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Antigens, haptens and immunogens
Definitions:
An antigen is any substance that react with T or B lymphocytes
simple to macromolecules e.g. carbohydrates, phospholiplids, nucleic acids and proteins.
Immunogens are substances that generate immune response
Haptens are small molecules which could never induce an immune response unless coupled to a carrier molecule (foreign protein)
e.g. dinitrophenyl, aminobenzene sulphonate, arsonate
Haptein-carrier molecule, unlike free haptein, can acts as an immunogen.
Antibody-Antigen Interactions
Binding of antibody to antigen is dependent on hydrogen bonds, electrostatic attractions and Van der
Waals attractions.
These bonds are weak compared to covalent bonds but the large number of weak bonds result in a stable complex.
Antibody-antigen binding is reversible.
What is an Epitope
An epitope is the small site on the antigen which is recognized by the antibody.
Usually between one and six sugars or amino acids on the surface of the antigen.
Antibody Uniqueness: B-cells produce somewhere between 1 x 108
and 1 x 1010 IgG antibodies with different binding sites.
Antigenic determinant is a cluster of epitopes on the surface of an antigen.
Antigen has several determinants each structurally different from each other.
A monoclonal antibody reacts with only one determinant on the same antigen.
The affinity or strength of binding of antigen and antibody depends on closeness of fitting.
It refers to strength of association between an individual epitope and a paratope high affinity antibodies bind strongly to antigen.
Avidity is the strength of binding two molecules or cells to one another at multiple sites.
It is determined by heterogeneity of antibodies in serum heterogeneity of antigenic determinants ‘bonus effect’ = k avid = k1 x k2
Avidity – measure of the functional affinity of an antiserum for the whole antigen.
The specificity of antigen recognition by an antibody is not absolute
Cross-reactivity is due to antiserum reacting with a partially related antigen.
Monoclonal antibodies are directed towards a single epitope less cross – reactivity.
Factors Influencing ImmunogenicityContribution of the Immunogen
Foreignness Size
Conformational determinants
Sequence determinants
• Chemical Composition– Primary Structure– Secondary Structure– Tertiary Structure– Quarternary Structure
Factors Influencing ImmunogenicityContribution of the Immunogen
Foreigness Size Chemical Composition Physical Form
Particulate > Soluble Denatured > Native
Factors Influencing ImmunogenicityContribution of the Immunogen
Foreigness Size Chemical Composition Physical Form Degradability
Ag processing by Ag Presenting Cells (APC)
Factors Influencing ImmunogenicityContribution of the Biological System
Genetics Species Individual
Responders vs Non-responders
Age
Factors Influencing ImmunogenicityMethod of Administration
Dose Route
Subcutaneous > Intravenous > Intragastric Adjuvant
Substances that enhance an immune response to an Ag
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
Types of AntigensT-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 AntigensT-dependent
Proteins
Structure Examples
Microbial proteins Non-self or
Altered-self proteins
What Does The B Cell Immunoglobulin (Ig) Receptor Recognize?
1. Proteins (conformational determinants, denatured or proteolyzed determinants)
2. Nucleic acids3. Polysaccharides4. Some lipids5. Small chemicals (haptens)
What Does the αβ T Cell Receptor (TCR) Recognize?
1. Only fragments of proteins (peptides) associated with MHC molecules on surface of cells
Helper T cells (Th) recognize peptide associated with MHC class II molecules
Cytotoxic T cells (Tc) recognize peptide associated with MHC class I molecules
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 (immunodominant epitopes)
Located on the external surfaces of the Ag
Fe
Antigenic DeterminantsRecognized by T cells
Composition Proteins (some lipids) Sequence determinants
Processed MHC presentation (lipid presentation by MHC-like
CD1)
Size 8 -15 residues
Number Limited to those that can bind to MHC
Conventional Antigen
αC βC
CHO CHO
CHOCHO
βVαV
α2 β2
β1α1CHO CHO
CHO
αC βC
CHO CHO
CHOCHO
βVαV
α2 β2
β1α1CHO CHO
CHO
MHC Class II
T cell receptor
AntigenSuper
antigen
T lymphocyte
Antigen presenting cell
Superantigen
SuperantigensProteins produced by pathogensNot processed by antigen presenting
cells Intact protein binds to variable region
of β chain on TCR of T cells and to MHC class II on antigen presenting cells (APC)
Large numbers of activated T cells release cytokines having pathological effects
Superantigens Definition Examples
Staphylococcal enterotoxins Staphylococcal toxic shock toxin Staphylococcal exfoliating toxin Streptococcal pyrogenic exotoxins
Antigen presenting cells (APC) Cells with the capacity to capture, process
and present antigenic peptides to T cells Antigens are presented in the context of
MHC class I or II Also deliver co-stimulatory signal (signal II)
to T cells leading to proper activation Only APCs can activate a naïve T cell
Dendritic cells, Macrophages, B cells
Pathway of Antigen Presentation by Antigen-Presenting Cells
CD4+ T cells T cells with CD4 marker (glycoprotein) 70% of T cells in the periphery T helper cells Play central role in modulating cellular immunity
via secretion of cytokines that modulate: B cell activation Immunoglobulin secretion (quality) Macrophage and dendritic cell activation Cellular chemotaxis and inflammation
Th1 versus Th2 cells
Differences b/w Th1 and Th2 cells
Produces type 1 cytokines IL-2, IFN-, TNF-,
TNF- Activates macrophages
and DCs for intracellular killing of pathogens
Mediates CMI
Produces type 2 cytokines IL-4, IL-5, IL-10, IL-13
Provides help to B cells in antibody response
Mediates allergy and immunity to extracellular pathogens, including parasites
Th1 cell Th2 cell
T cells T cell receptors (TCR) – Ag specific Glycoproteins CD4 (helper T cells) or CD8
(cytotoxic T cells)
CD4 T cell or helper T cell
CD8 T cell or cytotoxic T cell
CD4 CD8
TCR TCR
CD4+ T cells Helper T cells involved in Ab production Recognition of “exogenous Ag”
Bacteria Extracellular Ag
Recognize MHC class II molecule Present on “antigen presenting cells” = APC e.g. Macrophages, Dendritic Cells, B cells
CD8+ T cells
Cytotoxic T cells cell killing Recognition of “endogenous Ag”
Virus infected cells Cancerous cells
Recognize MHC class I molecule Present on all cells
All T cells are “Antigen specific”
Mediated by “T cell receptor” TCR Surface molecule analogous
to part of AbDiversity is generated by
rearrangement of TCR gene locus
T cell Membrane
T Cell Receptor
Antigen Recognition
Complement Binding Site
Phagocyte Receptor Binding Site
Antibody Structure
Figure 13.3, p. 251
TCR like this portion of Ab
TCR Recognizes its Epitope Only in the Context of MHC
CD4 TCR – peptide/MHC Class IICD8 TCR – peptide/MHC Class I
APC = e.g., Macrophage
TCR
PeptideAntigen
CD4
CD4 T Cell
MHCClass II
MHC Class I and Class II MHC I on all cells MHC II on APC Bind Ag only small peptides As an individual you make a small number of
different kinds of MHC I and MHC II Encoded by stable genes inherited; NOT
generated by rearrangements But in the population there are lots of genetic
variants of MHC I and MHC II Important in transplants Hence the name “Major Histocompatability Complex”
Cytotoxic T cells T cells that express CD8 molecule on their surface 30% of T cells in the periphery Destroy cells infected by intracellular pathogens and cancer cells Class I MHC molecules (nucleated body cells) expose foreign proteins TC cell releases perforin and granzymes, proteins that form pores in the target
cell membrane; causing cell lysis and/or apoptosis
Humoral response: B cells Stimulated by T-dependent antigens
(help from TH cells)
APCs with class II MHC proteins process and present antigen to CD4+ T cells (helper cells)
Helper T cell become activated
Activated T cell secretes cytokines that in turn activate B cell
B cell differentiates into effector and memory (plasma) cells and produce antibodies
Antibody-mediated effector mechanisms
Points Concerning Antigen Processing and Presentation1. Location of pathogen viruses in cytosol, MHC class I pathway,
Tc response
extracellular bacteria, MHC class II pathway, Th2 response, Ab formation
intracellular bacteria, MHC class II pathway, Th1 response
Thank you