epitope
CDR1
CDR2
CDR3
Heavy
chain
VARIABILITY IN DIFFERENT REGIONS OF THE Ig
DETERMINES Ig SPECIFICITY OR CLASS
Isotype
Sequence variability of H/Lchain constant regions
Sequence variability of H/Lchain constant regions
HUMAN IMMUNOGLOBULIN CLASSES
!
ENCODED BY DIFFERENT STRUCTURAL GENE SEGMENTS (ISOTYPES)
Heavy chain types:
•
•
•
•
•
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)
ISOTYPE SWITCHING
PHASES OF B CELL RESPONSE
!
MAIN CHARACTERISTICS OF ANTIBODY ISOTYPES
Ig isotype
Serum
concentration
Characteristics, functions
Trace
amounts
 Major isotype of secondary
(memory) immune response
 Complexed with antigen activates
effector functions (Fc-receptor
binding, complement activation
 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
12-14 mg/ml
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
MAIN CHARACTERISTICS OF ANTIBODY ISOTYPES
ANTIBODY PRODUCTION DURING THE
PRIMARY AND THE SECONDARY IMMUNE RESPONSES
Ig. Concentration
Level
of antibodies
secondary response against
Szekunder
antigen A ’lasyecondary respo
Primary response
against
antigen
A
primer
response
IgG
IgA
IgE
IgM
IgM
primary response
against antigen B
5
„A” antig éAn
Antigen
10
15
20
25
„A” és „B”
Antigen
A and
antigén
30
B
napok
Days
napok
ANTIBODY PRODUCTION DURING THE
PRIMARY AND THE SECONDARY IMMUNE RESPONSE
!
!!
EFFECTOR FUNCTIONS OF ANTIBODIES
Antibody-mediated immune responses
• NEUTRALIZATION
• OPSONIZATION
ADCC
MAST CELL DEGRANULATION
• COMPLEMENT FIXATION
NEUTRALIZATION
Covering of the pathogen’s surface
prevents replication and growth
Antigen binding
Complement binding site
Binding to Fc receptors
Placental transfer
OPSONIZATION
Flagging a pathogen
Antigen binding portion (Fab)
binds the pathogen, the Fc
region binds phagocytic cells
Fc-receptors speeding up the
process of phagocytosis
Antibody Dependent Cellular Cytotoxicity
(ADCC)
MAST CELL DEGRANULATION
FcεRI
+
IgEs
(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)
Antigen binding
Complement binding site
Binding to Fc receptors
Placental transfer
COMPLEMENT FIXATION
IgM and IgGs activate the classical pathway of
the complement system
OPSONIZATION BY C3b
Bacterium
C3b
Complement receptor
Macrophage
IMMUNOGLOBULIN ISOTYPES HAVE EACH
THEIR SPECIFIC CAPABILITIES
Antigen binding
Complement binding site
Binding to Fc receptors
Placental transfer
FcRn on the placenta
facilitate the transfer of
maternal IgG to the fetus’s
circulation
PRODUCTION OF IMMUNOGLOBULINS
BEFORE BIRTH
AFTER BIRTH
breast milk
IgA
100%
(adult)
maternal IgG
IgM
IgG
IgA
0
3
month
6
9
1 2 3 4 5 adult
year
 IgG transport is so efficient that at birth babies have as high a level of IgG in
their plasma as their mothers
 These transfers are a form of passive immunization. The babies protection by
IgG and IgA is against those pathogen that the mother has mounted
 At the first year (esp.3-12m) maternal IgGs are catabolized and breast feeding
diminishes so babies become most susceptible/vulnerable to infections
Pathological consequences of placental
transport of IgG
(hemolytic disease of the newborn)
anti-Rh
IgM
Passive anti-D IgG
DIMERIC IgA
(Transcytosis)
IgA dimers are in the highly vulnerable mucosal epithelia lining the
GI, respiratory, urinary and genital tracts, the eyes, nose and throat