Transcript DEFINITIONS - Tehran University of Medical Sciences

‫با نام و ياد خدا‬
Antigens
E. Salehi
Tel: 66419536
Email:
[email protected]
‫‪ -1‬تعاريف‬
‫‪ -2‬ويژگي هاي آنتي ژنها‬
‫‪ -3‬انواع آنتي ژنها‬
‫‪ -4‬اپي تپ و انواع آن‬
‫‪ -5‬انواع آنتي ژنها از نظر منشاء‬
‫‪ -6‬عوامل مواثر بر ايمونوژنسيته‬
‫‪ -7‬الگوهاي مولكولي و پذيرنده هاي آن‬
Definitions
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Immunogen
Antigen (Ag)
Tolergen
Allergen
Epitope or Antigenic Determinant
Hapten
Carrier
Super-Antigen
Adjuant
Characters of Antigen
• Degree of “foreignness”-Based on genetic
relatedness
• Molecular Size-Usually
MW >100,000; immunogenic
MW <10,000 non immunogenic
MW 10,000-100,000
is imunogenically variable
Characters of Antigen
• Chemical composition-Proteins;
Primary, secondary, tertiary and
quaternary structure all contribute.
• Ability to be processed by APCsFunction of size
Chemical Nature of
Immunogens
• Proteins
• Polysaccharides
• Nucleic Acids
• Lipids
– Some glycolipids and phosopholipids
can be immunogenic for T cells and illicit
a cell mediated immune response
Epitopes
• In protein antigens epitopes can be defined in
terms of:
– Amino acid composition
– Protein location
– Length (5-15 amino acids)
• epitopes:
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Immunodominant
– Epitopes bound by a greater proportion of antibodies
than others in a normal in vivo immune response
– Also known as Major Antigenic Sites
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Sequestered
• Epitopes can be divided into 2 classes:
– Discontinuous epitopes
– Continuous (linear) epitopes
Antigenic valence:
Total number of determinant which can
be combined with Ab.
Epitopes could be  contiguous (when Ab binds to a
contiguous sequence of amino acids)
 non-contiguous (when Ab binds to
non-contiguous residues, brought
together by folding).
 Sequential epitopes are contiguous
epitopes.
 Conformational epitopes are noncontiguous antigenic determinants.
Discontinuous Epitopes
• Constitutive residues are non-sequential
in the primary sequence.
• Highly conformational dependant.
• Account for approx. 90% of epitopes
on a given antigenic (globular) protein.
Linear (continuous)
Epitopes
• Constitutive residues are sequential in the primary sequence
of the protein.
• Fewer conformational constraints on Ab recognition.
• Often contain residues that are not
implicated in antibody interaction.
Epitopes
Sequential
Conformational
Ab-binding sites
Types of Epitopes
• Conformational / Discontinuous
epitopes:
• recognized by B cells
• non-linear discrete amino acid sequences,
come together due to folding.
• Sequential / Continuous
epitopes:
• recognized by T cells & B cells
• linear peptide fragments
Types of Peptide Epitope
Conformational
Antibody or “B cell” Epitope
Epitope
LinearB cell Epitope
Non-Conformational
T cell Epitope
Class I MHCs
Class II MHCs
all cells
Professional Antigen
Presenting cells
Foreign and self proteins
Foreign proteins
8-10 amino acids
8-20 amino acids
T cells and B cells use Distinct Antigen Receptors
to Recognize Fundamentally Different Forms of Antigen
B cells can recognize linear or conformational epitopes on cell surfaces
carbohydrates or of lipids. The B cell antigen receptor is a form of mem
T cells recognize linear peptide fragments bound to MHC class I or clas
Sperm whale myoglobin (1vxg) contains
five sequential epitopes (red, green,
magenta, blue, orange) and two
conformational epitopes (yellow, pink).
‫كاربرد شناسايي اپي تپ ها‬
Properties of Epitopes
• They occur on the surface of the protein
and are more flexible than the rest of
the protein.
• They have high degree of exposure to
the solvent.
• The amino acids making the epitope are
usually charged and hydrophilic.
Antigenic Determinants
Recognized by B cells and Ab
• Composition
– Proteins, polysaccharides, nucleic acids
– Sequence (linear) determinants
– Conformational determinants
• Size
– 4-8 residues
Antigenic Determinants
Recognized by B cells and Ab
• Composition
• Size
• Number
– Limited
(immunodomin
ant epitopes)
– Located on the
external
surfaces of the
Ag
Antigenic Determinants
Recognized by T cells
• Composition
– Proteins (some lipids)
– Sequestered determinants
• Processed
• MHC presentation (lipid presentation by
MHC-like CD1)
• Size
– 8 -15 residues
• Number
– Limited to those that can bind to MHC
Types of Antigens
• T-cell independent antigens-Does not
require T cell involvement;
polysaccharides
• T-cell dependent antigens-Requires T
cell involvement;
proteins
Types of Antigens
T-independent
• Polysaccharides
• Properties
– Polymeric structure
– Polyclonal B cell
activation
• Yes -Type 1 (TI-1)
• No - Type 2 (TI-2)
– Resistance to degradation
• Examples
– Pneumococcal polysaccharide, lipopolysaccharide
– Flagella
Types of Antigens
T-dependent
• Proteins
• Structure
• Examples
– Microbial proteins
– Non-self or Alteredself proteins
Hapten-carrier conjugates
• Definition
• Structure
– native determinants
– haptenic determinants
Haptenic determinants
Native determinants
Superantigens
• Definition
Conventional Antigen
Monoclonal/Oligoclonal
T cell response
1:104 - 1:105
Superantigen
Polyclonal T cell response
1:4 - 1:10
Superantigens
• Definition
• Examples
– Staphylococcal enterotoxins
– Staphylococcal toxic shock toxin
– Staphylococcal exfoliating toxin
– Streptococcal pyrogenic exotoxins
• T cell SAg:
exotoxin, protein of reverse translate virus
• B cell SAg:
SPA(staphylococcal protein A)
HIV:gp120
Types of Antigens regading
the source of Antigen
1. Alloantigens-”same species”
---- ABO blood type, HLA, et al.
2. Heteroantigens-”different species”
3. Xeno-substances
---- Various pathogens and their
products,xeno- proteins, etc.
4. Autoantigens- Self component
 Release of sequestered antigenSuch as lens protein,sperm etc.
 Change of molecular structure of autotissues
 Degeneration of protein
 Forbidden clone rejuvenate
5. Heterophile Ag (forssman Ag)
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common Ags shared by different species
no specificity of species
significance
immunopathology & Diagnosis
Tumor antigen
• Tumor specific Ag, TSA
--only express on the tumor cells but
normal cells
• Tumor associated Ag,TAA
--Its express is high on tumor cells but
low on normal cells,eg. AFP CEA
Factors influencing immune
response of Ag
Antigen Properties
1.Foreigness
2.Chemical properties of Ag
Chemical nature
Proteins>Polysaccharides >Nucleic
Acids >Lipids
Factors influencing immune
response of Ag
Antigen Properties
3.Molecule weight (size)
reasonable large molecule( >10.0 kd)
has good immuogenecity.
– more stationary
– more surface structure for
lymphocyte to recognize
Factors influencing immune
response of Ag
Antigen Properties
4. Complexity of Ag structure
ring > linear
aromatic ring
Factors influencing immune
response of Ag
Antigen Properties
5. Conformation and accessibility
6. Physical states :
Polymer > monomer
Particulate > Soluble
Denatured > Native
7.Degradability
– Ag processing by Ag Presenting Cells (APC)
Factors influencing immune
response of Ag
Body Factors
Genetics, Species:MHC
Individual :Age, health, etc.
Factors influencing immune
response of Ag
Method of Administration
Dose
Route
Subcutaneous>Intravenous>Intragastric
times
Adjuvant
– Substances that enhance an immune
response to an Ag
Biological Influences on
Immunogenicity
• Adjuvants-Enhance immunogenicity
– Potential mechanism
Types
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Ag persistence
Cell signaling or cytokine effect
Induction of inflammation
Lymphocyte stimulation
Change the chemical and physical charactes of Ag
Improves the Ag process and presentation ability of macrophages
stimulates proliferation of lymphocytes
• Biological adjuvant:BCG,LPS
• Synthesized adjuvant
Freund’s incomplete adjuvant
Freund’s complete adjuvant
• Chemical adjuvant
Alum
Cross reaction:
• Reaction between the same Ab
and different Ag with same
similar determiants.
Mechanism of cross reaction
• Common Ag determinant
• Similar structure of Ag determinant
• Significance:
Because there are some common
antigen determinants between
different microbes, so the antiserum
against one kind of Ag can also react
with another Ag and couse a cross
reaction .
Determinants Recognized by the
Innate Immune System
• Adaptive Immune System – Discrete
Determinants
– Reacts with a specific pathogen
• Innate Immune System – Broad
Molecular Patterns
– Reacts with a variety of pathogens
Determinants Recognized by the
Innate Immune System
• PAMPs – Pathogen Associated Molecular
Patterns
• PRRs – Pattern Recognition Receptors
Biological
Consequence of
Interaction
Opsonization;
Complement
activation
PAMP
PRR
Microbial cell wall
components
Complement
Mannosecontaining
carbohydrates
Mannose-binding
protein
Opsonization;
Complement
activation
Polyanions
Scavenger
receptors
TLR-2 (Toll-like
receptor 2)
Phagocytosis
Lipoproteins of
Gram + bacteria
Yeast cell wall
components
Macrophage
activation;
Secretion of
inflammatory
cytokines
PAMP
PRR
Double stranded
RNA
TLR-3
Biological Consequence of
Interaction
Production of interferon
(antiviral)
LPS
TLR-4
(lipopolysaccharid
e of Gram –
bacteria)
Macrophage activation;
Secretion of inflammatory
cytokines
Flagellin (bacterial TLR-5
flagella)
Macrophage activation;
Secretion of inflammatory
cytokines
PAMP
PRR
U-rich single
stranded viral RNA
TLR-7
CpG containing DNA TLR-9
Biological Consequence of
Interaction
Production of interferon
(antiviral)
Macrophage activation;
Secretion of inflammatory
cytokines