The Major HistocompatibilityComplex

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 8Topics Listed vs Topics Covered in BIO 447, See Page 189

1.General Organization and Inheritance of the MHC Genes2.MHC Molecules and Genes3.Detailed Genomic Map of MHC Genes (Not Covered in BIO 447)4.Cellular Expression of MHC Molecules5.Regulation of MHC Expression (Not Covered in BIO 447)6.MHC and Disease Susceptibility7.MHC and Immune Responsiveness8.Self-MHC Restriction of T-Cells9.Role of Antigen-Presenting Cells

Not Covered in BIO 44710. Evidence of Different Antigen-processing and Presentation Pathways11. Endogenous Antigen: The Cytosolic Pathway12. Exogenous Antigens: The Endocytic Pathway13. Cross Presentation of Exogenous Antigens14. 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

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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)?

Fill-in-the Blank Slide:In the picture below what do the letters “b” and “k” represent?

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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?

Figure 8-1, Kuby 6th Edition, Top Half

Human HLA (Histocompatibility Complex), Lower Half Next Slide

Mouse H2 Complex

Complement Proteins

SomeCytokines

In Humans the Genes Corresponding to MHC Region in Mice are Called

Human Leukocyte Associated Antigens or HLA Genes

Kuby, 6th Edition, Figure 8.01, Bottom Half

Class II LociEquivalent to IAa, IAb; IEa, IEb in Mice

Class I LociEquivalent toK, D, and L in Mice

Human HLA Loci

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

CML Assay

See Figure8-15, p. 207,Kuby, 6th EditionFor MHC Restriction.MHC Restriction will be covered later

See Figure 14-17, Kuby 6th Edition, p. 368. For CML Assay

Cell-Mediated Lympholysis Assay (CML Assay)

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.

Why is Strain X mouse doing this?

What does the strain X mouse “think” it sees?

Get lysis of Strain Y target cells

CML Assay

See Figure8-15, p. 207,Kuby, 6th EditionFor MHC Restriction.MHC Restriction will be covered later

See Figure 14-17, Kuby 6th Edition, p. 368. For CML Assay

Restriction to Self MHC Alleles

In Vitro exposure of target cells to spleen cells from LCM virus-infected mouse.

(Fill in the blank)In the picture below the H2k mouse is not attacking it own H2k

target cells on the left, but it is attacking self cells in the middle. What are its T-Cells “seeing” that leads to the attack in the middle?

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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?

1. Lysis

2. No Lysis

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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

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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

Ag in Site Class I

See figure 8-9(c), Kuby, 6th Edition, p. 199

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)

Trans-MembraneResidues

Kuby, 6th Edition, Figure 8-10(a) p. 201; MHCIVary

MHC-Class I PolymorphismsKuby, 6th EditionFigure 8-10(b)p. 201 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

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(Fill in the blank or short answer)What would happen to host response to a virally infected cell if the virus shut-down

production of Class I MHC proteins?

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MHC-II

See Figure 8-3,RightKuby, 6h Editionp. 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

See Figure 8-12,p. 203Kuby, 6th Edition)

Variety of MHC Loci & Allelles

(Fill in the blank)The MHC gene complex is called the “Major

Histocompatibility Complex because it controlled the acceptance or rejection of

__ ___ __ __ __ __ ___ __ __ __

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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 Associated HLA Allele Relative Risk** Ankylosing Spondylitis* B27 90

Hereditary HemochromatosisA3/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 AlleleHLASick

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) 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

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) 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

Figure 8-11, Kuby 6th Edition, p.202, (Selected Part)

DClass I Locus

K IA & IBMajorClass IILoci

Class I Locus

Mouse H2 Complex Detail

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Response GridResponse Grid

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