The Major Histocompatibility Complex

1
The Major HistocompatibilityComplex

• Antigen Presentation and Processing
• and the Relationship to
• Susceptibility and Resistance to Diseases
• Role of MHC in Tissue-Matching and
  Transplantation
• HLA Typing in Sibling Matches Slides 45 46
• (Supplemental Information, Not on Exam)

Folder Title MHC
Updated December 01, 2010
2
Factors and Immunogenicity 2
3
Factors and Immunogenicity 3
4
Antigens and MHC
5
Mixing Two Inbred Strain Haplotypes
p. 192
6
(No Transcript)
7
Mouse H2 Complex
Complement Proteins
Some Cytokines
Figure 8-1, Kuby 6th Edition, Top Half Human HLA
(Histocompatibility Complex), Lower Half Will Be
Discussed Later
8
H2 Haplotypes of some mouse strains
9
k and b Haplotype Team Members
See Table 7-1, Kuby 4th Edition, p. 175
10
Haplotype and Team Members
11
MLR Assay
See Figure 14-16, p.367, Kuby, 6th Edition
12
CML Assay
See Figure 14-17, Kuby 6th Edition, p. 368. For
CML Assay
See Figure 8-15, p. 207, Kuby, 6th Edition For
MHC Restriction. MHC Restriction will be covered
later
13
Restriction to Self MHC Alleles
14
This is a fill in the blank question. You should
already have your name transmitted so you should
get that string of letters and characters.If you
infected the mouse in the previous slide with
Influenza virus instead of LCM virus you would
not get Lysis of LCM-virus-infected self-cells.
What is missing from the spleen cells that are
used to test for lysis of LCM-virus-infected self
cells? What specific cells dont you have that
you need to get lysis?
15
(No Transcript)
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MHC-I
See figure 8-3, Kuby, 6th Edition, p. 194, left
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MHC-II
See figure 8-3, Kuby, 6th Edition, p. 194, right
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Class I MHC Protein Binding Cleft
19
Ag Site Class I
See figure 8-4, Kuby, 6th Edition, p. 195, right
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Ag-Bind
See figure 8-9(a,b), Kuby, 6th Edition, p. 199
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(No Transcript)
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Ag in Site Class I
See figure 8-9(c), Kuby, 6th Edition, p. 199
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Class I MHC Space-Filling
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H2K and Peptides
See figure 7-12, Kuby 4th edition, p. 184
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MHC ClassI and Flu
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MHC-Class I Polymorphisms
Kuby, 6th Edition Figure 8-10(b) p. 201 MHCIPoly
Positions of Polymorphic Amino Acid
Residues in a Human Class I MHC
Protein
27
Amino Acids Positions of Polymorphic Variations
in Class I MHC Proteins in Humans
Trans- Membrane Residues
Membrane Distal a1 and a2 Domains (Comprise
Peptide-binding Cleft)
Kuby, 6th Edition, Figure 8-10(a) p. 201
MHCIVary
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MHC-II
See Figure 8-3, Right Kuby, 6h Edition p. 194
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Class II MHC Space Filling
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HMC-Class II Dimers
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Comparison of Class I and Class II
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TCR and MHC-Class II
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MHC-Class II and Bound Antigen
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Class I and Class II Antigen Acquisition
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Variety of MHC Loci Allelles
See Figure 8-12, p. 203 Kuby, 6th Edition)
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Presentation of Exo-Antigen (Class II)
See Figure 8-8, Kuby, 4th Edition, p. 209
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(No Transcript)
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Presentation of Endogenous Antigen (Class I )
See Figure 8-8, Kuby, 4th Edition, p. 209
39
You do not have to send in your name unless you
borrowed a BIO transmitter this morning. Make
sure your name is entered onto any borrowed
transmitter. What would happen to host response
to a virally infected cell if the virus shut-down
production of Class I MHC proteins?_____________
_______________________
40
You do not have to send in your name unless you
borrowed a BIO transmitter this morning. Make
sure your name is entered onto any borrowed
transmitter. The MHC gene complex is called the
Major Histocompatibility Complex because it
controlled the acceptance or rejection of __ ___
__ __ __ __ ___ __ __ __
41
Human HLA Loci
Class I Loci Equivalent toK, D, and L in Mice
Class II Loci Equivalent to IAa, IAb IEa, IEb in
Mice
Kuby, 6th Edition, Figure 8.01, Bottom Half
42
Polymorphism of Class I and Class II Molecules in
Human HLA

• Humans 6 Different Class I Molecules
  HLA-A, HLA-B, HLA-C
• (3 Class I from one parent, 3 from the other)
• Approximate HLA Class I Alleles in Persons of
  European Descent
• HLA-A 60 HLA-B 110 HLA-C
  40
• Humans 12 Different Class II Molecules
  (Hetero-dimers) DPa,DPb, DQa,DQb, DRa, DRb
• (6 Class II from one parent, 6 from the other)
• Approximate HLA Class II Alleles in Persons of
  European Descent
• 122 Alleles of HLA-DRbeta
  alone
• Theoretical Combination of possible alleles is
  virtually infinite
• Combination is inherited at birth
• Does not diversify in an individual the way TCR
  or Antibodies do.
• Diversity among individuals depends on degree of
  familial relationship
• (full siblings histocompatible about 25 of
  the time)
• Linkage Disequilibrium favors allele combinations
  based on (1) time of
• divergence from population founder, (2)
  hot-spots facilitating genetic cross-overs,

MHCAlleles
43

• Illustration of HLA
  Polymorphism,
• Linkage Disequilibrium,and
  Tissue-Typing in Humans
• Class I Loci
  Class II Loci
• HLA-A HLA-B HLA-C DP DQ
  DR
• 1 1 1 1 1 1
• 2 2 2 2 2 2
• 3 3 3 3 3 3
• 4 4 4 4 4 4
• 5 5 5 5 5 5
• Example HLA-Types for Four
  Individuals
• 2 4 1 5 2 4
• 3 1 5 5 1 5
• 2 4 1 3 1 2
• 1 4 1 2 5 1

HLATyping
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Association of Human MHC Alleles and Risk for
Diseases(from Table 7-4, Kuby Immunology, 4th
Edition, p. 193)

• Disease Associated HLA Allele
  Relative Risk
• Ankylosing Spondylitis B27
  90
• Hereditary Hemochromatosis A3/B14
  90
• Insulin Dependent Diabetes DR4/DR3
  20
• Multiple Sclerosis DR2
  5
• Myasthenia Gravis DR3
  10
• Rheumatoid Arthritis DR4
  10
• Systemic Lupus Erythromatosis DR3
  5
• Narcolepsy DR2
  130
• Autoimmune Disease Percent of Patients
  with Allele Divided by Percent of
  Non-Affected Persons with this Allele

See Table 7-4, Kuby 4th edition, p. 194
HLASick
45
You do not have to send in your name unless you
borrowed a BIO transmitter this morning. Make
sure your name is entered onto any borrowed
transmitter. The online streaming media videos
that you played on your own as a substitute for
the Nov. 22nd class was about the general subject
of Immunity to_________________________ disease.
46
Tissue-Typing Among SiblingsWhy Are Blood
Relatives More Likely to Be Compatible Donors?

• Mom's Haplotypes (A,B,C, DP, DQ, DR) Dad's
  Haplotypes (A,B,C,DP, DQ, DR)
• 1,2,3,4,5,6 7,8,9,10,11,12
  13,14,15,16,17,18 19,20,21,22,23,24
• 
  Children's Possible Haplotypes
• 
  Inherit from Mom
• 1,2,3,4,5,6 1,2,3,4,5,6 7,8,9,10,11,12 7,8,9,
  10,11,12
• 
  Inherit from Dad
• 13 to 18 19 to 24 13 to
  18 19 to 24
• 25 of the Off-Spring
  Likely to be HLA Haplotypes
• 1,2,3,4,5,6
  13,14,15,16,17,18
• 1,2,3,4,5,6
  19,20,21,22,23,24
• 7,8,9,10,11,12
  13,14,15,16,17,18
• 7,8,9,10,11,12
  19,20,21,22,23,24

SibMatch
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Tissue-Typing Among SiblingsWhy Are Blood
Relatives More Likely to Be Compatible
Donors?(SibMatch for Dummies version)

• Mom's Parents (Nigel and Millicent)
  Dad's Parents (Duwayne and Loquida)
• Nigel's Haplotypes Nigel W
  Duwayne's Haplotypes Duwayne Y
• Millicent Haplotypes Millicent X
  Loquida's Haplotypes Loquida Z
• Mom's Possible Haplotypes Dad's Possible
  Haplotypes
• Nigel Millicent Duwayne Loquida
• Nigel X Duwayne Z
• W Millicent Y and
  Loquida
• W X Y Z
• 
  Your Possible Haplotypes
• Assume Your Mom got
  the Nigel Millicent Haplotypes
• Assume Your Dad got
  the Duwayne Loquida Haplotypes
• Inherit from Mom Nigel or Millicent
  Inherit from Dad Duwayne or Loquida
• 25 of the
  Off-Spring Likely to be these Haplotypes
• 
  Nigel Duwayne
• 
  Nigel Loquida
• 
  Millicent Duwayne
• 
  Millicent Loquida

48
Mouse H2 Complex Detail
D Class I Locus
K
IA IB Major Class II Loci
Class I Locus
Figure 8-11, Kuby 6th Edition, p.202, (Selected
Part)
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When this slide is opened be sure to use the
Send User Data directions to send in your name.
Remember to wait for the transmitter to go past
Presentation Mode Channel 41 In the previous
slide showing cells from the LCM virus challenged
mouse lysing LCM-infected self target cells What
will happen if the target cells are infected with
influenza virus?

• Lysis
• No Lysis

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I am here!(Testing your XR Transmitter)
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Hit Enter Get Receiver Found WAIT!!! Get
Presentation Mode WAIT! Get Blank Screen Now
enter the number 1 for your response Get Your
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• Yes
• No