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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 Subtypes
●Lambda light chains ●Lambda 1 (λ1) ●Lambda 2 (λ2) ●Lambda 3 (λ3) ●Lambda 4 (λ4)
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 ●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
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
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
Classification
Based on functions, cytokines can be divided into 3 groups: I. Mediate and regulate innate immunity II. Mediateandregulate adaptiveimmunity III. Regulate hematopoiesis
Autoimmunity ClassificationCan be classified into clusters that are either organ-specific or systemic
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