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Immunoglobulins: Structure and Function Immunoglobulins:Structure and Function Amount of serum protein • Definition: Glycoprotein molecules that are present on B-cells (BCR) or produced by plasma cells (antibodies) in response to an immunogen + albumin Separation of serum proteins depending on their charge, size, molecular weight globulins α1 α2 β γ Electroforetic mobility Immune serum Ag adsorbed serum Immunoglobulin Structure • Heavy & Light Chains • Disulfide bonds – Inter-chain – Intra-chain Disulfide bond Carbohydrate CL VL CH1 VH CH2 Hinge Region CH3 Immunoglobulin Fragments: Structure/Function Relationships Ag Binding Complement Binding Site Binding to Fc Receptors Placental Transfer Immunoglobulin Structure • Variable & Constant Regions • Hinge Region • Domains – VL & CL – VH & CH1 - CH3 (or CH4 in IgM) • Oligosaccharides Disulfide bond Carbohydrate CL CH1 VH CH2 Hinge Region CH3 Ribbon structure of IgG mIg = BCR HYPERVARIABLE REGIONS Immunoglobulin Fragments: Structure/Function Relationships • Fab – Ag binding – Valence = 1 – Specificity determined by VH and VL Papain VH VL • Fc – Effector functions Fc Fab Immunoglobulin Fragments: Structure/Function Relationships Pepsin • F(ab’)2 – Antigen binding: valence=2, bivalence! 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 • Inflammatory and effector functions associated with cells • Inflammatory and effector functions of complement • The trafficking of antigens into the antigen processing pathways NEUTRALISATION • Immunoglobulin Structure-Function Relationship • Cell surface antigen receptor on B cells (BCR) Allows B cells to sense their antigenic environment Connects extracellular space with intracellular signalling machinery • Secreted antibody Neutralisation Arming/recruiting effector cells Complement fixation Variability in different regions of the Ig determines Ig classes or specificity isotype allotype (Classes/subclasses) Allelic variants Sequence variability of H/Lchain constant regions IgG – Gm allels Ig classes: IgG, IgA, IgE, IgD, IgM; subclasses: IgA1-2, IgG1-4 (light chain izotypes: κ, λ) idiotype Sequence variability of H and L-chain variable regions (individual, clonespecific) responsible for antigen specificity Human Immunoglobulin Classes • • • • • 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) Izotypes! encoded by different structural gene segments (isotypes) 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 Free pentameric IgM structure (”star-shape”) IgM binding to an antigen (”crab-shape”) Different antibody isotypes Characterization of antibody-antigen binding Valence: the number of bonds that a given antibody can form with one or more antigens Affinity: strength of a single bond between a given antigen and a given antibody Avidity: in case of an antibody, it means the combined strength of multiple bonds IG ISOTYPE PRODUCTION OVER THE ONTOGENESIS BEFORE BIRTH AFTER BIRTH Breast milk IgA IgM 100% (ADULT) Maternal IgG IgG IgA 0 3 6 MONTHS 9 12 4 5 ADULT YEARS IgA in breast milk has an important bridge role! Secretory IgA and transcytosis S S SS SS SS SS ss ss J J S S S S S S S S S S S S B J ss SS Epithelial cell pIgR & IgA are internalised ss SS S S J S S J SS SS S S ss 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 SS B cells located in the submucosa produce dimeric IgA Polymeric Ig receptors are expressed on the basolateral surface of epithelial cells to capture IgA produced in the mucosa EFFECTOR FUNCTIONS OF ANTIBODIES 1) 2) 3) 4) Neutralisation Opsonization (facilitated phagocytosis) ADCC Complement activation (see it later) NEUTRALISATION OPSONIZATION An opsonin is any molecule that enhances phagocytosis by marking an antigen for an immune response. In the picture opsonins are antibodies. ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY (ADCC) Ig. Concentration ANTIBODY PRODUCTION DURING IMMUNE RESPONSE Immunoglobulin concentration Szekunder ’lasyecondary Secondary response response Primary primerresponse response IgG IgA IgE IgM IgM Primary response against the B antigen 5 „A” antigen „A” antig é n 10 15 20 25 30 „A” and „B” antigen „A” és „B” antigén napok days Polyclonal antibody response Ag Immunserum Polyclonal antibody Set of B-cells Ag Activated B-cells Antibodyproducing plasma-cells Antigen-specific antibodies I. Passive Methods of immunisation Serum containing the specific antibody (usually IgG) Endagered subject - Does not depend on the immune response of the recipient - Acts immediately - Short-term protection only (elimination of Ig’s!) The subject with specific antibody II. Active immunisation Vaccination is a good example, when not antibodies but inactivated or attenuated pathogens or purified antigens from pathogens are administered sc. Immune response depends on the immune state o the recipient, immune protection needs time to develop, but long term protection is provided (memory cells). Intravenous immunoglobulin PASSZÍV IMMUNIZÁLÁS Pooled intravenous immunoglobulin (IVIg) (Intratect, Intraglobin, Octagam, Gammagard) (approx. 59% IgG1, 36% IgG2, 3% IgG3, 2% IgG4 and maximally 5% IgA) PROTECTED SUBJECTS serum antibodies ENDANGERED SUBJECT No activation of the immune system Acts immediately The protection is short-term only Elimination of Immunoglobulins Intravenous immunoglobulin #1 Low dose: passive immunisation Indications: primary or secundary immune deficiency - congenital agammaglobulinaemia - severe combined immune deficiency (SCID) - Wiskott-Aldrich syndrome - multiplex myeloma or chronic lymphoid leukemia - premature babies - allogenic bone marrow transplantation - congenital HIV-infection (AIDS) Intravenous immunoglobulin #2 High dose: immune suppression The „physiologic” immunsuppressive agent! Especially useful in the autoimmune diseases of children, the only limit is the price. Indications: - immune thrombocytopenia (ITP) - dermatomyositis/polymyositis - myasthenic crisis (myasthenia gravis) - Guillain-Barré syndrome - graft versus host reaction (after transplantation)