Lecture on immunoglobulins

Immunoglobulins: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

Immune serum

Ag adsorbed serum

1 2

+ -

albumin

globulins

Mobility

Am

oun

t of

pro

tein

Immunoglobulin Has Two Roles

• Antigen Receptor– Recognition of and binding to antigens such as

toxins, viruses, and exposed molecules on the surface of pathogenic organisms

– V domain function

• Effector Molecule– Elimination or inactivation of the foreign antigen

or the cell that bears the antigen– C domain function

Basic Immunoglobulin Structure

• Immunoglobulins - heterogeneous

• Myeloma proteins - homogeneous immunoglobulins

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 RegionCH1

VL

CL

VH

CH2 CH3

Hinge Region

Carbohydrate

Disulfide bond

The first 108 amino acids in light chains and first 118 amino acids in heavy chains constitute the variable region

Immunoglobulin Structure

• Domains– VL & CL

– VH & CH1 - CH3 (or CH4)

• Oligosaccharides CH1

VL

CL

VH

CH2 CH3

Hinge Region

Carbohydrate

Disulfide bond

IgG molecule

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

Human Immunoglobulin Classes

Depending on the heavy chain make up, the

immunoglobulins are differentiated into 5 major

classes

• IgG - Gamma heavy chains

• IgM – Mu heavy chains

• IgA - Alpha heavy chains

• IgD - Delta heavy chains

• IgE - Epsilon heavy chains

Human Immunoglobulin Subclasses

• IgG Subclasses– IgG1 - Gamma 1 heavy chains– IgG2 - Gamma 2 heavy chains– IgG3 - Gamma 3 heavy chains– IgG4 - Gamma 4 heavy chains

• IgA subclasses– IgA1 - Alpha 1 heavy chains– IgA2 - Alpha 2 heavy chains

Human ImmunoglobulinLight Chain Types

• Kappa

• Lambda

In human beings, 60% light chains are of

Kappa variety and 40% are of Lamda type

Human ImmunoglobulinLight Chain Subtypes

• Lambda light chains– Lambda 1 – Lambda 2 – Lambda 3 – Lambda 4

IgG

• Structure– Monomer (7S)

IgG1, IgG2 and IgG4 IgG3

IgG Predominant Ig of blood (75-

80%) 1 unit, smallest Longest half-life Antibody seen in secondary

immnue response Passive transfer Crosses placental barrier – Rh

iso-immunization Agglutination Opsonization Complement Actn.

IgM

• Structure

– Pentamer (19S)

– Extra domain (CH4)

– J chain C4

J Chain

IgM It can combine with 5 antigens

simultaneously 3rd highest serum Ig First Ig made by fetus and B

cells Major Ig of primary response No hinge region Natural antibodies are IgM in

nature It cannot cross the placenta Agglutination, C’ act.

IgA

• Structure– Serum - monomer– Secretions (sIgA)

• Dimer (11S)

• J chain

• Secretory component

J ChainSecretory Piece

Origin of Secretory Component of sIgA

IgA Serum-monomer 2nd highest serum Ig 2 units

J chain secretory component produced by

epithelial cells Major secretory Ig (Mucosal or Local

Immunity)– Tears, saliva, gastric and pulmonary

secretions Prevents attachment & penetration of

microorganisms Does not fix complement (unless

aggregated)

IgD

• Structure– Monomer– Tail piece

Tail Piece

IgD

1 unit

4th highest serum Ig

Long hinge region.

Found as membrane receptor on early B cells.

Does not bind complement

Not in all species.

IgE

• Structure– Monomer

– Extra domain (CH4)

C4

IgE 1 unit Least common serum Ig Extra CH domain binds IgE specific receptors on

basophils and mast cells. Ag binding induces degranulation. Parasitic immunity

Binds to Fc receptor on eosinophils

Type I Hypersensitivity Allergy

Does not fix complement

IgE-Induced Degranulation of Mast CellsIn Allergy

Clinical aspect

• Paraproteinemias

– Multiple myeloma

– Bence-Jones proteinuria

– Waldenstrom’s macroglobulinemia

– Hyper gamma globulinemia

Multiple myeloma

• When Ig secreting cells are transformed into malignant cells, one clone alone is enormously proliferated

• This is seen in electrophoresis as the myeloma band or monoclonal band or M band

• It is characterised by paraproteinemia, anemia, lytic bone lesions and proteinuria

• Bone marrow examination reveals large number of malignant plasma cells

• Spontaneous pathological fracture of weight bearing bones, ribs and vertebrae may occur

• X-ray shows punched out osteolytic lesions

• Hypercalcemia and hypercalciuria

• Raised beta-2 microglobin

• Immunity is depressed

• Prognosis is good

Bence-Jones proteinuria

• Seen in 20% of patients with multiple myeloma

• Monoclonal light chains are excreted in urine

• They precipitate when heated between 45ºC and 60ºC; but redissolving at higher than 80ºC and lower than 45ºC

• Bradshaw’s test