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Antigen Presentation and Processing and the Relationship to Susceptibility and Resistance to Diseases;
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
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 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 = Im totally lost; 2 Im having a hard time but I get some of it. 3 = Im doing OK. I get a lot of it. Ill figure the rest out later. 4 = Im 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 doesnt 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
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
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
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
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? See Figure Get lysis of Strain Y target cells
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
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. 2.
Lysis No Lysis
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On a scale of 1 to 5: 1 = Im totally lost; 2 Im having a hard time but I get some of it. 3 = Im doing OK. I get a lot of it. Ill figure the rest out later. 4 = Im doing fine. I get most of it; 5 = +2 = This is no problem. Please get moving before I get bored
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MHC-I
MHC-II
Ag Site Class I
Ag-Bind
Ag in Site Class I
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?
MHC-Class I Polymorphisms
On a scale of 1 to 5: 1 = Im totally lost; 2 Im having a hard time but I get some of it. 3 = Im doing OK. I get a lot of it. Ill figure the rest out later. 4 = Im 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
HMC-Class II Dimers
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?
MHCAlleles
Hereditary Hemochromatosis
Insulin Dependent Diabetes* Multiple Sclerosis* Myasthenia Gravis* Rheumatoid Arthritis*
A3/B14
DR4/DR3 DR2 DR3 DR4
90
20 5 10 10
DR3
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
HLASick
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
1,2,3,4,5,6
Children's Possible Haplotypes: Inherit from Mom: 1,2,3,4,5,6 7,8,9,10,11,12 Inherit from Dad: 13 to 18
7,8,9,10,11,12
13 to 18
19 to 24
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
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
K Class I Locus
Figure 8-11, Kuby 6th p.202, (Selected Part)
D Class I Locus
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