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Basic concepts
An ANTIGEN is any structure/molecule/cell that is
recognized by the mature immune system.
The immune system is tolerant (fails to respond) to self antigens.
Antigens/Microbial antigens
Dr. Klra Megyeri
University of Szeged, Faculty of Medicine,
Department of Medical Microbiology and
Immunobiology
2014/2015
Conventional antigens
Theoretically every antigen is composed of two parts. One part is a carrier, while
the other part is the epitope or antigenic determinant.
The epitope is the smallest identifiable part of an antigen molecule that can be
recognized by a given TCR or BCR/antibody.
SPECIFIC REACTION
IMMUNOGENICITY
EPITOPES
WHOLE ANTIGEN
CARRIER
Haptens
Small molecules (Mw < 1000 Da) behave as incomplete antigens, ie they can not elicit an
antibody response alone but can do so if they are coupled to larger molecular weigth carriers.
Such small molecules were defined haptens by K. Landsteiner in order to distinguish them
from bona fide antigens.
Eg:
Poison ivy
Penicillin
Complexity of immunogen
More complex immunogens elicit more intense the immune response
Increase in complexity increases the heterogenicity of immune response
Foreigness
Autoantigen: self antigen recognized by the immune system
Alloantigen: an antigen present in some but not all individuals of a species
Xenoantigen: an antigen found in more than one species
Heterophile/Forssman antigen: an antigen common to more than one species
and whose species distribution is unrelated to its phylogenetic distribution
Eg:
Genotype of host
Immune response to a specific antigen is genetically determined.
The MHC molecules shape the TCR repertoire.
MHC genotype determines the hosts efficiency in presenting particular epitopes to T-cells.
Host genotype can also affect the structure of the cellular receptors to which parasites
attach.
Adjuvants
Substances that increase the immune response to a particular antigen by:
causing slow release of antigen in tissues
increasing immunogenicity of antigen in a non-specific manner:
-they increase migration of macrophages and other immune cells thereby recruit
them to the site of injection
-they stimulate PRR on macrophages and other immune cells, thereby induce
cytokine production, which in turn enhances antigen-specific B- and T-cell
responses
Adjuvants
Mode of action
Increase in the
duration of antigen
persistance
Induction of granuloma
formation
Non-specific stimulation of
lymphocytes
Increased co-stimulation
Aluminium salts
Freunds incomplete
Freunds complete
++
Mycobacterium
tuberculosis
Bordetella pertussis
LPS
Alterations
Virus
Capsid protein
Envelope protein
Non-structural proteins
Fungus/Protozoa/Helminth
Immune system control of microbiota
Component
-cell wall/cell membrane components
-capsid
Products (enzymes, metabolites)
4. Superantigens
Superantigens are polyclonal T-cell activators having the ability to
activate a large proportion (5-20%) of T-cells
Microbial superantigens
Bacteria
Staphylococcus aureus: toxic shock syndrome toxin
Staphylococcus aureus: enterotoxin A, B, C, D, E, F and H
Staphylococcus aureus: exfoliative toxin
Streptococcus pyogenes: pyrogenic exotoxin A, B and C
Streptococcus pyogenes: erythrogenic toxin
Mycoplasma arthritidis: mitogen I
Yersinia enterocolitica: not identified
Yersinia pseudotuberculosis: YPM (Y. pseudotuberculosis-derived mitogen)
Features:
They are NOT processed and presented
They interact with T-cells in a nonMHC-restricted fashion
They bind directly to the outer part of
MHC II and TCR-V chain
The interaction of superantigens with Tcells leads to a cytokin storm and
intensive lymphocyte proliferation
Viruses
Epstein-Barr virus superantigen
Cytomegalovirus superantigen
Rabiesvirus nucleocapsid protein
HIV superantigen
Human endogenous retrovirus (HERV): HERV-K18env
Fungi
Malassezia furfur superantigen
INFECTION
TSST-1
T-cell activation
IFN-
Monocyte activation
Fever
Endotoxin sensitivity
TNF-
IL-1
Capillary permeability
1. Molecular mimicry
2. Epitope spreading
Hypotension
Brain edema
Renal
failure
Respiratory
failure
3. Adjuvant effect
4. Bystander activation
Heart failure
5. Superantigenic effect
6. Immortalization of autoreactive T-cells by certain microbes
DEATH
Mimicry
Based on structural similarity between microbial antigens and human
molecules.
Factors that influence molecular mimicry:
the primary structure of antigen
the conformation of antigen
the charge distribution of antigen
Epitope spreading
Each parasite presents a large number of epitopes to the host's immune system. The immune response
focuses on only a few of the many potential epitopes, a process called immunodominance.
If the immunodominant response fails to clear the targets at first, the immune system will mount a more
diversified and possibly long-lasting inflammatory response locally or systemically. This process of
broadening the initially restricted immune response is called epitope/determinant spreading.
Spreading can occur within a single molecule (intramolecular) or among different nearby molecules
(intermolecular).
Unlike the immunodominant response, where regulation of the few dominant driver T cell clones
would be very efficient, a spreaded T cell response would be more difficult to regulate due to the
increased TCR diversity among the effector T cells.
If coupled with malfunctioning regulatory component(s), which are crucial for the downregulation
of the dominant T cells, a chronic autoimmune response would lead to irreversible pathogenesis.
Adjuvant effect
Microbial PAMPs :
activate immune cells
activate co-stimulatory signals
increase the production of pro-inflammatory cytokines
increase antigen-presentation
Superantigenic effect
Microbial superantigens trigger the simultaneous activation of a large
proportion of T lymphocytes (5-20%); among them autoreactive T cells
may also become activated.
Bystander activation
Pathogen-activated antigen-presenting cells can display self-antigens from dying
cells to autoreactive T lymphocytes in a process known as bystander activation.
Post-Streptococcal diseases
Epitopes present in the cell wall, cell membrane, and the A, B, and C repeat regions of
the streptococcal M protein are immunologically similar to molecules in human myosin,
tropomyosin, keratin, actin, laminin, vimentin, and N-acetylglucosamine. This molecular
mimicry is the basis for the autoimmune response that leads to certain post-streptococcal
diseases, including:
Acute rheumatic fever
PANDA (Pediatric Autoimmune Neuropsychiatric
Disorders Associated with Streptococcal infections):
-Obsessive-compulsive disorder (OCD)
-Tourette syndrome
Other CNS diseases:
-Sydenhams chorea
-Dystonia
-Myoclonus
-Paroxysmal Dystonic Choreoathetosis
-Motor Stereotypes
-Encephalitis lethargica
-Parkinsonism
Guillain-Barr szindrma
The body mounts an antibody response
against a pathogen (Campylobacter) protein
that
resembles
neural
glycolipids
(gangliosides), resulting in an attack on the
peripheral nervous system.
In the case of Campylobacter jejuni
infection, antibodies will be produced,
leading to activation of the complement
system and phagocytosis of the bacteria.
However, in rare cases the antibodies
produced against certain C. jejuni antigens
will also bind to gangliosides of the neurvous
tissue causing complement activation and
damage by phagocytes.
This results in damage to peripheral nervous
tissues, which leads to demyelination and
axonal damage.
GBS subtypes
Multiple sclerosis
Epitopes present in viral and bacterial peptides are immunologically similar to myelin
basic protein (MBP).
T cells specific to viral or bacterial antigens may also recognize and attack components
of the axonal myelin sheath destroying myelin and the underlying axon.
expressed in pancreatic beta cells, and coxsackievirus P2-C, an enzyme involved in the
replication of coxsackievirus B leads to mimicry and immunopathology.