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4th SEMINAR THE ADAPTIVE IMMUNE RESPONSE: ANTIGENS AND ANTIGEN-SPECIFIC RECEPTORS DEFENSE SYSTEMS ADAPTIVE IMMUNITY INNATE IMMUNITY SENSING Cells SENSING RECOGNITION Receptors RECOGNITION SIGNALING Signaling pathways SIGNALING Cell-Cell collaboration RESPONSE Effector functions RESPONSE RECOGNITION BY CELLS OF THE ADAPTIVE IMMUNE SYSTEM Antigen-specific receptors: B cell receptor (BCR) and T cell receptor (TCR) • The basic structure (90%) of the receptors (BCR or TCR) is common • Each cell expresses a receptor that is unique in specificity (the 10% difference means different specificity) • These differences in antigen-specificity are achieved during maturation in the central lymphoid organs (bone marrow and thymus) ANTIGEN Any structure that can be recognized by the adaptive immune system (BCR, TCR). Antigenicity: ability of a chemical structure to bind specifically to a TCR or a BCR/antibody According to the results of the specific binding an antigen may be either: • Immunogenic: recognition induces an immune response • Tolerogenic: recognition induces tolerance (specific immune nonresponsiveness) FACTORS INFLUENCING IMMUNOGENICITY • Size (the bigger the better) • haptens: antigens that can not provoke an immune response because of their small size unless they are attached to a carrier molecule (e.g. a self peptide) • Genetics • Species (evolutionary the farther the better) • Individual (e.g. transplantation antigens) • Age (young: immature, old: decreasing number of lymphocytes) • Dose • Route (vaccination) subcutaneous > intravenous > oral / intranasal Not true for live vaccines (e.g. oral polio vaccine) • Adjuvant (vaccination) • substances that enhance the immune response to an antigen (aluminum salts, LPS, Freund’s adjuvant, TLR ligands) • 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 APCs ANTIGENIC DETERMINANT (EPITOPE) Part of the antigen that directly interacts with the antigen binding site of the TCR or BCR/antibody. 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 and presentation by APCs ANTIGEN RECOGNITION ≠ CELL ACTIVATION BCR AND ANTIBODY Antigen binding L H H H Membrane-bound Ig Antigen-specific Receptor (BCR) RECOGNIZING MOLECULE L ab H L L Secreted Ig Antigen-specific soluble protein EFFECTOR MOLECULE signaling B CELL PLASMA CELL IMMUNOGLOBULINS Definition: Glycoprotein molecules that are present on B cells as part of the BCR or produced by plasma cells as antibodies in response to an immunogenic antigen. Membrane-bound immunoglobulin (mIg) - BCR Secreted immunoglobulin (sIg) – antibody serum antibodies = gamma globulin fraction STRUCTURE • 2x Heavy chain (light blue) disulfide bond • 2x light chain (dark blue) carbohydrate • Variable regions antigen binding CL VL • Constant regions CH1 VH CH2 hinge region CH3 HYPERVARIABLE REGIONS CDR1 CDR2 CDR3 Light chain Epitope CDR1 CDR2 CDR3 Heavy chain CDR3 CDR = Complementarity Determining Region – those amino acids of the variable regions that directly interact with the epitope variability index 150 100 CDR1 50 FR1 0 FR = frame – those amino acids of the variable regions that do not interact directly with the epitope (stabilizer function) CDR2 FR2 FR3 25 75 50 aminoacid sequence N – C terminal FR4 100 DIFFERENT VARIABLE REGIONS DIFFERENT ANTIGEN-BINDING SITE DIFFERENT SPECIFICITY isotype allotype idiotype (Classes/subclasses) Sequence variability of H/Lchain constant regions Allelic variants Sequence variability of H and L-chain 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) 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 IMMUNOGLOBULIN FRAGMENTS STRUCTURE/FUNCTION RELATIONSHIPS • Fab papain • antigen binding • valence = 1 • specificity determined by VH and VL • Fc VH VL • effector functions Fc Fab IMMUNOGLOBULIN FRAGMENTS STRUCTURE/FUNCTION RELATIONSHIPS pepsin • F(ab’)2 - Bivalent! Fc peptides F(ab’)2 ANTIBODY FUNCTION • Role of the Fab part: • Binds the antigen • May form crosslinks between antigens (precipitation / agglutination – see later) • Neutralization: binding can block the enzyme or toxin or other virulence factors of pathogens and can avoid damage to host cells • Role of the Fc part: • Activate cells carrying Fcreceptors on their surfaces: • Phagocytic cells – opsonized phagocytosis • NK cells – antibody-dependent cellular cytotoxicity (ADCC) • Activates the complement system via the classical pathway NEUTRALIZATION OPSONIZATION ADCC (A) High-affinity FcRs on the surface of the cell bind monomeric Ig before it binds to antigen. (mast cell) (B) Low-affinity FcRs bind multiple Igs that have already bound to a multivalent antigen. (macrophage, NK cell) COMPLEMENT ACTIVATION 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 SECRETORY IgA AND TRANSCYTOSIS SS SS ss J SS S S ss S S SS SS SS SS ss ss SS S S S S ss SS SS J J S S S S S S S S S S J S S ss ss SS SS J S S J J B SS S S S S B cells located in the submucosa produce dimeric IgA S S IgA and pIgR are transported to the apical surface in vesicles SS ‘Stalk’ of the pIgR is degraded to release IgA containing part of the pIgR (the secretory component) Epithelial cell pIgR and IgA are internalised Polymeric Ig receptors are expressed on the basolateral surface of epithelial cells to capture IgA produced in the mucosa M U C U S TCR • Alpha and beta chains instead of light and heavy (innate subgroup of T cells express gamma-delta chains as TCR) • Both chains are membrane-bound • Monovalent interaction with the antigen • Antigen recognition requires presentation by antigen presenting cells via MHC molecules • Recognize peptide antigens (mainly) • No secreted form ANTIGEN PRESENTATION • T cells that express CD8 as co-receptor (cytotoxic T cells) recognize peptides presented via MHC class I molecules • T cells that express CD4 as co-receptor (helper T cells) recognize peptides presented via MHC class II molecules • For activation both cell types require the help of APCs • Antigen presentations that lead to T cell activation take place in the secondary lymphoid tissues (e.g. lymph nodes) • MHC I is expressed by every nucleated cell RBCs don’t express them • Professional antigen presenting cells express MHC class I and class II molecules: » macrophage (innate) » DC (innate) » B cell (adaptive) MHC RESTRICTION OF T CELL RECOGNITION TCR TCR TCR 1. A given TCR recognizes a defined MHC – peptide complex 2. The same peptide presented by another MHC is not recognized by the same TCR M HC MHC MHC APC APC APC 1. 2. 3. 3. Another peptide bound to the same MHC is not recognized by the same TCR ACTIVATION OF TCR AND BCR APC MHC Antigen Antigen TCR BCR αβ s V s s sV s C s s sC ss ITAM Immunoreceptor Tyrosine-based Activation Motif CD3 CD3 εδ εγ s s s s s s s s ζζ s s ACTIVATION SUPERANTIGENS Microbial proteins that bind to and activate all the T cells that express a particular set or family of TCR molecules. The activation is independent from the presented antigen. Leads to polyclonal T cell activation that causes life threatening inflammatory responses. SUPERANTIGENS conventional antigen superantigen monoclonal/oligoclonal polyclonal T cell response T cell response 1:104 - 1:105 1:4 - 1:10 107 – 108 / 1011 activated T cells 1010 / 1011