Transcript Immunoglobulins structure and function

IMMUNOGLOBULINS
STRUCTURE AND FUNCTION
Arpad Lanyi
BSc Public Health
5th week, 2015
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 (antigen that provokes
immune response)
B CELL ACTIVATION
Immunoglobulin STRUCTURE
• 2x Heavy chain
(light blue)
• 2x light chain (dark
blue)
disulfide bond
carbohydrate
• Variable regions 
antigen binding
• Constant regions
CL
VL
CH2
CH1
VH
hinge region
CH3
FLEXIBILITY OF ANTIBODIES
BCR (B cell receptor)
Antibody
mIg
sIg
Associated chains
for signaling
MEMBRANE BOUND!
Transmembrane
domain
Cytoplasmic
domain
Antigen recognition  B cell
activation
SOLUBLE (freely circulating)
Antigen binding  effector
functions
Produced by plasma cells
ANTIBODY DOMAINS AND THEIR FUNCTIONS
Antigen recognition
antigénkötés
s
s
s
s
s
s
VH
s
s
VL
s
s
CH1
Variable
va riábilisdomain
d om ének
s
s
s
s
s
ss
ss
s
C
H2
s
konsta ns dom ének
Constant domains
effektor funkc iók
Effector functions
CH3 ss
s
s
s
s
s
s
s
s
s
CL
B CELL ACTIVATION
B cell
BCR oligomerization results in B cell
activation, proliferation and differentiation
ANTIGEN BINDING
Antigen Binding
Fragment (Fab)
Complement binding site
Constant fragment (Fc)
Binding to Fc receptors
on phagocytic cells
Placental transfer
HYPERVARIABLE REGIONS
B cell development in the red bone marrow  DNA recombination
(somatic gene rearrangement) of gene segments encoding variable
domains of heavy and light polypeptide chains is responsible for
generation of B cells with highly variable specificity
CDR2
CDR1
Light
chain
CDR3
Epitope
CDR1
CDR2
CDR3
Heavy
chain
CDR = complementarity determining
region = hypervariable region
The three-dimensional structure of immunoglobulin
C and V domains
DIFFERENT VARIABLE REGIONS 
DIFFERENT ANTIGEN-BINDING SITES 
DIFFERENT SPECIFICITIES
ISOTYPE (CLASS)
Sequence variability of H/Lchain constant regions
•
•
•
•
•
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
Each isotype has a distinct
constant region and the isotype
of the antibody determines the
effector functions….
PHASES OF B CELL RESPONSE
YIsotype Switching during B Cell Development
PE SWITCHING
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
IgG1-IgG4
IgA1-IgA2
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
EFFECTOR FUNCTIONS OF ANTIBODIES
Antibody-mediated immune responses
• Fab part: NEUTRALIZATION
• Fc part:
– OPSONIZATION followed by
• opsonized phagocytosis (macrophage; IgG)
• ADCC (NK cell; IgG)
• mast cell degranulation (parasite, allergy; IgE)
– COMPLEMENT ACTIVATION
NEUTRALIZATION
Antigen binding
Complement binding site
Binding to Fc receptors
Placental transfer
OPSONIZED PHAGOCYTOSIS
Flagging a pathogen
Antigen binding fragment (Fab)
binds the pathogen  the Fc
region is accessible for Fcreceptors of phagocytic cells,
facilitating (speeding up) the
process of phagocytosis
Opsonization facilitate and accelerate the recognition of the
pathogens by phagocytes
Main opsonins:
Phagocytes must express
receptors for the opsonins:
• antibodies
• Complement molecules
• Acute-phase proteins (CRP, SAP)
IgG  FcγRI
C3b  CR1
Antibody Dependent Cellular Cytotoxicity
(ADCC)
MAST CELL DEGRANULATION
FcεRI
+
IgE
(A) High-affinity FcRs on the surface of the cell bind
antibodies 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)
The complement system
• The complement system is a set of plasma proteins that
act in a cascade to attack and kill extracellular pathogens.
• Approximately 30 components:
–
–
–
–
activating molecules
complement receptors
regulator factors
membrane proteins wich inhibit the lysis of host cells
• Most of the complement proteins and glycoproteins are
produced in the liver in an inactive form (zymogen).
Activation is induced by proteolitic cleavage.
Amplification of the complement cascade
inactive
precursors
limited
proteolysis
enzyme
activating surface
Activating surface needed!
Pathways of complement activation
Cellular and Molecular Immunology, 7th ed., 2014 Elservier
Antigen
binding
Complement
binding site
Binding to Fc
receptors
Placental transfer
SUMMARY
Antigen binding
Complement binding site
Binding to Fc receptors
Placental transfer
FcRn on the placenta facilitate
the transfer of maternal IgG to
the body of the fetus
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
 The children are most vulnerable during the first year of life (esp.3-12m) when
maternal IgGs have disappeared but the de novo synthesis is at low level
Maternal IgG is transported by the neonatal Fc receptor
(FcRn) across the placenta to the fetus
The receptor FcRn transports IgG from the bloodstream
into the extracellular spaces of tissues
IgG half-life
• FcRn is also present in the adult and involved in protecting IgG from
degradation
• Accounts for the long (3 week) half-life of IgG compared to other Ig
isotypes
• Therapeutic agents that are
fused to IgG Fc regions take
advantage of this property
e.g. Enbrel (TNFR-Fc)
Pathological consequences of placental
transport of IgG
(hemolytic disease of the newborn)
anti-Rh
IgM
Passive anti-D IgG
Transcytosis of dimeric IgA antibody across epithelia
is mediated by the poly-Ig receptor (pIgR)