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Antibody-Cytokine- Autoimmune Surasak Wongratanacheewin, Ph.D Dean, Graduate School, KKU Microbiology, Faculty of Medicine, KKU [email protected] การอบรมหลักสูตรประกาศนียบัตรการขึ้นทะเบียนชีววัตถุ วันที7-11 มีนาคม 2559 โรงแรมดิเอมเมอรัล กรุงเทพมหานคร

Antibody-Cytokine- Autoimmune - NVInvi.ddc.moph.go.th/Download/eCTD/Module 1/8 Mar/5... · Antibody-Cytokine-Autoimmune Surasak Wongratanacheewin, Ph.D Dean, Graduate School, KKU

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Antibody-Cytokine-Autoimmune

Surasak Wongratanacheewin, Ph.DDean, Graduate School, KKU

Microbiology, Faculty of Medicine, [email protected]

การอบรมหลักสูตรประกาศนียบัตรการขึ้นทะเบียนชีววัตถุ วันที่ 7-11 มีนาคม 2559 ณ โรงแรมดิเอมเมอรัล กรุงเทพมหานคร

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

α1 α2β γ

+ -albumin

globulins

Mobility

Am

ount

of

prot

ein

Basic Immunoglobulin Structure

● Immunoglobulins - heterogeneous

● Myeloma proteins - homogeneous immunoglobulins

General Functions of Immunoglobulins

● Effector functions ● Fixation of complement ● Binding to various cells

(Usually require Ag binding)

• Ag binding – Can result in protection – Valency

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

Structure of the Variable Region● Hypervariable (HVR) or complimentarity

determining regions (CDR)HVR3

FR1 FR2 FR3 FR4

HVR1HVR2

Varia

bilit

y In

dex

25 7550 100Amino acid residue

150

100

50

0

• Framework regions

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

● 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

Human Immunoglobulin Subclasses● IgG Subclasses ● IgG1 - Gamma 1 (γ1) heavy chains ● IgG2 - Gamma 2 (γ2) heavy chains ● IgG3 - Gamma 3 (γ3) heavy chains ● IgG4 - Gamma 4 (γ4) heavy chains

● IgA subclasses ● IgA1 - Alpha 1 (α1) heavy chains ● IgA2 - Alpha 2 (α2) heavy chains

Human ImmunoglobulinLight Chain Types

●Kappa (κ) ●Lambda (λ)

Human ImmunoglobulinLight Chain Subtypes

●Lambda light chains ●Lambda 1 (λ1) ●Lambda 2 (λ2) ●Lambda 3 (λ3) ●Lambda 4 (λ4)

Immunoglobulins

●Nomenclature ●IgM (kappa) ●IgA1(lambda 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 (IgG2) ● Fixes complement (IgG4) ● Binds to Fc receptors (IgG2, IgG4) ● Phagocytes - opsonization ● K cells - ADCC

IgM

● Structure ● Pentamer (19S) ● Extra domain (CH4) ● J chain

C:4

J Chain

IgM

●Structure ●Properties ●3rd highest serum Ig ●First Ig made by fetus and B cells ●Fixes complement

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

IgA● Structure ● Serum - monomer ● Secretions (sIgA) ● Dimer (11S) ● J chain ● Secretory component

J ChainSecretory Piece

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

IgD

● Structure ● Monomer ● Tail piece

Tail Piece

IgD●Structure ●Properties ●4th highest serum Ig ●B cell surface Ig ●Does not bind complement

IgE

● Structure ● Monomer ● Extra domain (CH4)

C,4

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

THOMAS A. WALDMANN, Nature Medicine, 2003

Monoclonal Ab for treatments

What is cytokine?• Cytokine are Polypeptides or glycoproteins produced in

response to various antigens.

• Play role in innate and acquired immunity

• Produce from various kinds of cells such as monokine from monocytes, lymphokine from lymphocytes.

• Cytokine play role in chemotaxis for leukocytes is chemokine

Cytokine properties

Based on production: • Depends on Ag stimulation • Short‐time • By more than one type of cells • One cytokine can stimulate or inhibit the production of other cytokines

Cytokine properties

Based on function: • Hormone‐like action: autocrine, paracrine, endocrine • One cytokine can affect more than one types of cells ‐ Pleiotropism • Different cytokines can perform some similar functions ‐ Redundancy • One cytokine can influence the function(s) and/or production of other cytokines • Interleukins – cytokines interact between cells of the immune systems

Abbas et al, Cells and Molecular Immunology, 7 edition, 2012

Classification

Based on functions, cytokines can be divided into 3 groups: I. Mediate and regulate innate immunity II. Mediateandregulate adaptiveimmunity III. Regulate hematopoiesis

Cytokine in adaptive immunity

Abbas et al, Cells and Molecular Immunology, 7 edition, 2012

Cytokine in hematopoiesis

Abbas et al, Cells and Molecular Immunology, 7 edition, 2012

IFN-beta

G-CSF

Autoimmune diseases

Failure of immune tolerance

Autoimmunity ClassificationCan be classified into clusters that are either organ-specific or systemic

Causes of Autoimmunity

Exceptions to the Rule – Simple Genetic Autoimmune Illnesses

Disease Gene Mechanism

APS-1 (Autoimmune polyglandular syndrome type 1)

AIRE Decreased expression of self-antigens in the thymus, resulting is a defect in negative selection

IPEX (Immunodysregulation, polyendocrinopathy, enteropathy, X-linked)

FOXP3 Decreased generation of Tregs

ALPS (autoimmune lymphoproliferative syndrome )

FAS, FASL Failure of apoptotic death of self reactive T or B cells

Complex Disease and Genetics

There have been numerous disease associated genes or disease “susceptibility” genes linked to autoimmunity

Environment■ Pathogens, drugs, hormones, and toxins are just a

few ways that the environment can trigger autoimmunity

Pathogens

Nature Immunology 2, 777 - 780 (2001)

Sex differences in autoimmunity