Transcript 2. seminar 2012

DEFINITION AND PROPERTIES OF
ANTIGEN
IMMUNOLOGICAL DEFINITION
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
DEFINITIONS
ANTIGEN (Ag) - any substance, which is recognized by
the mature immune system of a given organism
ANTIGENICITY– capability of an antigen to bind
specifically with certain product of the adaptive
immunity: TCR or BCR/antibody,
– immunogenicity - capability of an antigen to induce
an (adaptive) immune response,
– tolerogenicity - capability to induce immunological
tolerance, specific immune non-responsiveness
FACTORS INFLUENCING
IMMUNOGENICITY I.
• Foreignness
• Size
• Genetics
– Species
– Individual
• Age
FACTORS INFLUENCING
IMMUNOGENICITY II.
• Dose
• Route subcutaneous > intravenous > oral / intranasal
Not true for live vaccines (i.e. oral polio vaccine)
• Adjuvant
– substances that enhance an immune response to an
antigen (aluminum salts, LPS, Freund’s adjuvant, TLR ligands)
COMPLEX EFFECTS
– depot effect – slower biodegradation, prolonged antigen
intake by antigen presenting cells
– activation of innate immunity
FACTORS INFLUENCING
IMMUNOGENICITY III.
• Physical status
– corpuscle (cell, colloid) or soluble
– denatured or native
• Degradability
– antigen presentation by APC
ANTIGENIC DETERMINANT (=EPITOPE)
part of the antigen
which is recognized
by a defined
immunoglobulin
(BCR / antibody)
or by T cell receptor
Ig
(antibody)
BCR
(mIg)
TYPES (STRUCTURE) OF ANTIGEN DETERMINANTS
linear determinant
(TCR, BCR, Ig)
conformational determinant
(BCR, Ig)
conformational
determinant Ab2
Ab1
surface/accessible
determinants
cleveage
denaturation
new/neoantigen
determinant
conformational/linear
determinant
hidden/revealed
determinant
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)
• cell or matrix associated
or soluble
• requires processing by
APC
ANTIGEN RECOGNITION ≠ CELL ACTIVATION
ANTIGEN RECOGNITION BY NAIVE T CELLS REQUIRES
PRESENTATION VIA MHC MOLECULES
Recognition/
No activation
Recognition/
Activation
Fever
SUPERANTIGENS
Microbial proteins that
bind to and activate all
the T cells that express
a particular set or
family of TCR
molecules resulting in a
polyclonal activation.
Interaction is not via the
peptide binding cleft of
MHC molecule.
Hypotension
Rash
Desquamation
SUPERANTIGENS
Microbial proteins that bind to and activate all the T cells in an individual
that express a particular set or family of TCR molecules
conventional antigen
superantigen
monoclonal/oligoclonal
polyclonal
T cell response
T cell response
1:104 - 1:105
107 – 108 / 1011
activated T cells
1:4 - 1:10
1010 / 1011
SUPERANTIGENS
Classification
Sources
Endogenous
1.Mouse mammary tomor virus (MMTV)
2.Epstein-Barr virus (EBV)
Exogenous
1.Staphylococcal enterotoxins (SEs): A, B, C1 to C3, D, E, G to Q
2.Staphylococcal toxic shock syndrome toxin-1 (TSST-1)
3.Staphylococcal exfoliative toxins: exoliatin A, exfoliatin B
4.Staphylococcal enterotoxin-like toxins formed due to recombination within enterotoxin gene cluster:
U2, V
5.Streptococcal pyrogenic exotoxins (SPEs): A1 to A4, C, G to M
6.Streptococcal mitogenic exotoxins: SMEZ
7.Streptococcal superantigen :SSA
8.Yersinia pseudotuberculosis: Yersinia pseudotuberculosis-derived mitogen (YAM)
9.Mycoplasma species: Mycoplasma arthritidis-derived mitogen (MAM)
10.Cholera toxin: subunit A of cholera toxin
11.Prevotella intermedia*
12.Mycobacterium tuberculosis*
13.Viral superantigens: (a) Mouse leukemia virus
(b) IDDMK1222- Ppol-ENV-U3
(c) HIV-Nef
(d) Rabies virus-nucleoside protein
.
B cell
1.Staphylococcal protein A
2.Protein Fv (PFv)
T CELL-DEPENDENT B CELL ACTIVATION
1
B cell
MHCII
+peptide
T cell
CD4
TCR
2
cytokines
Polysacharides are not presented!
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
(extra activation signal)
Strong crosslinking of BCR by
repetitive polysaccharide or
protein epitopes
B CELL ACTIVATION
(extensive receptor-aggregation)
B CELL ACTIVATION WITHOUT THE HELP OF T CELLS
Microorganisms have several different cell surface epitopes
COMPLEX ANTIGENS CONSIST OF THE CARRIER AND
MULTIPLE EPITOPES (=ANTIGEN DETERMINANTS)
HAPTEN
substance that is non-immunogenic but which can react with the products of a specific
immune response. Haptens are small molecules which could never induce an immune response
when administered by themselves but which can when coupled to a carrier molecule.
Free haptens, however, can react with products of the immune response after such
products have been elicited. Haptens have the property of antigenicity but not immunogenicity.
Haptenic/antigen determinant (epitope)
part of the antigen which are recognized by a defined
immunoglobulin (B cell receptor or antibody) or by T cell
receptor
Carrier
part of the antigen directly not involved in
connection with the defined Ig/BCR or TCR
These terms can only be used to describe the
interaction of particular antigenic determinant
and single immunoglobulin or T cell receptor
HAPTENS
Small chemical structures that cannot induce B cell response
on their own (e.g. drugs, reactive compounds)
hapten
(i.e. DNP:dinitrophenyl)
1.
+
carrier + hapten
2.
hapten
primed
+
Antibody response generated against a haptencarrier conjugate
carrier + hapten
antibodies
carrier specific
hapten specific
carrier + hapten
specific
INTERACTION BETWEEN
MICROORGANISMS AND THE
IMMUNE SYSTEM
ANTIGENIC PROPERTIES OF PATHOGENIC
AND NON-PATHOGENIC ORGANISMS
Symbiotic, non-pathogenic microbes
– mucosal membrane, skin
Bacteria, Fungi, Protozoa
Gut – colonalization after birth
1012 bacteria/g intestinal content
1000 species
100-times more bacterial genes than eukaryotic
- „peaceful” commensalisms
- vitamins (i.e. K1 vitamin)
- real ecosystem, survival of the fittest,
competition with pathogenic organism
- the few who brake in through the gut
epithelium induce local immune response
Patogens
Bacteria,
Fungi,
Protozoa,
Viruses
Helmints
COMPLEX ANTIGENS
Strong immunogens
HEALTHY MICROFLORA IS REQUIRED FOR PROPER
DEVELOPMENT OF THE IMMUNE SYSTEM
Important role in:
- development of mucosal and systemic immunity
- normal development of peripheral lymphoid organs
- maintenance of basic level of immunity
ACUTE INFLAMMATION
AND
ACUTE-PHASE RESPONSE
THE SKIN AND MUCOSAL EPITHELIUM AS INNATE BARRIERS
THE INFLAMMATORY RESPONSE
ACUTE INFLAMMATION
• Acute inflammation is a rapid response to an injurious
agent that serves to deliver mediators of host defense
— leukocytes and plasma proteins — to the site of
injury.
• Acute inflammation has three major components:
1) alterations in vascular caliber that lead to an increase in
blood flow
2) structural changes in the microvasculature that permit
plasma proteins and leukocytes to leave the circulation
3) emigration of the leukocytes from the micro-circulation,
their accumulation in the focus of injury, and their
activation to eliminate the offending agent
ACUTE INFLAMMATORY REACTIONS ARE
TRIGGERED BY A VARIETY OF STIMULI:
• Infections (pathogenic microbes and
microbial toxins)
• Trauma (blunt and penetrating)
• Physical and chemical agents (thermal
injury e.g. burns or frostbite; irradiation; some
environmental chemicals)
• Tissue necrosis (from any cause)
• Foreign bodies (splinters, dirt, sutures)
• Immune reactions (hypersensitivity and
autoimmune reactions)
The classic symptoms of inflammation:
redness (rubor),
swelling (tumor),
heat (calor),
pain (dolor),
loss of function (functio laesa)
CHEMICAL MEDIATORS OF
INFLAMMATION I.
• Vasodilation
– prostaglandins, nitric oxide
• Increased vascular permeability
– vasoactive amines (histamine, serotonin),
C3a and C5a, bradykinin, leukotrienes, PAF
• Chemotaxic leukocyte activation
– C3a, C5a, LTB4, chemokines
CHEMICAL MEDIATORS OF
INFLAMMATION II.
• Fever
– IL-1, IL-6, TNF, prostaglandins
• Pain
– prostaglandins, bradykinin
• Tissue damage
– neutrophil and macrophage products
• lysosomal enzymes
• oxygen metabolites
• nitric oxide (NO)
MIGRATION OF NEUTROPHILS
FROM BLOOD
TO INFLAMMED
TISSUE
MIGRATION OF NEUTROPHILS
Neutrophil Transendothelial Migration (Diapedesis)
ENDOTHELIAL ADHESION MOLECULES DURING INFLAMMATION
PUS
Pus is a whitish-yellow, yellow, or yellow-brown exudate produced by
vertebrates during inflammatory pyogenic bacterial infections. Pus consists of
a thin, protein-rich fluid, known as liquor puris, and dead cells.
CONSEQUENCES OF MACROPHAGE ACTIVATION
SYNTHESIS OF CYTOKINES
ACUTE-PHASE REACTION
ACUTE-PHASE RESPONSE
ACUTE PHASE REACTION
IL-6
Complement
C-reactive protein
(CRP)
Liver
Fibrinogen
Serum amyloid
protein (SAP)
Mannose
binding
lectin/protein
MBL/MBP
UNDER THE INFLUENCE OF IL-6 THE LIVER PRODUCES A
BUNCH OF ACUTE-PHASE PROTEINS
RESOLUTION OF ACUTE INFLAMMATION
SEPTIC SHOCK
Triggering factors :
• systemic infection (bacteraemia)
• microbial cell wall products and/or
toxins released from the pathogens
Result:
Systemic activation of
neutrophils and macrophages

High level of cytokine (TNF-alpha) production:
„cytokine storm”

Excessive inflammatory response
SEPTIC SHOCK
The key molecule of the process: TNF-alpha
TNF-alpha and other inflammatory cytokines
capillar permeability
blood pressure
high fever
multiorgan failure
DIC
disseminated
intravascular
coagulation
Therapy: anti-TNF-alpha antibody
DIC
Disseminated Intravascular Coagulation
• pathologic activation of
thrombotic process
• distress of thrombotic
process, bleeding
• other causes:
snake bite, septic
abortion, acute obstetric
complications, malignant
tumors, leukemias
DIC: Disseminated Intravascular Coagulation