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Immunology

Immunology. Protein Recognition Function. Immunology. Immune system Operates by distinguishing self from nonself Has two parts Cellular Humoral. SELF. All the antigenic determinants/epitopes of an individual constitute SELF

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Immunology

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  1. Immunology Protein Recognition Function

  2. Immunology • Immune system • Operates by distinguishing self from nonself • Has two parts • Cellular • Humoral

  3. SELF • All the antigenic determinants/epitopes of an individual constitute SELF • Immature antibody producing cells (B lymphocytes) extend antibodies on their surfaces • Those which react with/bind to SELF are destroyed BEFORE BIRTH

  4. NONSELF • Any epitope which did not appear before birth and establish itself by reacting with an antibody is NONSELF • NONSELF material can be detected by antibodies or by T cells.

  5. Antigens • An antigen can be a small molecule called a hapten or a large one • An antigen is usually proteinaceous, but not necessarily • To elicit the production of antibodies, a hapten must be bound to a larger molecule carrier

  6. Antigens, continued • An antibody to a bound hapten may react with the unbound hapten as well • An antigen must possess at least two epitopes to lead to precipitation, which leads to PHAGOCYTOSIS • If there is only one epitope, or the An-Ab complex does not precipitate, it is destroyed by macrophages

  7. Monovalent antibody forms soluble complex Polyvalent antibody can crosslink to form insoluble network

  8. Formation of antibodies • Instruction theory - 1940 Pauling. • antigen interacts with uncommitted material, which enfolds and patterns it • antibodies are made from this pattern • Experimental result - antibody can be denatured and still returns to the same structure, even in the absence of antigen

  9. Formation of antibodies, cont • Clonal selection theory • Each antibody producing cell produces antibodies of A SINGLE KIND • EVERY KIND OF ANTIBODY PRODUCING CELL is present initially • The specificity of an antibody is specified by its primary structure • which is specified by a nucleic acid sequence • If an antibody producing cell encounters an antigen with which it can react, it is stimulated

  10. Formation of antibodies, cont • Clonal selection theory, cont • A stimulated cell divides and produces CLONES • The clones lead to the production of large amounts of soluble antibodies

  11. Formation of antibodies, cont • Clonal selection Details • Helper T cells recognize An-B Cell complex and stimulate the production of clones • AIDS causes the destruction of helper T’s thus limiting severely the production of Ab’s • Some B cells become memory cells • memory cells are available for a rapid response to the same antigen

  12. Plasma cells Soluble antibodies B lymphocytes B cell clones antigen with 2 determinants Helper T cell antigen with 2 determinants B stem cell Helper T cell Humoral Immunity Bone Marrow Lymphoid Tissue Circulation

  13. Formation of antibodies, cont • Initial response IgM • For a typical antigen, response seen in a few days • Falls after ~1 week • IgG specific for the antigen rises later and plateaus in a few weeks

  14. Formation of antibodies, cont • Another exposure to antigen boosts the antibody again (memory effect) • The antiserum (blood minus erythrocytes and fibrin) contains ~ 1 mg/ml of antibody specific to the antigen!

  15. Monoclonal antibodies - Millstein and Köhler 1975 • Multiple myeloma • Single kind of plasma cell divides uncontrollably • Can be fused with regular lymphocytes to produce hybridomas • Exact specificity can be selected from the hybridomas produced

  16. Kinds of antibodies - Distinguished by heavy chain ([G],[M],[A],[D],[E]) • IgM • first Ab produced upon invasion • pentameric with one J chain binder • MW 950 kD • confined to bloodstream • serum concentration ~ 1 mg/ml

  17. Kinds of antibodies, cont • IgG (gamma globulin) • Most abundant • monomeric (two heavy chains and two light chains) • MW ~150 kD • can cross walls of bloodstream to other tissues • can cross placenta to protect fetus • Rh factor • serum concentration ~12 mg/ml

  18. Kinds of antibodies, cont • IgA • Protects surfaces from attachment • monomer, or dimer with J chain holder • MW ~180 or ~500 kD • Found in sweat, saliva, tears, along the walls of intestines, colostrum, milk • serum concentration ~ 3 mg/ml

  19. Kinds of antibodies, cont • IgD • function not clear • monomer • MW ~175 kD • present on the surface of B cells • serum concentration ~ 0.1 mg/ml

  20. Kinds of antibodies, cont • IgE • confers protection from parasites BUT • causes immune reactions • monomer • MW ~200 kD • present of surface of B cells, reacts with Mast cells • produces histamine • serum concentration ~ 0.001 mg/ml

  21. Structure of IgG • Two light chains, ~23 kD ( or ) • Two heavy chains, ~53 kD • Features • Variable and Constant sections for heavy and light chains • Constant section of heavy chain has 3 ~identical parts, identical to constant section of light chain

  22. Fig 7-23a

  23. Fig 7-23b

  24. Structure of IgG, cont • Fab and Fc - cleavage products of papain • Fab will bind antigen • Separated on carboxyl terminal side of S-S linking L and H chains • X-ray crystallography • homologous antiparallel -sheet domains

  25. Structure of IgG, cont • Immunoglobulin Fold • Similar variable and constant regions • antiparallel sheets connected by one disulfide bond • Variable region • 2 extra strands • hypervariable CDR loops • Can be formed by any H with any L variable regions

  26. Antigen Binding by Fab • X-ray crystallography • Same themes as in enzyme catalysis • numerous H- bonds, van der Waals, and hydrophobic interactions provide strong specific bonds • “induced fit” capability increases the number of antigens which can be bound

  27. Fc functions as recognition element • Effector functions • Complement Fixation - lysis of foreign cells • Macrophage engulfment of monovalent An-Ab complexes • Phagocytosis of precipitated An-Ab complexes

  28. IgG Diversity • Variable Region - About 300 different VH and 300 different V genes • Joining Region - 4 different for light chains, 5 for heavy chains • Diversity Region - 15 different for heavy chains

  29. Class Switching • Different classes of antibodies formed by one type of antibody producing cell • Same light chain used, but different constant regions of heavy chain used

  30. D JH VH C C C3 C1 C2b C2a C C Germ-line DNA JH D VH C C C3 C1 C2b C2a C C complete VH gene After Translocation

  31. IgG Diversity, cont • Splicing Frames - ~3 different lengths of connection between VH and D • Somatic Diversity - Mutation

  32. T Cells • Killer T Cells (“Natural Killers” NK) • Receptor tests peptide fragments presented on the surface of all cells for fit (Receptor knows foreign material) • Most cells display peptide fragments tightly held by Class I MHC proteins • Cell which has fit, Class I MHC protein is killed by lysing the cell membrane

  33. T Cells, cont • Helper T Cells • B cells, macrophages, and dendritic cells display peptide fragments tightly held by Class II MHC proteins • These peptides have all been digested in endosomes(not in the cytosol) • Helper T receptors check these displays for foreign material • If there is a fit, appropriate B cell is stimulated

  34. T Cell, cont • T Cell Receptor structure • 43 kD  chain joined by disulfide bond to 43 kD  chain • Both chains are integral and C terminal extends into cytosol • Both chains have a variable and constant region homologous to V and C domains of immunoglobulins

  35. T-Cell Receptor N N S S V C S S S S C C S S -S-S- T-cell membrane T-cell membrane C C

  36. Major Histocompatibility Complex Proteins • Great diversity • ~3.5 Mb of genome (= E. Coli) devoted to MHC proteins • 75 different genes • Six different Class I genes and six different Class II genes expressed by humans • Many alleles of each gene exist • Tissue transplantation difficult ; very unusual for two persons to have the same MHC proteins

  37. Major Histocompatibility Complex Proteins, cont • Structure • Class I -- 44 kD chain noncovalently bound to 12 kD polypeptide called 2-microglobulin • 1,, 2 chains provide most of difference in ability to bind proteins, 3 largely conserved and interacts with 2m

  38. Major Histocompatibility Complex Proteins, cont • Structure, cont • Class II -- 33kD  chain noncovalently bound to 30 kD  chain

  39. Fig 7-20a

  40. Fig 7-21

  41. CD8 and CD4 on killer and helper cells • T-cell proteins that participate in recognition of MHC-peptide complexes of target cells • CD = “cluster of differentiation” • Immunoglobulin folds

  42. Fig 7-22

  43. TC , TH cells and immunity • When self antigens destroyed, many TC , TH destroyed • “The vast majority of these cells never encounter a foreign antigen to which they can bind and typically die within a few days, replaced by new generations of T cells endlessly patrolling in search of the interaction that will launch the full immune response.” Lehninger Principles of Biochemistry, 3rd Edn, p 225

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