Immunoglobulin:

Structure and Function

Immunoglobulins:Structure and Function

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

General Functions of Immunoglobulins

Ag binding

Can result in protection Valency Fixation of complement Binding to various cells Usually requires Ag binding

Effector functions

Immunoglobulins (Ig) are glycoproteins made up of light (L) and heavy(H) polypeptide chains. The simplest antibody molecule has a Y shape and consists of four polypeptide chains:two H chains and two L chains. The four chains are linked by disulfide bonds.

Immunoglobulin Structure
Disulfide bond

Variable & Constant Regions

Carbohydrate

CL
VL CH1 CH2
Hinge Region

VL & CL VH & CH

CH3

Hinge Region

VH

Immunoglobulin Fragments: Structure/Function Relationships

Fab

Papain

Fc

Ag binding Valence = 1 Specificty determined by VH and VL

Fc Fab

Effector functions

Immunoglobulin Fragments: Structure/Function Relationships

Ag Binding

Complement Binding Site Binding to Fc Receptors Placental Transfer

H chains are distinct for each Of the five Ig classes or isotypes and are designated for the respective classes of Ig, namely IgG IgA IgM

IgD IgE.

Domain Structure of Immunoglobulins

Domains are folded, compact, protease resistant structures Fc
S S

Fab

S S S S

Light chain C domains k or l

Heavy chain C domains a, d, e, g, or m Pepsin cleavage sites Papain cleavage sites

F(ab)2 - 1 x (Fab)2 & 1 x Fc - 2 x Fab 1 x Fc

CH3

CH2

CH3

CH1

CH2

CH3

VH1 CH1

CH2

CH3

VH1 CH1 VL

CH2

CH3

VH1 CH1 VL CL

CH2

CH3

VH1 CH1 VL CL

CH2

CH3

VH1 CH1 CL VL

CH2 Elbow Hinge

CH3

Human Immunoglobulin Classes

IgG - Gamma IgM - Mu IgA - Alpha IgD - Delta IgE - Epsilon

L chains are one of two types

Designated and and only

one type is found in Ig.

L and H chains are subdivided into variable and constant regions.The regions

are composed of three-dimensionally folded,

repeating segments called domains. An L chain consists of one variable (VL) and one constant (CL) domain.Most H chains consist of one variable (VH) and three constant(CH) domains.(IgG and IgA have three CH domains,whereas IgM and IgE have four.)

The various regions are responsible

for antigenbinding ,whereas the constant

regions are responsible for various

biologic functions

eg,

complement

activation and binding to cell surface receptors.

The variable regions of both L and H chains have three extremely variable (hypervariable) amino

acid sequence at binding site.

the

amino-

terminal end that form the antigen-

Human Immunoglobulin Subclasses

IgG Subclasses IgG1 - Gamma 1 IgG2 - Gamma 2 IgG3 - Gamma 3 IgG4 - Gamma 4 IgA subclasses IgA1 - Alpha 1 IgA2 - Alpha 2

IgG

Structure

Monomer (7S)

IgG1, IgG2 and IgG4

IgG3

IgG

Properties

Major serum Ig Major Ig in extravascular spaces The only antibody to cross the placental Fixes complement Binds to Fc receptors

Phagocytes - opsonization NK cells ADCC

IgG facts and figures

Heavy chains: Half-life: Serum level (mgml-1): % of Ig in serum: Complement activation: Interactions with cells:

g 1 g 2 g3 g4 - Gamma 1 - 4
IgG1 IgG3 IgG1 IgG3 IgG1 IgG3 IgG1 IgG3 21 - 24 days 7 - 8 days 5 - 12 0.5 - 1 45 - 53 3-6 +++ ++++ IgG2 IgG4 IgG2 IgG4 IgG2 IgG4 21 - 24 days 21 - 24 days 2-6 0.2 - 1 11 - 15 1-4 + No

IgG2 IgG4

All subclasses via IgG receptors on macrophages and phagocytes

Transplacental transfer:

IgG1 IgG3

++ ++

IgG2 IgG4

+ ++

IgM

Structure

Pentamer (19S) composed 5 H2L2 units plus one molecule of J chain Extra domain (CH4) J chain

J Chain

C 4

IgM

Properties

3rd highest serum Ig First Ig made by fetus and B cells Produced early in the primary response The most efficient Ig Fixes complement

Agglutinating Ig Binds to Fc receptors B cell surface Ig

Tail Piece

IgM facts and figures

Heavy chain:

m - Mu
5 to 10 days
10 0.25 - 3.1 ++++ by classical pathway Phagocytes via C3b receptors Epithelial cells via polymeric Ig receptor No

Half-life:
% of Ig in serum: Serum level (mgml-1): Complement activation: Interactions with cells: Transplacental transfer:

Affinity for antigen:

Monomeric IgM - low affinity - valency of 2 Pentameric IgM - high avidity - valency of 10

Fixation of C1 by IgG and IgM Abs

No activation

Activation

IgA

Structure Serum - monomer Secretions (sIgA) Dimer (11S), sIgA molecule consists of two H2L2 units plus one molecule each of J chain and secretory component(SC or SP)

Secretory Piece

J Chain

IgA

Properties 2nd highest serum Ig Major secretory Ig ( saliva, tears, respiratory, intestinal, and genital tract secretions.) Does not fix complement unless aggregated Binds to Fc receptors on some cells

Origin of sIgA: The

SP is a polypeptide synthesized by epithelial cells that provides for IgA passage to the mucosal surface. It also protests IgA from being degraded in the intestinal tract.

IgA facts and figures

Heavy chains: Half-life: Serum levels (mgml-1): % of Ig in serum: Complement activation: Interactions with cells: Transplacental transfer:

a1 or a2 - Alpha 1 or 2
IgA1 5 - 7 days IgA2 4 - 6 days IgA1 1.4 - 4.2 IgA2 0.2 - 0.5 IgA1 11 - 14 IgA2 1 - 4 IgA1 - by alternative and lectin pathway IgA2 - No Epithelial cells by pIgR Phagocytes by IgA receptor No

To reduce vulnerability to microbial proteases the hinge region of IgA2 is truncated, and in IgA1 the hinge is heavily glycosylated. IgA is inefficient at causing inflammation and elicits protection by excluding, binding, cross-linking microorganisms and facilitating phagocytosis