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
