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Immunoglobulins: Structure and Function

Immunoglobulins: Structure and Function. Immunoglobulins:Structure and Function. Definition: Glycoprotein molecules that are present on B-cells (BCR) or produced by plasma cells (antibodies) in response to an immunogen.

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Immunoglobulins: Structure and Function

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  1. Immunoglobulins:Structure and Function

  2. Immunoglobulins:Structure and Function • Definition: Glycoprotein molecules that are present on B-cells (BCR) or produced by plasma cells (antibodies) in response to an immunogen Separation of serumproteinsdependingontheircharge, size, molecularweight - + albumin Amount of serum protein globulins γ β α1 α2 Immune serum Ag adsorbed serum Electroforetic mobility

  3. Immunoglobulin Structure • Heavy & Light Chains • Disulfide bonds • Inter-chain • Intra-chain Disulfide bond Carbohydrate CL VL CH2 CH3 CH1 Hinge Region VH

  4. Ag Binding Complement Binding Site Binding to Fc Receptors Placental Transfer Immunoglobulin Fragments: Structure/Function Relationships

  5. Disulfide bond Carbohydrate CL CH2 CH3 CH1 Hinge Region VH Immunoglobulin Structure • Variable & Constant Regions • Hinge Region • Domains • VL & CL • VH & CH1 - CH3 (or CH4in IgM) • Oligosaccharides

  6. Ribbon structure of IgG

  7. mIg = BCR

  8. HYPERVARIABLE REGIONS

  9. Papain VH VL Immunoglobulin Fragments: Structure/Function Relationships • Fab • Ag binding • Valence = 1 • Specificity determined by VH and VL • Fc • Effector functions Fc Fab

  10. Pepsin Fc Peptides F(ab’)2 Immunoglobulin Fragments: Structure/Function Relationships • F(ab’)2 • Antigen binding: valence=2, bivalence!

  11. 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 Why do antibodies need an Fc region? NEUTRALISATION

  12. 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

  13. Variability in different regions of the Ig determines Ig classes or specificity isotype allotype idiotype Sequence variability of H and L-chain variable regions (individual, clone- specific) responsible for antigen specificity (Classes/subclasses) Allelic variants Sequence variability of H/L-chain constant regions IgG – Gm allels Ig classes: IgG, IgA, IgE, IgD, IgM;subclasses: IgA1-2, IgG1-4 (light chain izotypes: κ, λ)

  14. Human Immunoglobulin Classesencoded 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 Izotypes! Light Chain Types • Kappa (κ) • Lambda (λ)

  15. Free pentameric IgMstructure (”star-shape”) IgM binding to an antigen (”crab-shape”)

  16. Differentantibodyisotypes

  17. 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

  18. IG ISOTYPE PRODUCTION OVER THE ONTOGENESIS BEFORE BIRTH AFTER BIRTH Breast milk IgA IgM 100% (ADULT) Maternal IgG IgG IgA ADULT MONTHS YEARS IgA in breast milk has an important bridge role!

  19. S S S S S S S S S S S S S S S S S S S S IgA and pIgR are transported to the apical surface in vesicles s s s s s s s s s s C C C C C J J J J J C C C C C S S S S S S S S S S C C C C C C C C C C pIgR & IgA are internalised S S S S S S S S S S Polymeric Ig receptors are expressed on the basolateral surface of epithelial cells to capture IgA produced in the mucosa C C C C C C C C C C B B cells located in the submucosa produce dimeric IgA Secretory IgA and transcytosis ‘Stalk’ of the pIgR is degraded to release IgA containing part of the pIgR - the secretory component Epithelial cell

  20. EFFECTOR FUNCTIONS OF ANTIBODIES • Neutralisation • Opsonization (facilitated phagocytosis) • ADCC • Complement activation (see it later)

  21. NEUTRALISATION

  22. OPSONIZATION An opsoninis any molecule that enhances phagocytosis by marking an antigen for an immune response. In the picture opsonins are antibodies.

  23. ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY (ADCC)

  24. ANTIBODY PRODUCTION DURING IMMUNE RESPONSE Secondaryresponse Primaryresponse Immunoglobulinconcentration Primaryresponseagainstthe B antigen days „A” antigen „A” and „B”antigen

  25. Polyclonal antibody response Ag Ag Ag Polyclonal antibody Immunserum Set of B-cells Activated B-cells Antibody-producing plasma-cells Antigen-specific antibodies

  26. Methods of immunisation I. Passive Serum containing the specific antibody (usually IgG) - 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 Endagered subject 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 of the recipient, immune protection needs time to develop, but long term protection is provided (memory cells).

  27. Intravenousimmunoglobulin 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 No activation of the immune system Acts immediately The protection is short-term only Elimination of Immunoglobulins ENDANGERED SUBJECT

  28. 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)

  29. 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)

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