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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 1356344


Protein Recognition Function



  • Immune system

    • Operates by distinguishing self from nonself

    • Has two parts

      • Cellular

      • Humoral

Immunology 1356344


  • 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



  • 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.



  • 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

Antigens continued

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

Immunology 1356344

Monovalent antibody forms soluble complex

Polyvalent antibody can crosslink to form insoluble network

Formation of antibodies

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

Formation of antibodies cont

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

Formation of antibodies cont1

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

Formation of antibodies cont2

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

Humoral immunity

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


Formation of antibodies cont3

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

Formation of antibodies cont4

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!

Monoclonal antibodies millstein and k hler 1975

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

Kinds of antibodies distinguished by heavy chain g m a d e

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

Kinds of antibodies cont

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

Kinds of antibodies cont1

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

Kinds of antibodies cont2

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

Kinds of antibodies cont3

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

Structure of igg

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

Fig 7 23a

Fig 7-23a

Fig 7 23b

Fig 7-23b

Structure of igg cont

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

Structure of igg cont1

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

Antigen binding by f ab

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

F c functions as recognition element

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

Igg diversity

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

Class switching

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

Immunology 1356344












Germ-line DNA












complete VH gene

After Translocation

Igg diversity cont

IgG Diversity, cont

  • Splicing Frames - ~3 different lengths of connection between VH and D

  • Somatic Diversity - Mutation

T cells

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

T cells cont

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

T cell cont

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

T cell receptor

T-Cell Receptor
















T-cell membrane

T-cell membrane



Major histocompatibility complex proteins

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

Major histocompatibility complex proteins cont

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

Major histocompatibility complex proteins cont1

Major Histocompatibility Complex Proteins, cont

  • Structure, cont

    • Class II -- 33kD  chain noncovalently bound to 30 kD  chain

Fig 7 20a

Fig 7-20a

Fig 7 21

Fig 7-21

Cd8 and cd4 on killer and helper cells

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

Fig 7 22

Fig 7-22

T c t h cells and immunity

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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