DEFINITION AND TYPES OF
ANTIGENS
Any chemical structure
Soluble or corpuscle
Simple or complex
Originated from the body or comes from outside
Genetically self or non-self
Natural or artificial…
…that binds specifically to an immunoglobulin or that
can be presented on MHC complex molecules to TCR
Antigenicity – capability of an antigen to bind
specifically with components of the adaptive immune
system; TCR or BCR/antibody.
Immunogenicity – the capability of an antigen to induce
an adaptive immune response.
Tolerogenicity – the capability to induce immunological
tolerance; specific immune non-responsiveness.
COMPLEX ANTIGENS CONSIST OF THE CARRIER AND
MULTIPLE ANTIGENIC DETERMINANTS (EPITOPES)
Antigenic determinants
- those parts of the antigen,
which are recognized by a
defined immunoglobulin (Bcell receptor or antibody) or by
T-cell receptor
Carrier
- not directly involved in the
binding of immunoglobulin or Tcell receptor
These terns can only be used to describe the
interaction of particular antigenic determinant
and single immunoglobulin or T-cell receptor
Antigenic determinant / Epitope
The part of the antigenic
molecule that is recognized
by a defined immunoglobulin
(B cell receptor or antibody)
or by a T cell receptor.
Factors influencing immunogenicity
•
•
•
•
•
Foreignness
Size
Age
Dose
Route
• Genetics
– Species
– Individual
• Responders vs. non-responders
– subcutaneous > intravenous > oral > intranasal
• Adjuvant
– substances that enhance an immune response to an antigen
(aluminium salts, LPS, Freund’s adjuvant, TLR ligands)
COMPLEX EFFECTS
depot effect – prolonged antigen uptake by APCs
Activation of innate immunity
Factors influencing immunogenicity II.
• Physical form
- particle (cell, colloid) or
soluble
- denaturated or native
• Possibility of further degradation and
processing
- antigen presentation by APC
Factors influencing immunogenicity III.
Chemical structure:
Proteins: proteins, lipoproteins, glycoproteins. Usually they
are highly immunogenic antigens.
Polysaccharids: lipopolysaccharids, polysaccharids are
immunogenic. B cells are able to recognise them, but B
cells do not process or present any polysaccharids to T
cells.
Nucleic acids: have a very weak immunogenicity. However,
simple strand DNA or protein+nucleic acid can be very
immunogenic!
Lipids: usually are not immunogenic, but can be haptens
The nature of antigenic determinants
B cell epitope
T cell epitope
Recognized by B cells
Recognized by T cells
proteins
polysaccharides
Lipids
DNA
Steroids
etc. (many artificial
molecules)
proteins mainly (8-23
amino acids)
Requires processing by
APC
cell- or matrix associated
vs. solute
B cell activation with the help of T cells
1
T-cell
MHC II + peptide
B-cell
CD4
TCR
2
cytokines
A polysaccharids are not involved in antigen presentation!
B-cell activation without the help of T-cells
T-INDEPENDENT ANTIGEN
TI-1
T-INDEPENDENT ANTIGEN
TI-2
B-Cell
Simultaneous activation of BCR and
other receptors on B cells (i.e. LPS
binding protein /CD14/) induces the B
cells to proliferate and differentiate
Strong crosslinking of BCR by
repetitive polysaccharide or
protein epitopes
T-independent B cell activation
BCR
(mIg)
Ig
(antibody)
Complex macromolecules usually contain several epitopes
! The antibodies that bind to exposed and accessible molecules on
the surface of a pathogen are generally more effective.
! The binding of an antigen to an antibody is based solely on noncovalent forces: Van der Waals forces and hydrophobic
interactions accompanied by electrostatic forces (salt bridges) and
hydrogen bonds between the chemical group on the antigen and
particular amino acid residues on the antibody.
ANTIGEN RECOGNITION = CELL ACTIVATION
Superantigens
• Proteins which can bind to several T-cells with adequate
TCR and activate them.
• Definition
Conventional Antigen
Superantigen
Monoclonal/Oligoclonal
T cell response
Polyclonal T cell response
1:104 - 1:105
1:4 - 1:10
(107/1011
activated T cell
1010 / 1011)
SUPERANTIGENS
Simultaneous binding to TCR and
MHC complex molecules
mimicking a specific antigen
(without a peptide being actually
presented). These sites are
shared by many TCRs causing
their activation and differentiation,
resulting in an excessive
polyclonal response that can
involve 2-20% of the CD4 T cells!
Consequently,
 massive cytokine production and
release IL-1, IL-2, TNF-α
 SYSTEMIC SHOCK
+ a useful adaptive immune
response is suppressed!
Superantigens
•Examples
–Staphylococcal enterotoxins
–Staphylococcal toxic shock toxin
–Staphylococcal exfoliating toxin
–Streptococcal pyrogenic exotoxins
In patients undergoing immune suppressive treatment, suffering from
staphylococcal food toxicity, or in patients with severe burn injuries, the S.
aureus can be life-threatinng, causing toxic shock and Disseminated
Intravascular Coagulation (DIC). Therefore, it is vey important to know the local
and actual resistency profile! (The early and successful empirical antibiotic
treatment together with correct resistency profiling can be life-saver for these
patients!
HAPTEN
Small chemical structures cannot induce B-cell response
on their own
Hapten
(i.e. DNP)
1.
+
Carrier + Hapten
2.
Hapten
primed
+
Antibody response generated against a haptencarrier conjugate
Carrier + hapten
Antibodies
Carrier specific
Hapten specific
Carrier + Hapten
specific
Drugs as haptens
The immune responses induced by drugs are dose independent
responses.
Drug induced hemolytic anaemia
• The drug is a hapten, and attached to the red blood cells, it acts as
full antigen (pl. high dose penicillin, cephalosporins, tetracyclin –
Pay attention! The RBC alone is not an antigen!)
Drug induced thrombocytopenia
• Chinin type: the drug is hapten, or the membrane components of the
thrombocytes (usually GPIIb/IIIa) change their structure, and
become neoantigen.
• Heparin induced thrombocytopenia: heparin alone, or with
thrombocyte factor 4 (Pf4) can induce immune respone.
Antigenic determinants recognized by the innate
immune system
•
•
PAMP PRR (the basis of the immune response)
Components in the microbes’ cell wall - complement system - opsonisation,
complement activation
•
Mannose containing-polysaccharids - mannose-binding proteins –
opsonisation, complement activation
Polyanions - scavenger receptors – Phagocytosis
Lipoproteins, cell wall components (Gram + bacteria) - TLR-2 - Macrophag
activation, secretion of inflammatory cytokines
•
•
•
•
•
•
•
dsRNS - TLR-3 – antiviral interferon secretion
LPS (Gram - bacteria) - TLR-4 - Macrophag activation, secretion of
inflammatory cytokines
Flagellin (bacterium) - TLR-5 - Macrophag activation, secretion of inflammatory
cytokines
simple strand viral RNA - TLR-7 – antiviral interferon secretion
CpG containing DNA - TLR-9 - Macrophag activation, secretion of inflammatory
cytokines
Example (eg. Prevenar – pneumococcus vaccine)
In case of immunisation against bacteria it is a problem that purified bacterial
polysaccharide components of the vaccine cannot activate T cells,
consequently, there will be no memory B cell response.
Therefore in several polysaccharide vaccines, polysaccharide chains are
conjugated to proteins to induce T cell dependent immune response.
A protein used for this purpose is called CRM197  modified diphteria toxin
(toxoid): one amino acid of the original protein is changed (Glu  Gly) thus the
new protein is not toxic (toxoid).
(Although it keeps its immunogenicity and induces a neutralizing antitoxin
antibody response.)
Glu  Gly
toxin
toxoid
toxoid
polysaccharides
toxoid
B cells after the recognition of polysaccharide epitopes
are able to present peptides derived from the carrier
protein to the T cells
polysaccharide
BCR
toxoid
Peptides
from the
toxoid
MHCII
TCR
T cell
B cell
cytokines
(SLE: bakterial DNA-protein complexes  anti-DNA antibodies)