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

General Functions of Immunoglobulins

• Effector functions – Fixation of complement– Binding to various cells

(Usually require Ag binding)

• Ag binding– Can result in protection– Valency

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

Immunoglobulin Structure

• Domains– VL & CL

– VH & CH1 - CH3 (or CH4)

• Oligosaccharides CH1

VL

CL

VH

CH2 CH3

Hinge Region

Carbohydrate

Disulfide bond

IgG molecule

Structure of the Variable Region

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

HVR3

FR1 FR2 FR3 FR4

HVR1HVR2

Var

iabi

lity

Ind

ex

25 7550 100Amino acid residue

150

100

50

0

• Framework regions

IMMUNOGLOBULIN

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

Ag Binding

Complement Binding Site

Placental Transfer

Binding to Fc Receptors

Immunoglobulin Fragments: Structure/Function Relationships

• Fab– Ag binding

• Fc– Effector functions

• F(ab’)2

Pepsin

Fc Peptides

F(ab’)2

Human Immunoglobulin Classes

Difference in amino acid sequence

in the C-region of H-chains

• 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

CH

1

VL

CL

VH

CH

2 C

H3

Hin

ge Region

Carb

ohyd

rate

Disu

lfide b

ond

Human Immunoglobulin SubclassesSmall difference in amino acid sequence

in the C-region of H-chains

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

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

Human ImmunoglobulinLight Chain Types

Difference in amino acid sequence

in the C-region of L-chains

• Kappa (κ)

• Lambda (λ)

Human ImmunoglobulinLight Chain Subtypes

• Lambda light chains– Lambda 1 (λ 1)– Lambda 2 (λ 2)– Lambda 3 (λ 3) – Lambda 4 (λ 4)

Immunoglobulins

• Nomenclature– IgM (κ)– IgA1(λ 2)– IgG

• Heterogeneity

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 (α IgG2)– Fixes complement (α IgG4)– Binds to Fc receptors (α IgG2, IgG4)

• Phagocytes - opsonization• K cells - ADCC

• Increases in:

a) Chronic granulomatous infectionsb) Infections of all typesc) Hyperimmunizationd) Liver diseasee) Malnutrition (severe)f) Dysproteinemiag) Disease associated with hypersensitivity granulomas, dermatologic disorders, and IgG myelomah) Rheumatoid arthritis

• Decreases in:

a) Agammaglobulinemiab) Lymphoid aplasiac) Selective IgG, IgA deficiencyd) IgA myelomae) Bence Jones proteinemiaf) Chronic lymphoblastic leukemia

IgM

• Structure– Pentamer (19S)

– Extra domain (CH4)

– J chainC4

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-Ig-

• Increases (in adults) in:

a) Waldenström's macroglobulinemiab) Trypanosomiasisc) Actinomycosisd) Carrión's disease (bartonellosis)e) Malariaf) Infectious mononucleosisg) Lupus erythematosush) Rheumatoid arthritisI) Dysgammaglobulinemia (certain cases)

In the newborn, a level of IgM above 20 ng./dl is an indication of in utero stimulation of the immune system and stimulation by the rubella virus, the cytomegalovirus, syphilis, or toxoplasmosis.

• Decreases in:

a) Agammaglobulinemiab) Lymphoproliferative disorders (certain cases)c) Lymphoid aplasiad) IgG and IgA myelomae) Dysgammaglobulinemiaf) Chronic lymphoblastic leukemia

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

• Increases in:

a) Wiskott-Aldrich syndromeb) Cirrhosis of the liver (most cases)c) Certain stages of collagen and other autoimmune disorders such as rheumatoid arthritis and lupus erythematosusd) Chronic infections not based on immunologic deficienciese) IgA myeloma

• Decreases in:

a) Hereditary ataxia telangiectasiab) Immunologic deficiency states (e.g., dysgammaglobulinemia, congenital and acquired agammaglobulinemia, and hypogammaglobulinemia)c) Malabsorption syndromesd) Lymphoid aplasiae) IgG myelomaf) Acute lymphoblastic leukemiag) Chronic lymphoblastic leukemia

IgD

• Structure– Monomer– Tail piece

Tail Piece

IgD

• Structure

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

• Increases in:

a) Chronic infectionsb) IgD myelomas

IgE

• Structure– Monomer

– Extra domain (CH4)

C4

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

• Increases in:

a) Atopic skin diseases such as eczemab) Hay feverc) Asthmad) Anaphylactic shocke) IgE-myeloma

• Decreases in:

a) Congenital agammaglobulinemiab) Hypogammaglobulinemia due to faulty metabolism or synthesis of immunoglobulins

IgDiv1

IgDiv2

IgDiv3