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1.

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

Tolerance to self antigens is an essential feature of the immune


system; when tolerance is lost, the immune system can destroy self tissues,
as happens in autoimmune disease.

Non-self antigens elicit an immune response.


ANTIGENICITY is the ability of the antigen to interact with the
antibodies or T lymphocytes in a specific manner.
IMMUNOGENICITY is the ability of an antigen to elicit an immune
response.
TOLEROGENICITY is the ability of an antigen to induce specific
immunologic nonresponsiveness.

Antigenic determinants recognized by B cells and the antibodies are created by


the primary sequence of residues in the polymer (linear or sequence
determinants) and/or by the secondary, tertiary or quaternary structure of the
molecule (conformational determinants).
Antigenic determinants recognized by T cells are created by the primary
sequence of amino acids in proteins. Free peptides are not recognized by T cells,
rather the peptides associate with molecules encoded by the major
histocompatibility complex (MHC), and it is the complex of MHC molecules +
peptide that is recognized by T cells. Some T cells can recognize lipids in
conjugation with a MHC-like molecule called CD1.

EPITOPES

WHOLE ANTIGEN

CARRIER

Haptens

2. Factors affecting immunogenicity

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

Chemical nature of immunogen


A. Proteins The vast majority of immunogens are proteins. These may be
pure proteins or they may be glycoproteins or lipoproteins. In general,
proteins are usually very good immunogens.
B. Polysaccharides Pure polysaccharides and lipopolysaccharides are
good immunogens.
C. Nucleic acids Nucleic acids are usually poorly immunogenic. However
they may become immunogenic when they are single stranded or
complexed with proteins.

Penicillin

D. Lipids In general lipids are non-immunogenic, although they may be


haptens. Some glycolipids and phospholipids can stimulate T cells and
produce a cell-mediated immune response.
E. Metal ions, synthetic chemical compound (drugs) In general small
chemicals are non-immunogenic, but can be haptens.

Based on their chemical structure, antigens


eliciting antibody production can be classified
to two groups:
1. Thymus-dependent (TD), protein antigens
2. Thymus-independent (TI), non-protein antigens
TD antigens are those that do not directly stimulate the production of
antibody without the help of the T cells. Proteins are TD antigens.
Structurally these antigens are characterized by a few copies of
many different antigenic determinants. Following binding of
BCR to the TD antigen, B-cells present it for T-cells as a peptideMHCII complex. T-B interaction leads to mutual activation of
both cell types; and T-cells provide the second activation signal
for B-lymphocyte activation. Thus, antibody production occurs
under the influence of T-cells, and involves isotype switching,
affinity maturation and memory B cell development.
TI antigens are antigens, which can directly stimulate the B-cells to
produce antibody without the requirement for T cell help. TI
antigens are polyclonal B-cell activators. Structurally these
antigens are characterized by repetitive polymer structure. TI
antigens are not presented by the B-cells, and antibody
production occurs in the absence of T-cell signals, therefore
isotype switching, affinity maturation and memory B-cell
production can not take place.

Complexity of immunogen
More complex immunogens elicit more intense the immune response
Increase in complexity increases the heterogenicity of immune response

Molecular weight of immunogen


Large Mw antigens are strong immunogens, while small Mw antigens are weak
immunogens or haptens.
100 kDa strong immunogen; 5-10 kDa hapten

Polyclonal antibody production in response to large, complex immunogen

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:

Rickettsia prowazekii and Proteus vulgaris OX19 (Weil-Felix test)


Epstein-Barr virus and sheep red blood cells (Paul-Bunnel test)

Dose and route of antigen


Too low dose / too high dose; tolerance
Immunogenicity: subcutan > intraperitoneal > intravenous / per os
An antigen administered per os can be an antigen (not only parenterally administered
immunogens elicit immunity)

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.

Duration of antigen persistence


Extension of antigen persistence increases the intensity of immune response and alters
several features of immunity.

3. Microbial antigens Friends or foes?

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

Microbial antigens can be present on pathogenic and commensal


microorganisms in the human body.
Pathogen colonization is transient; and antigen recognition on pathogenic
microorganisms facilitates the removal of the harmful microorganisms.
Humans harbor a complex population of commensal microorganisms in the GI
tract, on the skin and urogenital tract.
This complex population of commensal microorganisms is termed the
microbiota.
Human Microbiome Project (HMP) and the European Metagenomics of the Human
Intestinal Tract (MetaHIT) Project have analyzed these human-associated microbial
communities and their genes termed the microbiome.
The

continuous presence of commensal microorganisms shapes host immunity.


in microbiota composition may lead to increased susceptibility to
various diseases, including:
-inflammatory (inflammatory bowel disease, Crohns disease),
-metabolic (diabetes, obesity, metabolic syndrome),
-allergic (asthma, atopy),
-autoimmune (arthritis, multiple sclerosis), and
-psychological/neurologic (autism)

Alterations

Host microbiota dialog

3. Microbial antigens present on commensal and


pathogenic microorganisms
Bacterium
Component
-cell wall - (O) antigen
-flagellar - (H) -pili -capsular (polysaccharide, D-glutamic acid polymer, hyaluronic acid)
Product
-exotoxin (diphtheria-, tetanus-)
-enzyme (lecitinase, fibrinolyzin, streptolyzin O, coagulase, hemolyzin)

Virus
Capsid protein
Envelope protein
Non-structural proteins

Fungus/Protozoa/Helminth
Immune system control of microbiota

Microbiota shape host immunity

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

5. Microbial antigens as triggers of autoimmune


processes

INFECTION
TSST-1

PICIS=Post-infectious clinical and immunological syndrome

T-cell activation

PIFSIS=Post-infectious secondary immunodeficiency syndome

IFN-

Monocyte activation

Fever

Endotoxin sensitivity

PIFAS=Post-infectious autoimmune syndrome


PIFSIS+PIFAS

TNF-

IL-1

Immunological mechanisms implicated in PIFAS:

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.

Increase in the viability of autoreactive T cells in


response to infections
Certain viruses may immortalize lymphocytes, including autoreactive cells.

Potential role of microbial antigens in induction of


autoimmune processes

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.

Similarity between human ganglioside GM1 and GM1-like epitope


of C. jejuni LOS

Relationship between infections, anti-ganglioside antibodies


and clinical course of GBS

GBS subtypes

Guillain-Barre Syndrome (GBS) is a rare, post-infectious, inflammatory autoimmune disease that is


characterized by an ascending limb weakness and numbness in the extremities that can progress, in some
cases, to paralysis.
GBS can be divided into three subtypes that can be differentiated through electrodiagnostic techniques:
acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy
(AMAN), acute motor and sensory axonal neuropathy (AMSAN), and Miller Fisher syndrome (MFS).

Insulin-dependent diabetes mellitus

Multiple sclerosis

Basis: sequence homology between glutamate decarboxylase (GAD65), an enzyme

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.

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