DEFINITION AND PROPERTIES OF ANTIGEN IMMUNOLOGICAL DEFINITION Any chemical structure Soluble or corpuscle Simple or complex Originated from the body or.

DEFINITION AND PROPERTIES OF DEFINITION AND PROPERTIES OF ANTIGENANTIGEN

IMMUNOLOGICAL DEFINITIONAny chemical structure

Soluble or corpuscle

Simple or complex

Originated from the body or comes from outside

Genetically self or non-self

Natural or artificial

DEFINITIONSDEFINITIONSANTIGEN (Ag) - any substance, which is recognized by

the mature immune system of a given organism

ANTIGENICITY– capability of an antigen to bind to bind specificallyspecifically with certain product of the adaptive immunity: TCR or BCR/antibody,

– immunogenicity - capability of an antigen to induceinduce an (adaptive) immune response,

– tolerogenicity - capability to induce immunological tolerance, specific immune non-responsiveness

FACTORS INFLUENCING FACTORS INFLUENCING IMMUNOGENICITY I.IMMUNOGENICITY I.

• Foreignness

• Size

• Genetics– Species– Individual

• Age

FACTORS INFLUENCING FACTORS INFLUENCING IMMUNOGENICITY II.IMMUNOGENICITY II.

• Dose

• Route subcutaneous > intravenous > oral / intranasalNot 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 FACTORS INFLUENCING IMMUNOGENICITY III.IMMUNOGENICITY III.

• Physical status

– corpuscle (cell, colloid) or soluble

– denatured or native

• Degradability

– antigen presentation by APC

part of the antigen which is recognized by a defined immunoglobulin (BCR / antibody) or by T cell receptor

ANTIGENIC DETERMINANT (ANTIGENIC DETERMINANT (==EPITOPE)EPITOPE)

BCR(mIg)

Ig(antibody)

Ab1Ab2

hidden/revealed determinant

denaturation

new/neoantigen determinant

conformational determinant

cleveage

conformational/linear determinant

TYPES (STRUCTURE) OF ANTIGEN DETERMINANTSTYPES (STRUCTURE) OF ANTIGEN DETERMINANTS

surface/accessible determinants

linear determinantlinear determinant conformational determinantconformational determinant

(TCR, BCR, Ig) (BCR, Ig)

B cell epitopeB cell epitope T cell epitopeT cell epitope

recognized by B cells

• proteins polysaccharides lipids DNA steroids etc. (many artificial molecules)

• cell or matrix associated or soluble

recognized by T cells

• proteins mainly (8-23 amino acids)

• requires processing by APC

ANTIGEN RECOGNITION ≠ CELL ACTIVATIONANTIGEN RECOGNITION ≠ CELL ACTIVATION

ANTIGEN RECOGNITION BY NAIVE T CELLS REQUIRES ANTIGEN RECOGNITION BY NAIVE T CELLS REQUIRES PRESENTATION VIA MHC MOLECULESPRESENTATION VIA MHC MOLECULES

Recognition/No activation

Recognition/Activation

SUPERANTIGENSSUPERANTIGENS

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

Fever

conventional antigen

monoclonal/oligoclonal

T cell response

1:104 - 1:105

superantigen

polyclonal

T cell response

1:4 - 1:10

Microbial proteins that bind to and activate all the T cells in an individual that express a particular set or family of TCR molecules

107 – 108 / 1011 1010 / 1011activated T cells

SUPERANTIGENSSUPERANTIGENS

SUPERANTIGENSSUPERANTIGENS

Classification Sources

Endogenous 

Exogenous        

B cell

1.Mouse mammary tomor virus (MMTV)2.Epstein-Barr virus (EBV)   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*•Viral superantigens:  (a) Mouse leukemia virus                                         (b) IDDMK1222- Ppol-ENV-U3                                         (c) HIV-Nef                                        (d) Rabies virus-nucleoside protein   •Staphylococcal protein A 1.Protein Fv (PFv)

 .

T CELLT CELL--DEPENDENT BDEPENDENT B CELL ACTIVATIONCELL ACTIVATION

Polysacharides are not presented!

B cell

cytokines

CD4TCR

MHCII+peptide T cell

2

1

T-INDEPENDENT ANTIGENTI-1

T-INDEPENDENT ANTIGENTI-2

Strong crosslinking of BCRcrosslinking of BCR by repetitive polysaccharide or

protein epitopes

Simultaneous activation of BCR and BCR and other receptorsother receptors on B cells (i.e. LPS

binding protein /CD14) induces the B cells to proliferate and differentiate

B cell

B CELL ACTIVATION (extensive receptor-aggregation)(extra activation signal)

B CELL ACTIVATION WITHOUT THE HELP OF T CELLSB CELL ACTIVATION WITHOUT THE HELP OF T CELLS

B CELL ACTIVATION WITHOUT THE HELP OF T CELLSB CELL ACTIVATION WITHOUT THE HELP OF T CELLS

Microorganisms have several Microorganisms have several different different cell surface epitopescell surface epitopes

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

COMPLEX ANTIGENSCOMPLEX ANTIGENS CONSIST OF THE CARRIER AND CONSIST OF THE CARRIER AND MULTIPLE EPITOPES (=ANTIGEN DETERMINANTS)MULTIPLE EPITOPES (=ANTIGEN DETERMINANTS)

Carrierpart 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

HAPTENsubstance 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.

carrier + hapten

Small chemical structures that cannot induce B cell response on their own (e.g. drugs, reactive compounds)

hapten

(i.e. DNP:dinitrophenyl)

-

+

HAPTENSHAPTENS

hapten +

1.

2.

primed

carrier specific hapten specific carrier + hapten specific

carrier + haptenantibodies

Antibody response generated against a hapten-carrier conjugate

INTERACTION BETWEEN INTERACTION BETWEEN MICROORGANISMS AND THE MICROORGANISMS AND THE

IMMUNE SYSTEMIMMUNE SYSTEM

Symbiotic, non-pathogenic microbes– mucosal membrane, skinBacteria, Fungi, Protozoa Gut – colonalization after birth1012 bacteria/g intestinal content1000 species100-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

PatogensBacteria, Fungi, Protozoa,VirusesHelmints

COMPLEX ANTIGENS

Strong immunogens

ANTIGENIC PROPERTIES OF PATHOGENIC ANTIGENIC PROPERTIES OF PATHOGENIC AND NON-PATHOGENIC ORGANISMS AND NON-PATHOGENIC ORGANISMS

Important role in:- development of mucosal and systemic immunity- normal development of peripheral lymphoid organs- maintenance of basic level of immunity

HEALTHY MICROFLORA IS REQUIRED FOR PROPER HEALTHY MICROFLORA IS REQUIRED FOR PROPER DEVELOPMENT OF THE IMMUNE SYSTEMDEVELOPMENT OF THE IMMUNE SYSTEM

ACUTE INFLAMMATIONACUTE INFLAMMATION

AND AND

ACUTE-PHASE RESPONSEACUTE-PHASE RESPONSE

THE SKIN AND MUCOSAL EPITHELIUM AS INNATE BARRIERS THE SKIN AND MUCOSAL EPITHELIUM AS INNATE BARRIERS

THE INFLAMMATORY RESPONSE THE INFLAMMATORY RESPONSE

ACUTE ACUTE IINFLAMMATIONNFLAMMATION

• 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 ACUTE INFLAMMATORY REACTIONS ARE TRIGGERED BY A VARIETY OF STIMULITRIGGERED 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 CHEMICAL MEDIATORS OF INFLAMMATIONINFLAMMATION I. 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 CHEMICAL MEDIATORS OF INFLAMMATIONINFLAMMATION II. 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 MIGRATION OF NEUTROPHILS

FROM BLOOD

TO INFLAMMED TISSUE

MIGRATION OF NEUTROPHILS MIGRATION OF NEUTROPHILS

Neutrophil Transendothelial Migration (Diapedesis)

ENDOTHELIAL ADHESION MOLECULES DURING INFLAMMATION ENDOTHELIAL ADHESION MOLECULES DURING INFLAMMATION

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.

PUS PUS

CONSEQUENCECONSEQUENCESS OF OF MACROPHAGE AMACROPHAGE ACTIVATIONCTIVATIONSYNTHESIS OF SYNTHESIS OF CCYTOKINESYTOKINES

ACUTE-PHASE REACTIONACUTE-PHASE REACTION

ACUTE-PHASE RESPONSEACUTE-PHASE RESPONSE

Liver

Mannose binding

lectin/proteinMBL/MBP

Fibrinogen

Serum amyloid protein (SAP)

C-reactive protein (CRP)

UNDER THE INFLUENCE OF IL-6 THE LIVER PRODUCES A BUNCH OF ACUTE-PHASE PROTEINS

ComplementIL-6

ACUTE PHASE REACTIONACUTE PHASE REACTION

RESOLUTION OF ACUTE INFLAMMATIONRESOLUTION OF ACUTE INFLAMMATION

SEPTIC SHOCKSEPTIC 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 SHOCKSEPTIC SHOCK

The key molecule of the process: TNF-alpha

TNF-alpha and other inflammatory cytokines

capillar permeability blood pressure

DIChigh fever multiorgan failure

Therapy: anti-TNF-alpha antibody

disseminated intravascular

coagulation

DICDICDDisseminated isseminated IIntravascular ntravascular CCoagulationoagulation

• 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 CoagulationDIC: Disseminated Intravascular Coagulation