IMMUNOGLOBULINS:Structure and Function

MHC COMPLEXCYTOKINES

Immunoglobulins:Structure and Function

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

• FUNCTIONS:• Recognizing and binding to foreign

substances and facilitating their removal• Binding to various cells– phagocytic,

lymphocytes mast cells, basophils, placental trophoblast

• Increase phagocytosis• Neutralizing toxins and viruses• Activating complement

Immunoglobulin Structure• Y shaped protein

molecule- flexible hinge

4 polypeptide chains:

• 2- Light (L) chains– kappa/ lambda

• 2- Heavy (H) chains– alpha, beta, gamma, mu, epsilon

• Chains held together by disulphide bonds

CH1

VL

CL

VH

CH2 CH3

Hinge Region

Carbohydrate

Disulfide bond

Antibody Structure

Immunoglobulin Structure: on basis of their A. acid

sequence. DOMAINS• Variable (V) • Constant (C) Regions

VL & CL VH & CH

• Hinge Region• CL 110 A.Acid• VL 110• VH 11O• CH 33O—44O• L CHAINS- 214 • H CHAINS- 446 • The stem and lower part

of Y arms are called constant (C) region

• Fc region—responsible for immunological reactions.

CH1

VL

CL

VH

CH2 CH3

Hinge Region

Carbohydrate

Disulfide bond

Immunoglobulin Fragments: Structure/Function

Relationships• Cleavage by papain enzyme at hinge area:

- 2 -Fab (Fragment antigen binding)

-1 –Fc ( crystallizable fragment) CH2 __CH3

• Fab --- binds to epitopes• Fc -- binds to

complement, bonding to macrophage, participates in allergic reactions, can cross placental barrier

• Fab Ag binding Valence = 1 Specificty determined by VH and VL

Papain

Fc

FabEffector functions

Immunoglobulin Fragments:

Structure/Function Relationships

Ag Binding

Complement Binding Site

Placental Transfer

Binding to Fc Receptors- M*,

Polymorps

FC REGION

FAB REGION

Human Immunoglobulin Classes

• ON BASIS OF DIFFERENCE IN A.ACID SEQUENCE IN CONSTANT REGION OF HEAVY CHAINS:

• IgG - Gamma () heavy chains• IgM - Mu () heavy chains• IgA - Alpha () heavy chains• IgD - Delta () heavy chains• IgE - Epsilon () heavy chains

Human Immunoglobulin Subclasses• ON BASIS OF DIFFERENT DISTINCTIVE

HEAVY CHAINS WITHIN CLASS:• IgG Subclasses

IgG1 - Gamma 1 (1) heavy chainsIgG2 - Gamma 2 (2) heavy chainsIgG3 - Gamma 3 (3) heavy chainsIgG4 - Gamma 4 (4) heavy chains

• IgA subclassesIgA1 - Alpha 1 (1) heavy chainsIgA2 - Alpha 2 (2) heavy chains

Human ImmunoglobulinLight Chain Types

• Kappa ()• Lambda () • Subtypes Lambda light chain:

Lambda 1 (1)Lambda 2 (2)Lambda 3 (3) Lambda 4 (4)

IgG• Structure

Monomer (7S)Subclasses differ in number of disulfide bonds and

length of hinge regionThese give rise to difference in biological behaviour

IgG1, IgG2 and IgG4 IgG3

IgG• Properties• Most versatile immunoglobulin

Major serum Ig- 75% of serum IgMajor Ig in extravascular spacesPlacental transfer – Does not require

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

Phagocytes - opsonization K cells – ADCC Neutralize bacterial toxins

IgG Molecule

IgM

• StructurePentamerMacromolecule mu chainsExtra domain

(CH4)J chain

C4

J Chain

IgMProperties

3rd highest serum IgFirst Ig made by fetus

and B cellsFixes complementAgglutinating/ cytolytic

antibodyBinds to Fc receptors

IgA• StructureSerum - monomerSecretions (sIgA)

Dimer – J chain Secretory component-

recruited from serous epithium.

J

Chain

Secretory Piece

Origin of Secretory Component of sIgA

IgAProperties

2nd highest serum Ig1ST line of defense in mucous membrane

pathogen 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 cellsNeutralizes viruses and toxins

IgE

• StructureMonomerExtra domain

(CH4)

C4

IgEProperties

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

require Ag binding)Allergic reactionsParasitic infections (Helminths)

Binds to Fc receptor on Eosinophils Activation of macrophages--- ADCC

Does not fix complement

IgD• Structure

MonomerTail piece Tail Piece

Properties

4th highest serum Ig

B cell surface Ig

Does not bind complement

Increased levels in AIDS

Characteristics of Various Classes of Immunoglobins

Characteristics of Various Classes of Immunoglobins

PROPERTIES OF ANTIBODIES

Elimination of foreign agents by antibiotics

MHC COMPLEX

MAJOR HISTOCOMPATIBLE COMPLE (MHC)

• MHC complex defines uniqueness of the individual

• Part of the genome encoding for MHC antigens– clustered on a small segment of chromosome 6– CONSTITUTE HLA COMPLEX

• At least 20 different genes encode for MHC PROTEINS

• Variety of MHC proteins exist in humans• Identical twins have same MHC

molecules• All family members have a mixture of

similar and different MHC molecules

MAJOR HISTOCOMPATIBLE COMPLEX(MHC)

Functions:• The principle function is to bind

peptide fragments of foreign proteins and present it to antigen specific T cell.

• Immune recognition• Interaction between B and T and

other cells• Rejection of allograft

MHC COMPLEX• MHC 1 ANTIGENS MHC II ANTIGENS1.Present on the surface 1. Present on the B cell, of all nucleated cells macrophages and of the body, platelets. activated T cells.2. Bind Ag/ peptide 2. Bind Ag/ peptides endogenously produce exogenously produced eg. viral proteins. then processed

within cell after

phagocytosis.3. Present Ag to CD8 - 3.Present Ag to CD4

cells- TC cells. TH Cells

CLASS1 AND 11 GENES ENCODE CELL SURFACE GLYCOPROTEINS. CLASS III GENES ENCODES FOR COMPONENTS OF COMPLEMENT SYSTEM

CYTOKINES

CYTOKINES• Defined as a class of non antibody

molecules that are produced by many different cells (both immune and non immune) in a highly regulated manner

• Hormone like peptides or glycopeptides with wide spectrum of effects

• Short acting soluble mediators released during interaction between lymphocytes, monocytes, macrophages, inflammatory cells and endothelial cells

• Concerned with induction and regulation of immune response

• Control of lymphocyte growth• Activation of innate immunity mechanism

including inflammation

CYTOKINESPROPERTIES• Individual cytokines produced by different cell

types eg. IL-I,TNF -- PRODUCED BY VIRTUALLY ALL CELLS

• Cytokines have PLEOTROPIC effect– act on many cell types—IL2 ---T cells, B, NK CELLS

• Cytokines produce their effect by combining with high affinity receptors on the target cell eg:IL2 activate T cells by binding to IL2 receptor

• They can act on the same cell that produces it eg IL 2 produced by activated T cell promote T cell growth

FAMILIES OF CYTOKINES5 families recognized currently:INTERLEUKINS (IL I – IL15)TUMOUR NECROSIS FACTOR (TNF)INTERFERONS( IFN)COLONY STIMULATING FACTOR (CSF)OTHERS (TGB transforming growth

factor LIF- leukaemia inhibitory

factor)

CYTOKINES

EFFECTS OF CYTOKINES

EFFECT OF IL-2

Important Cytokines