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

• Constant regions

hinge region

carbohydrate

disulfide bond

CH

1

VL

CL

VH

CH2 CH3

!

Ribbon structure of IgG

AntibodyBCR (B cell receptor) !!

MEMBRANE BOUND!

Associated chains for signaling

Transmembrane domain

Cytoplasmic domain

Antigen recognition and B cell activation

SOLUBLE (freely circulating)

Antigen recognition and effector functions.

Produced by plasma cells

s

s

s

s

s

s

s

s

s ss s

CH2

CH3

s

s

s

s

s

s

s

s

ss

VL

VH

CL

CH1 ss

ss

ss

ss

ss

effektor funkciók

konstans domének

antigénkötés

variábilis domének

ANTIBODY DOMAINS AND THEIR FUNCTIONS !!

Constant domain

Effector functions

Antigen recognition

Variable domain

mIg = BCRmIg = BCR

Associated chains providing signaling capacity

!

B cell

B CELL ACTIVATION

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

Placental transferConstant fragment (Fc)

Binding to Fc receptors on phagocytic cells

Sequence variability of H/L-chain constant regions

VARIABILITY IN DIFFERENT REGIONS OF THE Ig DETERMINES Ig SPECIFICITY OR CLASS

isotype

Sequence variability of H/L-chain variable regions

Idiotype

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)

Epitope

CDR1 CDR2CDR3

CDR1CDR2

CDR3

Light chain

Heavy chain

Sequence variability of H/L-chain constant regions

VARIABILITY IN DIFFERENT REGIONS OF THE Ig DETERMINES Ig SPECIFICITY OR CLASS

Sequence variability of H/L-chain constant regions

Isotype

• 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

HUMAN IMMUNOGLOBULIN CLASSES

ENCODED BY DIFFERENT STRUCTURAL GENE SEGMENTS (ISOTYPES)

• kappa (κ)• lambda (λ)

Heavy chain types:

Light chain types:

!

ISOTYPE SWITCHING

PHASES OF B CELL RESPONSE !

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

MAIN CHARACTERISTICS OF ANTIBODY ISOTYPES

MAIN CHARACTERISTICS OF ANTIBODY ISOTYPES

Ig . C onc entra tion

na p o k

p rim er response

„A” a ntig né

IgM

IgGIgAIgE

Szekund er ’la syec ond a ry response

„A” és a ntig én

„B”

5 10 15 20 25 30

IgM

secondary response against antigen A

Primary response against antigen A

Level of antibodies

napok

primary response against antigen B

Antigen A

Days

Antigen A and B

ANTIBODY PRODUCTION DURING THE PRIMARY AND THE SECONDARY IMMUNE RESPONSES

ANTIBODY PRODUCTION DURING THE PRIMARY AND THE SECONDARY IMMUNE RESPONSE !

EFFECTOR FUNCTIONS OF ANTIBODIES

Antibody-mediated immune responses

• NEUTRALIZATION• OPSONIZATION

ADCCMAST CELL DEGRANULATION

• COMPLEMENT FIXATION

!!

NEUTRALIZATION

Covering of the pathogen’s surface prevents replication and growth

Antigen binding

Complement binding site

Placental transfer

Binding to Fc receptors

OPSONIZATIONFlagging 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)

(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)

MAST CELL DEGRANULATION

FcεRI+

IgEs

Antigen binding

Complement binding site

Placental transfer

Binding to Fc receptors

COMPLEMENT FIXATIONIgM and IgGs activate the classical pathway of

the complement system

BBaacctteriumerium

CComplementomplement r reecceptoreptor

MMaaccrorophagephage

OPSONIZATION BY C3b

C3b

IMMUNOGLOBULIN ISOTYPES HAVE EACH THEIR SPECIFIC CAPABILITIES

Antigen binding

Complement binding site

Placental transfer

Binding to Fc receptors

FcRn on the placenta facilitate the transfer of

maternal IgG to the fetus’s circulation

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

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 Pathological consequences of placental transport of IgGtransport of IgG

(hemolytic disease of the newborn)(hemolytic disease of the newborn)

Passive anti-D IgG

anti-RhIgM

DIMERIC IgA

IgA dimers are in the highly vulnerable mucosal epithelia lining the GI, respiratory, urinary and genital tracts, the eyes, nose and throat

(Transcytosis)