The Major Histocompatibility
Complex
Antigen Presentation and Processing
and the Relationship to
Susceptibility and Resistance to Diseases;
Folder Title: MHC
Updated: November 25, 2012
Kuby Immunology, 6th Edition, Chapter 8
Topics Listed vs Topics Covered in BIO 447, See Page 189
1.
2.
3.
4.
5.
6.
7.
8.
9.
General Organization and Inheritance of the MHC Genes
MHC Molecules and Genes
Detailed Genomic Map of MHC Genes (Not Covered in BIO 447)
Cellular Expression of MHC Molecules
Regulation of MHC Expression (Not Covered in BIO 447)
MHC and Disease Susceptibility
MHC and Immune Responsiveness
Self-MHC Restriction of T-Cells
Role of Antigen-Presenting Cells
10.
11.
12.
13.
14.
Not Covered in BIO 447
Evidence of Different Antigen-processing and Presentation Pathways
Endogenous Antigen: The Cytosolic Pathway
Exogenous Antigens: The Endocytic Pathway
Cross Presentation of Exogenous Antigens
Presentation of Non-Peptide Antigens
What we saw earlier in the course: What Affects Host
Response to Potential Antigens?
What else affects host response to potential antigens?
What are we looking at?
Groups of Mice with Same Collection of MHC Alleles
(Haplotype)
How do these groups respond to two different
experimental antigens?
Haplotype = Combination of MHC Genes Inherited from Each
Parent
Co-dominantly Expressed = both sets of alleles are expressed
On a scale of 1 to 5: 1 = I’m totally lost;
2 I’m having a hard time but I get some of it.
3 = I’m doing OK. I get a lot of it. I’ll figure the rest out later.
4 = I’m doing fine. I get most of it;
5 = +2 = This is no problem. Please get moving before I get bored
5
4
3
2
1
Duration: 0 Seconds
Both parents are of course histocompatible with their own tissues,
and their progeny tolerate skin grafts from either parent because
the progeny recognizes antigens from either parent as self.
Transplanting hematopoietic stem cells from parent to mixed
progeny could generate graft-vs-host reaction
What happens if we transplant skin from one b/k progeny hybrid
to another b/k hybrid?
What happens if we transplant from a b/k hybrid back to either of
the parental strains (b/b or k/k)?
Why is this collection of genes controlling
whether one can transplant a tissue from one
mouse to another or from one human to
another?
Nature doesn’t do transplants.
Why does Nature bother to generate genes
that control transplantability of tissue?
What are these genes controlling tissue compatability
(“histocompatibility”)?
“Histocompatability Complex or
Major Histocompatability Genes = MHC Genes”
What products are these genes coding for that control
histocompatibility?
Mouse H2 Complex
Complement Some
Proteins
Cytokines
Figure 8-1, Kuby 6th Edition, Top Half
Human HLA (Histocompatibility Complex), Lower
Half Next Slide
In Humans the Genes Corresponding to
MHC Region in Mice are Called
Human Leukocyte Associated Antigens or
HLA Genes
Human HLA Loci
Class I Loci
Equivalent to
K, D, and L in Mice
Class II Loci
Equivalent to IAa, IAb; IEa, IEb in Mice
Kuby, 6th Edition, Figure 8.01,
Bottom Half
Recombinant Collection of HLA Genes not
existing in this grouping in either parent
k and b Haplotype “Team
Members”
See Table 7-1, Kuby 4th Edition, p. 175
Haplotype and Team Members
These H2 Genes Control Recognition of Self
when cells from mouse strains with two
different H2 Haplotypes are mixed together
in cell culture.
Mixed Lymphocyte Test in Cell Culture
MLR Assay
See Figure 14-16, p.367,
Kuby, 6th Edition
Strain X Cells are activated to proliferate by exposure to
unmatched cells from Strain Y
Strain X Cells are also activated by exposure
to strain Y cells in the living mouse
Strain X mouse makes T-cells that will lyse
strain Y cells
Cell-Mediated Lympholysis Assay
(CML Assay)
CML
Assay
Strain X Cells are also activated by
exposure to strain Y cells in the living
See Figure 14-17, Kuby
mouse
6th Edition, p. 368. For
CML Assay
Strain X mouse makes T-cells that will
lyse strain Y cells.
Why is Strain X mouse doing this?
What does the strain X mouse “think”
it sees?
Get lysis of Strain Y target cells
See Figure
8-15, p. 207,
Kuby, 6th Edition
For MHC Restriction.
MHC Restriction
will be covered later
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
Restriction to Self
MHC Alleles
In Vitro
exposure of
target cells to
spleen cells
from LCM
virus-infected
mouse.
On a scale of 1 to 5: 1 = I’m totally lost;
2 I’m having a hard time but I get some of it.
3 = I’m doing OK. I get a lot of it. I’ll figure the rest out later.
4 = I’m doing fine. I get most of it;
5 = +2 = This is no problem. Please get moving before I get bored
5
4
3
2
1
Duration: 0 Seconds
What Do MHC Class I and
Class II Proteins Look Like?
How do they bind and present
peptide antigens?
MHC-I
See figure 8-3,
Kuby, 6th Edition,
p. 194, left
MHC-II
See figure 8-3, Kuby,
6th Edition, p. 194, right
Class I MHC Protein Binding
Cleft
Ag Site Class I
See figure 8-4, Kuby,
6th Edition, p. 195, right
Ag-Bind
See figure 8-9(a,b),
Kuby, 6th Edition,
p. 199
See figure 8-9(c), Kuby,
6th Edition, p. 199
Ag in Site Class I
Class I MHC Space-Filling
H2K and Peptides
See figure 7-12,
Kuby 4th edition
p. 184
Class I and Class II proteins have sequence
differences inherited in the germ line (they are
polymorphic)
Where are the variations located in the Class I
and Class II proteins?
Amino Acids Positions of Polymorphic Variations
in Class I MHC Proteins in Humans
Membrane Distal a1 and a2 Domains
(Comprise Peptide-binding Cleft)
TransMembrane
Residues
Kuby, 6th Edition, Figure 8-10(a)
p. 201; MHCIVary
Kuby, 6th Edition
Figure 8-10(b)
p. 201
MHC-Class I Polymorphisms
MHCIPoly
Positions of
Polymorphic Amino
Acid Residues in a
Human Class I
MHC Protein
MHC ClassI and Flu
On a scale of 1 to 5: 1 = I’m totally lost;
2 I’m having a hard time but I get some of it.
3 = I’m doing OK. I get a lot of it. I’ll figure the rest out later.
4 = I’m doing fine. I get most of it;
5 = +2 = This is no problem. Please get moving before I get bored
5
4
3
2
1
Duration: 0 Seconds
MHC-II
See Figure 8-3,
Right
Kuby, 6h Edition
p. 194
Class II MHC Space Filling
HMC-Class II Dimers
Comparison of Class I and Class II
TCR and MHC-Class II
MHC-Class II and Bound
Antigen
Class I and Class II Antigen
Acquisition
Variety of MHC Loci & Allelles
See Figure 8-12,
p. 203
Kuby, 6th Edition)
Why are there so many different Class I and
Class II proteins in a given individual and in a
species gene pool?
Why are these gene products so polymorphic?
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,
(3) selection for or against certain combinations
MHCAlleles
Association of Human MHC Alleles and Risk for Diseases
(from Table 7-4, Kuby Immunology, 4th Edition, p. 193)
Disease
Ankylosing Spondylitis*
Associated HLA Allele
B27
Relative Risk**
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
* Autoimmune Disease
HLASick
DR2
130
**Percent of Patients with Allele Divided by Percent of
Non-Affected Persons with this Allele See Table 7-4, Kuby 4th
edition, p. 194
Limited diversity in HLA gene polymorphism due to breeding
bottle-neck in recent past leaves cheetahs exceptionally
susceptible to viral infections. (6th Ed. P. 206)
MHC Genes and Tissue Typing:
Not covered in BIO 447 in 2012
Tissue-Typing Among Siblings:
Why Are Blood Relatives More Likely to Be Compatible Donors?
Mom's Haplotypes (A,B,C, DP, DQ, DR)
1,2,3,4,5,6
7,8,9,10,11,12
1,2,3,4,5,6
13 to 18
Dad's Haplotypes (A,B,C,DP, DQ, DR)
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
7,8,9,10,11,12
19 to 24
Inherit from Dad:
13 to 18
7,8,9,10,11,12
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
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
Tissue-Typing Among Siblings:
Why Are Blood Relatives More Likely to Be Compatible Donors?
(SibMatch for Dummies version)
Mom's Parents (Nigel and Millicent)
Nigel's Haplotypes: Nigel & W
Millicent Haplotypes: Millicent & X
Dad's Parents (Duwayne and Loquida)
Duwayne's Haplotypes: Duwayne & Y
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
Mouse H2 Complex Detail
K
Class I Locus
Figure 8-11, Kuby 6th
p.202, (Selected Part)
IA & IB
Major
Class II
Edition, Loci
D
Class I
Locus
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H2 Haplotypes of some mouse strains
Presentation of Exo-Antigen
(Class II)
See Figure 8-8, Kuby,
4th Edition, p. 209
Presentation of Endogenous
Antigen (Class I )
See Figure 8-8,
Kuby, 4th Edition,
p. 209