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  1. DEPARTMENT OF IMMUNOBIOLOGY Antibody (Ab) Xiaowu Hong 021-54237093 Department of Immunology Shanghai Medical College of Fudan University

  2. Nobel Prize winners Emil von Behring, 1901, antitoxins Paul Ehrlich , 1908, production of antibody Georeges Kohler and Cesar Milstein, 1984, monoclonal antibody Gerald Edelman and Rodney Porter, 1972, structure of antibody Susumu Tonegama,1987, structure of Ig gene

  3. Emil von Behring (1845-1917) Emil von Behring, 1901, antitoxins

  4. Contents I Definition of antibody II Structure of antibody III Function of antibody IV Biological characteristics of different antibodies

  5. Antibody (Ab) A globulin which is produced by plasma cell as a result of the introduction of an antigen and which has the ability to combine with the antigen that stimulated its production.

  6. Immunoglobulins (Ig) Globulins composed of H and L chains, or globulins function as antibody. Immunoglobulins Antibody-containing serum is place in an electrical field Antibodies migrated with the globular proteins.

  7. The relationship between Ab & Ig All antibodies are immunoglobulins, but it is not certain that all immunoglobulins have antibody function.

  8. Distribution of antibody Antibody molecules are found in serum (account for approximately 20% of the total plasma protein ), in extravascular fluids, in exocrine secretions, and on the surface of some lymphocytes.

  9. Section 1 Structure of Ig

  10. 1 Basic four chain structure * A four polypeptide chains: two identical light chains two identical heavy chains , held by disulfide bonds. ** Y-shape structure, symmetric. *** –NH2 terminal, -COOH terminal. **** variable & constant regions. ***** domains

  11. (1)Heavy chain (H): ① Composed of about 500 aa, oligosaccharide(+) ② Class : heavy chain ,  ,  , , . immunoglobulin(Ig) IgA, IgG, IgM IgD, IgE (2) Lght chain (L): ① Composed of about 214 aa, oligosaccharide(-) ② Type:  ,

  12. 2 Variable (V) and Constant (C) regions

  13. (1) V region ①N-terminal1/2L+1/4(1/5)H; VL, VH

  14. (2) Constant region(C-terminal 1/2L+3/4(4/5)H) CL CH1 CH2 CH3 (CH4)

  15. (3) hypervarible region (HVR) (complimentarity determining region,CDR) : formation of the Ag binding site Framework region( FR ) : maintaining the 3- dimensional configuration

  16. CDR (complimentarity determining region,)

  17. antibody antigen-antibody complex: antigen purple : HV CDR ( in both the ribbon and ball and stick views) green : antigen HV sequences contact the antigen.

  18. antibody CDR Epitope Representation of the disassociation of an antibody (top) and antigen (botton) molecule. antigen

  19. CH2 CH3 CH4 (4) Hinge region NH3+ VH VL Properties: 1) Flexible 2) Rich in proline Function: 1) Facilitating the interaction between Ag and Ab 2) Facilitating complement fixation CH1 CL Hinge region COO–

  20. IgG Molecule Conformational Changes Induced by Antigen Binding POSTBINDING PREBINDING Fab CH1 Exposed C1q-binding site Barricaded C1q-binding site CH2 Fc (IgM CH3,IgG CH2)

  21. Flexibility of immunoglobulins

  22. domains: polypeptide chains folded by disulfide bonds into globular regions.

  23. domains: VH+VL a Ag- binding site CH1+CL Allotypic marker (IgG)CH2 C1q binding (IgG)CH3 FcR binding (MC, M, B,NK) (IgM)CH3 C1q binding (IgE)CH2+CH3 FcR binding (mast, basophil)

  24. Figure 3-3 part 1 of 2 3 Enzymatically generated Ab fragments (1) Papain: Fab (Ag-binding Fragment ) Fc (Crystallizable Fragment ) : complement fixation, FcR

  25. Figure 3-3 part 2 of 2 (胃蛋白酶) (2) Pepsin ( Fab’ ) 2 pFc ( peptides of Fc )

  26. Section 2 Biological functions of antibodies

  27. 1 Antibody function in the absence of other factors • V region: Ag binding • Neutralizing toxin & virus • Agglutination microbes, • Prevention adhesion

  28. Neutralization By Antitoxin Antibodies

  29. Neutralization By Antiviral Antibodies

  30. Bacterial ‘Neutralization’ By Ab

  31. 2 Role of antibodies in complement activation C region: Fixation of complement

  32. 3 Role of antibodies binding to effector cells C region: Binding cells Opsonization Mediating ADCC

  33. (1) Opsonization: The process of attaching opsonins , such as IgG or complement fragments, to microbial surfaces to target the microbes for phagocytosis.

  34. Recognition of microbes by neutrophils and macrophages complement antibody Surface receptor on macrophage CD11b/CD18 CD16 (FcR III) IL-2 Lactoferrin CD25 CD71 B7-2 CD28 CD64 (Fc  R I) CD35 (CR1) CD32 (Fc  R II) antibody complement antibody

  35. Adherence of bacteria via receptors

  36. Opsonin. A macromolecule that becomes attached to the surface of a microbe and can be recognized by surface receptors of neutrophils and macrophages and that increase the efficiency of phagocytosis of the microbe. Opsonins includeIgG antibodies, which are recognized by the Fc receptor on phagocytes, and fragment of complement proteins, which are recognized by CR1.

  37. FcgR and Complement Receptors Cooperate To Induce Greater Phagocytosis

  38. (2) ADCC FcgRIII CD16Antibody Marks Target Cells For NK Cell Attack (ADCC)

  39. Figure 1-24 part 2 of 3

  40. Section 5 Biological characteristics of different antibodies

  41. 1 IgG 7.4.1 11 interchain disulfide bonds.

  42. (1) Properties (A) IgG is the major Ig in serum - 75% (B) The longest half life (t ½ =23days) (C) IgG is the major Ig in extravascular spaces (D) Placental transfer (E) Fixation complement – (F) Binding to cells –Opsonization mediating ADCC Immunity is transferred from mother to fetus through placental transfer of IgG.

  43. Iga Igb Iga Igb 2 IgM (1) Structure Secreted IgM (sIgM): pentamer Membrane-bound IgM (mIgM): monomer J chain

  44. Joining chain (1)Chemical nature: polypeptide chain secreted by plasma cell Secrete piece J CHAIN Joining chain IgM IgA (2) Presence: polymeric Igs such as IgM (pentamer), sIgA (dimer).

  45. (2) Properties (A) The first Ig made by fetus and B cells (B) Fixation complement –classical pathway (C) The largest size of molecule (D) Natural blood type antibody (E) Binding to cells – Opsonization. mediating ADCC

  46. 3 IgA (1) Structure

  47. Secretory Piece ( SC ) synthesized by nonmotible epithelial cells near the mucosal membrane IgA dimer Function: i. Enabling IgA to be transported across mucosal tissues into secretions. Secrete piece Joining chain ii. Protecting sIgA from being proteolytic attack.