Download 2nd - antigen, acute phase response 2013-14

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
• Dose
• Route subcutaneous > intravenous > oral / intranasal
Not true for live vaccines (i.e. oral polio vaccine)
FACTORS INFLUENCING
IMMUNOGENICITY II.
•
Adjuvant (vaccination)
– 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
• 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
.
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
Antibody response generated against a haptencarrier conjugate
carrier + hapten
antibodies
carrier specific
hapten specific
carrier + hapten
specific
ACUTE INFLAMMATION
AND
ACUTE-PHASE RESPONSE
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.
• Vascular phase
– Vasoconstrictionvasodilation
– Increased permeability  edema, leakage of plasma proteins
(acute phase proteins, antibodies)
• Cellular phase
– Migration of leukocites from the circulation to the site of
inflammation
CAUSES LEADING TO ACUTE
INFLAMMATORY REACTIONS:
• 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)
• Foreign bodies (splinters, dirt, sutures)
• Immune reactions (hypersensitivity and
autoimmune reactions)
The classic symptoms of inflammation:
redness (rubor) - vasodilation,
swelling (tumor) - edema,
heat (calor) – increased perfusion,
pain (dolor) – factors stimulating nociceptors,
loss of function (functio laesa)
CHEMICAL MEDIATORS OF
INFLAMMATION I.
• Vasodilation
– Prostaglandins (PG..), nitric oxide (NO)
• Increased vascular permeability
– vasoactive amines (histamine, serotonin),
C3a and C5a, bradykinin, leukotrienes (LT..),
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 radicals
• 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
proinflammatory cytokines
hypothalamic control of
body temperature
increased ‚set-point’ value
fever
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
ACUTE-PHASE RESPONSE
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