Antigens, hapteins, immunogens lectures 10.1.06

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 10 8
and 1 x 10 10 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 Immunogenicity Contribution of the Immunogen
Foreignness
Size
Chemical Composition
Primary Structure
Secondary Structure
Tertiary Structure
Quarternary Structure
Conformational determinants Sequence determinants

Foreigness
Size
Physical Form
Particulate > Soluble
Denatured > Native

Foreigness
Size
Physical Form
Degradability
Ag processing by Ag Presenting Cells (APC)

Factors Influencing Immunogenicity Contribution of the Biological System
Genetics
Species
Individual
Responders vs Non-responders
Age

Factors Influencing Immunogenicity Method 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 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 Altered-self proteins

What Does The B Cell Immunoglobulin (Ig) Receptor Recognize?
Proteins (conformational determinants, denatured or proteolyzed determinants)
Nucleic acids
Polysaccharides
Some lipids
Small chemicals (haptens)

What Does the αβ T Cell Receptor (TCR) Recognize?
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 Determinants Recognized 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 Superantigen αC βC CHO CHO CHO CHO βV αV α2 β2 β1 α1 CHO CHO CHO αC βC CHO CHO CHO CHO βV αV α2 β2 β1 α1 CHO CHO CHO MHC Class II T cell receptor Antigen Super antigen T lymphocyte Antigen presenting cell

Superantigens
Proteins produced by pathogens
Not 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 Ab
Diversity is generated by rearrangement of TCR gene locus

T cell Membrane   T Cell Receptor Antigen Recognition

Antibody Structure Figure 13.3, p. 251 TCR like this portion of Ab Complement Binding Site Phagocyte Receptor Binding Site

TCR Recognizes its Epitope Only in the Context of MHC
CD4 TCR – peptide/MHC Class II
CD8 TCR – peptide/MHC Class I

APC = e.g., Macrophage TCR Peptide Antigen CD4 CD4 T Cell MHC Class 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
T C 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 Presentation
1. 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

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Antigens, hapteins, immunogens lectures 10.1.06

by BRUNO THADEUS on Jul 03, 2011

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