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Chapter 5 Immunoglobulin

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Title: Chapter 3 Immunoglobulin Author: fan Last modified by: GUO Created Date: 2/21/2003 1:49:26 PM Document presentation format: – PowerPoint PPT presentation

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Title: Chapter 5 Immunoglobulin


1
Chapter 5 Immunoglobulin
2
Contents
  • Introduction
  • Section? Molecular Structure of Ig
  • Section? Characteristics and Functions of the 5
    Classes of Ig
  • Section ? Fc Receptors for Ab Molecules
  • Section ? Biological Activity of Ab
  • Section? Immunogenicity of Ig
  • Section ? Artificial Ab

3
Concepts
  • Antibody (Ab) Glycoprotein molecules that are
    produced by plasma cells and can combine with the
    corresponding Ag specifically are called Ab.
  • Ab is produced by B cells in the response to a
    stimulation of Ag.
  • Ab possesses a high degree of specificity and
    affinity

4
  • Immunoglobulin (Ig)
  • It refers to all globulins that possess the
    activity of Ab or show a similar structure to Ab
  • Therefore, All Abs are Igs, but not all Igs
    possess the functions of Abs

5
Other Concepts
  • - Globulin
  • Antiserum
  • Humoral Immunity
  • sIg and mIg(BCR)

6
Section? Molecular Structure of Ig
7
?. Basic structure
  • Ig is composed of four polypeptide chains joined
    by S-S bonds.
  • inter-chain disulfide bonds (S-S)
  • intra-chain disulfide bonds (S-S)

8
  • It shows T or Y shape.

9
1. H and L chain
  • . Heavy chains (H)
  • 450 550 aa,
  • 50 75 KD
  • . Light chains (L)
  • 214 aa, 25 KD

10
  • Two terminal ends for each peptide chain
  • N terminal end
  • C terminal end
  • L chains attach to H chains
  • from N end


N
C
11
2. classes and types of Ig
  • (1) According to the differences of H chains
  • (amino acid composition, sequence)
  • Igs can be divided into 5 classes
  • Five classes of H Chain ? ? ? ? ?
  • Five classes of Igs IgG IgA IgM IgD IgE

subclasses
IgG1 IgG4
IgA1, IgA2
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  • (2) According to the differences of L chains
  • Two types of L chain ?, ?
  • ? ? 201 (in mice) 21 (in human)

? 1 ? 4
14
3. Two regions of each peptide chain
(1) Constant region (C)
(2) Variable region (V)
(3) Hinge region
15

3. Two regions of each peptide chain
  • (1) Constant region ( C )
  • CH 3/4 or 4/5 (?,?) of H chain from the c end
  • CL 1/2 of L chain from the c end
  • (2) Variable region ( V )
  • CH 1/4 or 1/5 (?,?) of H chain from the N end
  • CL 1/2 of L chain from the N end

16
(2) Variable region ( V )
  • Hypervariable region(HVR)
  • There are three highly diversity stretches
    within the V egion,
  • they are called HVR.

17
  • Framework region(FR) FR1-FR4

18
Ag-binding sites
19
Complementarity determining regions(CDR)
20
(2) Variable region (V)
  • Complementarity determining regions(CDR)
  • L CDR1, CDR2, CDR3

  • H CDR1, CDR2, CDR3

21
Idiotype of Ig
  • Igs produced by different B cells possess
    unique structure respectively in hypervariable
    region (HVR), the unique structure of Ig is
    called idiotype or idiotypic determinant

22
  • In fact
  • HVR
  • CDR
  • Idiotype
  • are in the same sites of Ig

23
  • (3) Hinge region
  • Flexible and suitable for CDR of Ig binding to
    antigenic determinants.
  • Sensitive to proteolytic enzyme
  • IgM, IgE

24
Other structures of Ig
  • Joining chain(J)
  • Secretory piece(SP)

25
Joining chain(J )
  • Produced by plasma cells
  • Functionslinker, to compose dimer?pentamer or
    polymer(IgA, IgM)

26
Secretory piece( SP)
  • . Produced by mucosa epithelial cells
  • . Secretory IgA (sIgA)
  • . Functions protect sIgA, resist
    proteolysis in extra secretory liquid.

IgA
27
?. Domains of Ig


28
1. Domain
  • Polypeptide chains of Ig are folded into a
    globular structure by intra chain s-s bond within
    each 110aa region which is called a domain

29
2.   Domains of Ig
  • L chain(2) VL, CL
  • H chain(45)
  • VH,
  • CH1, CH2, CH3
  • CH4(in IgM,IgE)
  • hinge region

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3. Function of each domain
  • VH, VL antigen-binding site
  • CH1, CL allogeneic marker
  • CH2/CH3 complement-fixing site,
  • permeate placenta(IgG)
  • CH3/CH4 cell-binding site
  • Hinge region flexible and suitable for CDR of Ig
    binding to antigenic determinants

32
?. Hydrolytic fragments of Ig
  • Ig can be digested by papain and pepsin
  • Position
  • Fragments
  • Function

33
1. Digested by papain
  • Position
  • near the S-S bonds of H inter-chains fromthe
    N end
  • Fragments
  • 2Fabfragment antigen-binding
  • Fcfragment crystallizable
  • Function
  • Fab recognize and bind Ag Fc
  • (1) fix complement
  • (2) crossing the placenta
  • (3) bind to FcR in different cells

34
  • 2. Digested by pepsin
  • Position
  • near the S-S bond of H inter-chains from the C
    end
  • Fragments and function
  • F(ab')2 bind antigen(2 valence)
  • pFc' no function

35
Significance
  •  Elucidating the relationships between the
    structure and function of Igs
  • Decrease the immunogenicity of Ig for clinical
    treatment

36
  • Section? Characteristics and Functions of the 5
    Classes of Igs

37
?. IgG
  • 1. Highest concentration in serum (75 of total
    Ig)

38
  • 2. Four subclasses IgG1, IgG2, IgG3, IgG4

39
  • 3. Unique Ig that can pass through placenta
  • 4. Half-life is longer( 16-24 days )
  • 5. Starts to be produced at 2-3 month after birth
    and reach the level of adult at 5 years old

40
  • 6. Functions of IgG
  • Against bacteria and virus,neutralize toxin
  • Combine with the Fc receptor(Fc?R)
  • Activate complement
  • Combine with SPA
  • Some belong to the auto-antibodies
  • Take part in type ? and ? hypersensitivity

41
1. Highest MWpentamer(90 KD),10 valences
?. IgM
42
  • 2. Half-life is shorter(45 days)
  • 3. The first Ig to be synthesized
  • Appear in the early stage after infection
  • Be produced during fetus
  • The first mIg of the B cells, act as the antigen
    receptors(BCR)

43
4. Functions
  • IgM is more effective in binding Ag and
    activating C, and play an important role in
    anti-infection
  • Natural Ab for blood-type antigen
  • Auto-antibody rheumatoid factor(RF)
  • Take part in type ? and ? hypersensitivity

44
?. IgA 1. Two types Serum type
monomer Secretary type(sIgA) dimer,trimer
or polymer 2. Two subclassesIgA1,IgA2
45
  • 3. To be produced at 4 months after birth
  • 4. Exist in almost all body fluid

46
6. Local mucosal immunity
  • Immune barrier
  • Neutralize virus/toxin
  • Rich in colostrum
  • Activate C by alternative pathway
  • Take part in type ? hypersensitivity

47
?. IgD
  • 1. The concentration in serum is low and
    sensitive to proteinase
  • 2. Act as the antigen receptor on B cells (mIgD)
  • Regulate the differentiation of B cells

48
?. IgE
  • 1.Concerntration of IgE in serum is the lowest in
    normal individual, but is very high in some
    patients.
  • 2.Related to type?persensitivity
  • FceR? mast cell, basophil

49
Section ? Fc Receptors for Ab Molecules
50
  • IgG---Fc?R Fc?R?(CD64)---phagocyte
  • Fc?R?(CD32)---immune complex
  • Fc?R?(CD16)---NK, MF,T cell
  • IgE---Fc?R Fc?R?--- mast cell, basophil
  • Fc?R?--- macrophage, B cell
  • IgA---FcaR(CD89)---phagocyte, neutrophil

51
Section? Biological Activity of Ab
52
  • 1. Recognize and bind to antigen specifically
  • 2. Fix complement
  • 3. Bind to Fc receptor on some cells
  • 4. Transfer selectively
  • .Planceta transfer (IgG)
  • .Mucosa transfer (sIgA)

53
Affinity and Avidity
54
Neutralization
55
IgM,IgG13 classical pathway IgA,IgG4,IgE altern
ative pathway
56
MAC
57
  • (1) Opsonization(IgG, IgM)
  • Enhance the phagocytosis of MF

58
(2) ADCC( antibody dependent cell mediated
cytotoxicity)
59
  • (3) Hypersensitivity type?
  • - mast cell, basophil(Fc?R?)

60
Section? Immunogenicity of Ig
61
Isotype CH, CL
62
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63
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64
AllotypeCH, CL
65
Idiotype VH, VL Anti-idiotype antibody
66
Section? Artificial Ab
  • Polyclonal Ab
  • Monoclonal Ab
  • Gene engineering Ab

67
1. Polyclonal Ab
  • A mixture Ab with different specificities and
    affinities
  • Generate in a natural response or artificial
    immunization
  • Cross reaction

68
Cross-reactivity if two antigens share an
epitope an antibody recognizes an
unrelated, but chemically similar, epitope
69
2. Monoclonal Ab (mAb)
  • Ab produced by single clone (or one hybridomas
    clone ) and having a single specificity

70
mAb / McAb
  • Prepared by hybridomas technique
  • Immunized spleen cells(B) hybride with myeloma
    cells----hybridomas

71
Artificial antibodies
POLYCLONAL.
MONOCLONAL.
Derived from different B Lymphocytes cell lines
Derived from a single B cell clone
mAb offer Reproducible, Predictable Potentially
inexhaustible supply of Ab with exquisite
specificity
Batch to Batch variation affecting Ab reactivity
titre
Enable the development of secure immunoassay
systems.
NOT Powerful tools for clinical diagnostic tests
72
3.Gene engineering Ab
  • Abs prepared by the method of gene recombination
  • Chimeric Abhuman Fc bind with mice Fab
  • Recombinant single chain AbVH-linker-VL

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74
Human-mouse chimeric Ab

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