Major Histocompatibility complex and Immunoglobulins

1. 1
Major Histocompatability
Complex

2.  Give an overview of the role of the major
histocompatibility complex in immune response
 Describe the structure and function of class I and class II
MHC molecules
 Discuss the nature of polymorphism in class I and class II
MHC molecules
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What you should know after completion of this lesson:

3. Outline
6.0 Introduction to MHC
6.1 MHC Molecules and Gene
6.2 Cellular Distribution of MHC Molecules
6.3 Regulation of MHC Expression
6.4 MHC and Immune Responsiveness
6.5 MHC and Disease Susceptibility
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4. Introduction
 MHC is a tightly linked cluster of genes whose product
plays an important role in IC recognition and in
discrimination between self and non-self
 Genes in the MHC were first identified as being important
genes in rejection of transplanted tissues
They are also called Human leukocyte antigens (HLA)
 Genes within the MHC are highly polymorphic in that
there are large numbers of alleles for each gene, and they
are polygenic in that there are a number of different MHC
genes
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5. Introduction to MHC . . .
 The MHC participates in the development of both
humoral and cell mediated immune responses.
 While B cells may react with antigens alone, most T
cells recognize antigen only when it is combined with
an MHC molecule.
 A peptide must associate with a given MHC of an
individual, otherwise no immune response can occur.
That is one level of control.
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6.  Located on human chromosome 6
MHC genes encode 3 classes of molecules
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7. MHC genes encode 3 classes of molecules
A. Class I MHC genes: Encode glycoproteins
Major function of Class I gene products is presenting peptide
antigens to TC (CD8) cells.
 Class I antigens are produced by the A, B, and C subloci genes
B. Class II MHC genes: Encode glycoproteins
They present processed antigenic peptides to TH (CD4)
cells.
Class II antigens are produced by the DP, DQ, and DR
subloci genes 7

8. C. Class III MHC genes
 Encode various secreted proteins that involve in
Inflammation, and
Immune functions, including components of the
complement system such as C4, C2, and inflammatory
cytokines, including tumor necrosis factor (TNF)
 Have no role in antigen presentation
MHC-II molecule cont….
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9. Structure of Class I MHC
• Two polypeptide chains, a long α
chain and a short β (β2
microglobulin)
• Four regions
• Cytoplasmic region containing
sites for phosporylation and
binding to cytoskeletal
elements
• Transmembrane region
containing hydrophobic amino
acids
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10. Structure of Class I MHC
• Four regions
• A highly conserved α3
domain to which CD8 binds
• A highly polymorphic
peptide binding region
formed from the α1 and α2
domains
• Β2-microglobulin helps
stabilize the conformation
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11. Structure of Class II MHC
 Two polypeptide chains α and β
of roughly equal length
 Four regions
• Cytoplasmic region
containing sites for
phosporylation and binding
to cytoskeletal elements
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12. Structure of Class II MHC
Four regions
• Transmembrane region
containing hydrophobic
amino acids
• A highly conserved α2, and a
β2 contains sequence for
CD4 binding
• A highly polymorphic peptide
binding region formed from
the α1 and β1 domains
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13. MHC I Compared to MHC II Structure
MHC I MHC II
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14. The interaction of MHC with T cells
CD8 binds the α3 domain of MHC-I CD4 binds the β2 domain of MHC-II
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15. 15
 The peptide-binding cleft in class I is blocked at both
ends, but open in MHC-II……. Why?

16. MHC Class I polymorphism
Locus
Number of alleles
(allotypes)
HLA - A 218
HLA - B 439
HLA - C 96
There are also HLA - E, HLA
- F and HLA - G
Relatively few alleles
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17. Cellular distribution of MHC
A. Class I MHC genes
 Expressed on the surface of nearly all nucleated cells; but
vary in concentration on different cell types
 The highest levels of class I molecules are expressed by
lymphocytes.
In contrast, fibroblasts, muscle cells, liver hepatocytes, and
neural cells express very low levels of class I MHC molecules.
 The low level on liver cells may contribute to the considerable success of
liver transplants by reducing the likelihood of graft recognition by Tc of
the recipient
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18. MHC molecule cont….
B. Class II MHC genes
 Encode glycoproteins
 Expressed primarily on APC(macrophages, DC and
B cells)
The expression level is different across these cells
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19. Expression of MHC. . .
Class I MHC
Class II MHC
RBCs
APCs
Nucleated cells
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20. Regulation of MHC Expression
 The expression of MHC molecules is regulated by
Cytokines
 Interferons (alpha, beta, and gamma) and TNF
increase expression of class I MHC molecules on
cells.
 Interferon gamma (IFN-γ) induce the expression II
MHC genes on many cells, including non-APC
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21. Regulation of MHC Expression cont….
 Other cytokines influence MHC expression only in certain
cell types; for example,
 IL-4 increases expression of class II molecules by
resting B cells.
 However, IFN- downregulate the Expression of class II
molecules by B cells
 MHC expression is decreased by infection with certain
viruses, including human cytomegalovirus (CMV), hepatitis
B virus (HBV), and adenovirus 12 (Ad12).
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22. MHC and Disease Susceptibility
 Some HLA alleles occur at a much higher frequency in
those suffering from certain diseases than in the general
population.
 Diseases associated with particular MHC alleles
Diseases HLA RR
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23. Antibody
Antibody
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24. Outline
7.1 Introduction to Immunoglobulins and antibodies
7.2 Immunoglobulin Basic and Fine Structure
7.3 Antibody-Mediated Effector Functions
7.4 Antibody Classes and Biological Activities
77.5 Antigenic Determinants on Immunoglobulins
7.6 Class switching and generation of antibody diversity
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25. Antibodies
 Molecules that are produced by the body in response to a
foreign substance and are antagonist to it.
 They are known as Immunoglobulins when not referring to
their specificity
• Immunoglobulins reside in the globulin fraction of serum, mean the
γ - globulin fraction was identified as containing serum antibodies,
which were called immunoglobulins, to distinguish them from any
other proteins that might be contained in the γ globulin fraction.
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26. Antibody
 Most antigens are complex and contain many different
antigenic determinants,
• Thus, the immune system usually responds by producing
antibodies(homogenous) to several epitopes on the antigen.
 This response requires the recruitment of several
clones of B cells.
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27. Antibody structure
 The structure consists of two identical light (L) chains, and two
identical heavy (H) chain
Heavy chain
Contains two regions, a) a region with great sequence variation and
therefore called the variable (V) region.
The remaining part of the protein revealed five basic sequence
patterns, corresponding to five different heavy-chain constant (C)
regions
• Namely (µ, y, a, d, and £ )so the heavy chain determines what class of the
antibody is.
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28. Antibody structure cont...
Light chain
Has variable and constant chain
There were two light chain types, kappa () and lambda ().
In humans, 60% of the light chains are kappa and 40% are
lambda
NB; it is important to remember that antibodies generally do
not kill or remove pathogens solely by binding to them.
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29. Antibody structure
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Hinge region
Five Immunoglobulin Classes; IgG, IgA, IgM, IgD, & IgE

30. Antibodies characterstics
A. Genetic Variation in Antibody Heterogeneity
 Isotypic variation- variability in the CH and distinguish
immunoglobulin subclasses and subclasses within a species
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31. 31
Allotypic variation- AAs substitutions on a given molecule
Idiotypic variation- variation of AAs sequence in the antigen
binding region given the molecule its antigenic specificity
Antibodies

32. Antibody variations cont….
B. Properties
 C’ Fixation
 Placental transfer
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33. 33
Antibody Classes

34. Antibodies - Properties
 Extreme importance to Laboratory testing and interpretation
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35. IgG
 Characteristics
150,000 MW
Highest serum conc.
Transported across placenta via Fc
IgG1 and IgG3 bind with high affinity to
Fc receptors on
phagocytic cells and thus mediate
opsonization
Four subclasses (IgG1-4)
Monomeric in form
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36. IgA
 Characteristics
• Dimer, monomer
• Two subtypes (1,2)
• Secretions
• Tears, Saliva, GI tract, Colostrum
• Secretory IgA has Secretory component made by epithelial
cells, that protects it from enzymatic and other chemical
degradation
• It prevents viral and some bacterial attachment to mucosal
epithelial cells
• Dimeric form has J chain - connects
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37. IgM
 Characteristics
 Pentameric form
 Soluble and cell associated
 Primary antibody response
• Role in Lab Diagnostics, RBC
 Does not pass placenta
 Effective agglutinator
 Most efficient C’ fixation
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B
IgM
IgD

38. IgE
 Characteristics
 Extra Constant region domain
(C4)
 Lowest serum concentration
 Binds to Mast cells via Fc -
Allergic reactions
 Responsible for immediate
hypersensitive reactions for the
symptoms of hay fever, asthma, hives,
and anaphylactic shock.
 Protection - Parasitic infections
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39. IgD
• Low concentration in serum (<1%)
• Function largely unknown - may act as Antigen
receptor for B cells
• No clinical need to measure - clue to physician
competence & clerical error
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40. Antibody - Antigen Interactions
• Antibody binding site
• Folded structure - forming cleft
between Heavy and Light chains -
tertiary
• Apple analogy - best fit
• Antigen binding site
• Quite small
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41. 1. Neutralization of microbes and microbial toxins
A. Blocks microbes binding
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The biological function of antibodies

42. B. Blocks other cells infection
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The biological function of antibodies cont…

43. C. Blocks toxins before they find the their receptors
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The biological function of antibodies cont…

44. 2. Antibody mediated opsonization and phagocytosis
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The biological function of antibodies cont…

45. 3. Antibody dependent cell mediated cytotoxicity
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The biological function of antibodies cont…
(A)
A. Killing of the
antibody coated
cells
B. Killing of
helminths

46. 4. Complement
activation
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The biological function of antibodies cont…

47. Summary
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