ImmunoglobulinsStructure and Function

By

Eisa Salehi PhD

Department of Immunology

Immunoglobulins:Structure and Function

Definition: Glycoprotein molecules that are produced by plasma cells in response to an immunogen and which function as antibodies

Immune serum

Ag adsorbed serum

α1 α2 β γ

+ -

albumin

globulins

Mobility

Am

oun

t of

pro

tein

Basic Immunoglobulin Structure

Immunoglobulins - heterogeneous

Myeloma proteins - homogeneous immunoglobulins

Immunoglobulin vs. Antibody

Immunoglobulin Structure

Heavy & Light Chains Disulfide bonds

Inter-chain Intra-chain

CH1

VL

CL

VH

CH2 CH3

Hinge Region

Carbohydrate

Disulfide bond

Immunoglobulin Structure

Variable & Constant Regions VL & CL

VH & CH

Hinge Region

CH1

VL

CL

VH

CH2 CH3

Hinge Region

Carbohydrate

Disulfide bond

Immunoglobulin Structure

Domains VL & CL

VH & CH1 - CH3 (or CH4)

Oligosaccharides

CH1

VL

CL

VH

CH2 CH3

Hinge Region

Carbohydrate

Disulfide bond

Immunoglobulin Fragments: Structure/Function Relationships

Fab Ag binding Valence = 1 Specificty

determined by VH and VL

Papain

Fc

Fab

Fc Effector functions

Immunoglobulin Fragments: Structure/Function Relationships

Fab Ag binding

Fc Effector functions

F(ab’)2

Pepsin

Fc Peptides

F(ab’)2

Immunoglobulin Fragments: Structure/Function Relationships

Ag Binding

Complement Binding Site

Placental Transfer

Binding to Fc Receptors

Structure of the Variable Region

Hypervariable (HVR) or complimentarity determining regions (CDR) Framework regions

Human Immunoglobulin Classes

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 Subclasses

IgG Subclasses IgG1 - Gamma 1 (γ1) heavy chains IgG2 - Gamma 2 (γ2) heavy chains IgG3 - Gamma 3 (γ3) heavy chains IgG4 - Gamma 4 (γ4) heavy chains

IgA subclasses IgA1 - Alpha 1 (α1) heavy chains IgA2 - Alpha 2 (α 2) heavy chains

Human ImmunoglobulinLight Chain Types

Kappa (κ) Lambda (λ)

Human Immunoglobulin Light Chain Subtypes

Lambda light chains Lambda 1 (λ1) Lambda 2 (λ 2) Lambda 3 (λ 3) Lambda 4 (λ 4)

IgG moleculeدهد نمي تراش را ها صخره چكش

بلكهدهد مي شكل بدان آوازش و رقص و طراوات با آب

IgG

Structure Monomer (7S)

IgG1, IgG2 and IgG4 IgG3

IgG

Structure Properties

Major serum Ig Major Ig in extravascular spaces Placental transfer – Does not require Ag

binding ( IgG2) Fixes complement ( IgG4) Binds to Fc receptors ( IgG2, IgG4)

Phagocytes - opsonization K cells - ADCC

IgM

Structure Pentamer (19S) Extra domain (CH4) J chain

Cμ4

J Chain

IgM

Structure Properties

3rd highest serum Ig First Ig made by fetus and B cells Fixes complement

Fixation of C1 by IgG and IgM Abs

C1r C1s

C1qC1r C1s

C1q

No activation Activation

IgM

Structure Properties

3rd highest serum Ig First Ig made by fetus

and B cells Fixes complement

Tail Piece

Agglutinating Ig Binds to Fc receptors B cell surface Ig

B Cell Antigen Receptor (BcR)

Ig- αIg- α Ig- βIg-β

IgA

Structure Serum - monomer Secretions (sIgA)

Dimer (11S) J chain Secretory

component

J ChainSecretory Piece

Origin of Secretory Component of sIgA

IgA

Structure Properties

2nd highest serum Ig Major secretory Ig (Mucosal or Local Immunity)

Tears, saliva, gastric and pulmonary secretions Does not fix complement (unless aggregated) Binds to Fc receptors on some cells

IgD

Structure Monomer Tail piece

Tail Piece

IgD

Structure Properties

4th highest serum Ig B cell surface Ig Does not bind complement

IgE

Structure Monomer Extra domain (CH4)

Cε4

IgE

Structure Properties

Least common serum Ig Binds to basophils and mast cells (Does not

require Ag binding) Allergic reactions Parasitic infections (Helminths)

Binds to Fc receptor on eosinophils Does not fix complement

Immunoglobulin:Isotypes, Allotypes and Idiotypes

Human IgM

antiserum Reacts withIgM, IgG, IgA, IgD, IgE

React with IgG, IgA, IgD and IgE

Absorbed antiserum Reacts only with IgM

Recognizes determinantsspecific for μ heavy chains

(isotypes)

Immunoglobulin Isotypes

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Immunoglobulin Isotypes

Definition - Antigenic determinants that characterize the classes and subclasses of heavy chains and types and subtypes of light chains

Immunoglobulin Isotypes

Occurrence Importance

Ig levels B cell tumors Immunodeficiencies

• Definition

• Location

IgM (kappa)

حسن

IgG1 (kappa)

حسن

Immunoglobulin Allotypes

• Definition - Antigenic determinants specified by allelic forms of the Ig genes

• Location

• Occurrence

– Source of anti-allotypic Abs

IgG1 (kappa)

نقی

IgG1 (kappa)

حسن

Human Immunoglobulin Allotypes

• Nomenclature– G1m(3)– Km(1)

Chain Domain Allotype Amino Acid

Position

CH1 G1m(f) = (3) Arg 214

CH1 G1m(z) = (17) Lys 214

IgG1

CH3 G1m(a) = (1) Arg, Asp, Glu, Leu

355-358

CL Km(1) Val, Leu 153, 191 κlight chain

CL Km(3) Ala, Val 153, 191

Human Immunoglobulin Allotypes

• Genetics (alleles)– Co-dominant autosomal genes

Km(1)/Km(3) X Km(1)/Km(1)

Km(1)/Km(1) and Km(1)/Km(3)

– Allelic exclusion

Chain Domain Allotype Amino Acid

Position

CH1 G1m(f) = (3) Arg 214

CH1 G1m(z) = (17) Lys 214

IgG1

CH3 G1m(a) = (1) Arg, Asp, Glu, Leu

355-358

CL Km(1) Val, Leu 153, 191 κlight chain

CL Km(3) Ala, Val 153, 191

Chain Domain Allotype Amino Acid

Position

CH1 G1m(f) = (3) Arg 214

CH1 G1m(z) = (17) Lys 214

IgG1

CH3 G1m(a) = (1) Arg, Asp, Glu, Leu

355-358

CL Km(1) Val, Leu 153, 191 κlight chain

CL Km(3) Ala, Val 153, 191

Genetics (pseudoalleles) Co-dominant

G1m(17) G1m(1)

214 355-358

Human Immunoglobulin Allotypes

Immunoglobulin Allotypes

Definition Location Occurrence Importance

Monitoring bone marrow grafts Forensic medicine Paternity testing

Immunoglobulin Idiotypes

Definition - Unique antigenic determinants present on individual antibody molecules or on molecules of identical specificity

DNP-BSAStrain A Mouse

Anti-DNP Ab

Purifiedanti-DNP Ab

Strain A Mouse

Ab againstcombining site of anti-DNP Ab

Immunoglobulin Idiotypes

Antigenic determinants created by the HVR = Idiotypes

Immunoglobulin Idiotypes

Definition Location

IgG1 (kappa)

نقیanti-B

IgG1 (kappa)

نقیanti-A

Immunoglobulin Idiotypes

Definition Location Importance

V region marker Regulation of immune responses

Ag Id anti-Id

+

-

anti-anti-Id

+

-

Regulation by Id/anti-Id

Immunoglobulin Idiotypes

Definition Location Importance

V region marker Regulation of immune responses Vaccines

Ag Id anti-Id

+

-

Anti-Idiotype Vaccines

Ag Id anti-Id

+

Immunoglobulin Idiotypes

Definition Location Importance

V region marker Regulation of immune responses Vaccines Treatment of B cell tumors (T cell)

Immunoglobulin Superfamily

General Functions of Immunoglobulins

Effector functions Fixation of complement Binding to various cells

(Usually require Ag binding)

• Ag binding– Can result in protection– Valency

General Functions of

Immunoglobulins

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