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DEFINITION AND PROPERTIES OF ANTIGEN • Antigen (Ag) - any substance, which is recognized by the mature immune system of a given organism – antigenicity - specific reactivity with cells or molecules of the immune system – immunogenicity - capability to elicit an immune response – tolerogenicity - capability to induce immunological tolerance COMPLEX ANTIGENS CONSIST OF THE CARRIER AND MULTIPLE ANTIGENIC DETERMINANTS (EPITOPES) Antigenic 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 antibody These terms can only be used to describe the interaction of particular antigenic determinant and single immunoglobulin or T cell receptor 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) requires processing by APC cell or matrix associated or soluble B cell activation without the help of T cells T-INDEPENDENT ANTIGEN TI-1 T-INDEPENDENT ANTIGEN TI-2 B cell Complete absence of T-cell help. No interactions no cytokines. At high concentration B-cell mitogens. Simultaneous activation of BCR and other receptors on B cells (i.e. LPS binding protein /CD14/TLR4) induces the B cells to proliferate and differentiate Strong crosslinking of BCR by repetitive polysaccharide or protein epitopes. Cytokine help provided by T, NK cells etc.TI-2 usually do not act as polyclonal B cell activators. B CELL ACTIVATION HAPTENS Small chemical structures 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 hapten-carrier conjugate carrier + hapten carrier specific antibodies hapten specific carrier + hapten specific Factors influencing immunogenicity I. • Foreignness • Size • Genetics – Species – Individual • Responders vs non-responders • Age Factors influencing immunogenicity II. • Dose • Route – Subcutaneous > intravenous,> oral > intranasal • Adjuvant – substances that enhance an immune response to an antigen (alum, LPS, Freund’s adjuvant, TLR ligands) COMPLEX EFFECTS depo effect – slow antigen intake by antigen presenting cells activation of innate immunity Factors influencing immunogenicity II. • Physical status - corpuscle (cell, colloid) or soluble - denaturated or native • Degradability - antigen presentation by APC 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 monoclonal/oligoclonal polyclonal T cell response 1:104 - T cell response 1:105 107 – 108 / 1012 superantigen activated T cells 1:4 - 1:10 1011 / 1012 Immunoglobulins Amount of protein • Definition: Glycoprotein molecules that are present on B cells (BCR) or produced by plasma cells (antibodies) in response to an immunogen + albumin globulins α1 α2 β Mobility γ Immune serum Antigen adsorbed serum Immunoglobulin Structure • heavy and light chains • disulfide bonds – inter-chain – intra-chain disulfide bond carbohydrate CL VL CH1 VH CH2 hinge region CH3 Immunoglobulin Fragments: Structure/Function Relationships antigen binding complement binding site binding to Fc receptors placental transfer Immunoglobulin Structure • variable and constant regions • hinge region disulfide bond carbohydrate • domains – VL & CL – VH & CH1 - CH3 (or CH4) • oligosaccharides CL CH1 VH CH2 hinge region CH3 Ribbon structure of IgG Immunoglobulin Fragments Structure/Function Relationships • Fab papain – antigen binding – valence = 1 – specificty determined by VH and VL • Fc Fc – effector functions Fab Immunoglobulin Fragments: Structure/Function Relationships • Fab pepsin – antigen binding • Fc – effector functions • F(ab’)2 - Bivalent! Fc peptides F(ab’)2 Why do antibodies need an Fc region? the (Fab)2 fragment can • detect antigen • precipitate antigen • block the active sites of toxins or pathogen-associated molecules • block interactions between host and pathogen-associated molecules but can not activate (role of Fc region) • inflammatory and effector functions associated with cells • inflammatory and effector functions of complement • the trafficking of antigens into the antigen processing pathways Immunoglobulin Structure-Function Relationship • cell surface antigen receptor on B cells allows B cells to sense their antigenic environment connects extracellular space with intracellular signalling machinery • secreted antibody neutralization opsonization complement fixation Variability in different regions of the Ig determines Ig classes or specificity isotype allotype idiotype (Classes/subclasses) Sequence variability of H/Lchain constant regions Allelic variants Sequence variability of H and Lchain variable regions (individual, clone- specific) Human Immunoglobulin Classes encoded by different structural gene segments (isotypes) • • • • • IgG - gamma (γ) heavy chains IgM - mu (μ) heavy chains IgA - alpha (α) heavy chains IgD - delta (δ) heavy chains IgE - epsilon (ε) heavy chains light chain types • kappa (κ) • lambda (λ) PRODUCTION OF IMMUNOGLOBULINS BEFORE BIRTH AFTER BIRTH breast milk IgA 100% (adult) maternal IgG IgM IgG IgA 0 3 month 6 9 1 2 3 4 5 adult year Ig. Concentration level of antibodies secondary response against Szekunder ’lasyecondary resp antigen A primary response against antigen A response primer IgG IgA IgE IgM IgM primary response against antigen B 5 „A” antigA én Antigen 10 15 20 25 30 „A” és „B” Antigen A and B antigén napok days napok Polyclonal antibody response Ag Polyclonal antibody Immunserum Set of B-cells Ag Activated B-cells Antibodyproducing plasma-cells Antigen-specific antibodie Ig isotype Serum concentration Characteristics, functions Trace amounts Major isotype of secondary (memory) immune response Complexed with antigen activates effector functions (Fc-receptor binding, complement activation The first isotype in B-lymphocyte membrane Function in serum is not known Trace amounts Major isotype in protection against parasites Mediator of allergic reactions (binds to basophils and mast cells) 3-3,5 mg/ml Major isotype of secretions (saliva, tear, milk) Protection of mucosal surfaces 12-14 mg/ml 1-2 mg/ml Major isotype of primary immune responses Complexed with antigen activates complement Agglutinates microbes The monomeric form is expressed in B-lymphocyte membrane as antigen binding receptor Antibodies with different isotypes differ in their Binding affinity, effector functions and their Transport. Carbohydrate antigens are usually recognized By IgM type antibodies. Differences in transport makes all the differece: Antibodies spec. to blood group antigens Structures of the ABO blood group antigens Defined by specific enzymes inherited co-dominant genes (Mendelian rules) Donors and recipients for blood transfusion - + + + - - + + - + - + - - - - Rhesus (Rh) blood group antigen (D) POLYPEPTIDE TYPE ANTIGEN extracellular space cytoplasm membrane intracellular space IgG type antibody - incomplete no direct agglutination but human immunglobulin-reactive 2. antibody can cause agglutination indirect agglutination Pathological consequences of placental transport of IgG (hemolytic disease of the newborn) Effects of agglutination in vivo ABO incompatibility intravascular haemolysis (complement mediated haemolysis) Rh incompatibility haemolytic disease of the newborn (erythroblastosis fetalis) (opsonisation of red blood cells, which are then phagocytosed by macrophages and granulocytes) Rh profilaxis