Transcript Major Histocompatibility Complex 02/28/06

Principles of Immunology
Major Histocompatibility
Complex
2/28/06
“Change is not merely necessary for life. It is life.”
A Toffler
Word List
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Congenic
Haplotype
HLA complex
MHC
Polygenic
Syngeneic
MHC
 Cluster of genes that influence:
1. Intercellular recognition
2. Self vs. non-self
 HLA complex in humans
HLA Complex
 Three regions
 Class I genes
 MHC I molecules
 Nucleated cells
 T cytotoxic cells (CD8)
 Class II genes
 MHC II molecules
 APCs
 T helper cells (CD4)
 Class III genes
 Complement components (C2 and C4) plus TNF
MHC I Molecules
 Membrane bound glycoprotein (Ig super family)
 Alpha chain
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Three domains
Encoded by HLA complex
Anchored in cell membrane
Cytoplasmic tail
 Beta chain
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A single domain
Encoded by a different gene on another chromosome
Not anchored in cell membrane
Bound to alpha chain non covalently
Necessary for MHC I expression
MHC I Molecules
 Antigen presenting features
 Alpha 1 and alpha 2 domains form
peptide-binding cleft
 8-10 amino acid peptides can bind to
MHC I molecule
 Alpha 3 interacts with CD 8 on T
cytotoxic cells
MHC II Molecules
 Membrane bound glycoprotein (Ig super family)
 Alpha chain
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Two domains
Encoded by HLA complex
Anchored in cell membrane
Cytoplasmic tail
 Beta chain
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Two domains
Encoded by HLA complex
Anchored in cell membrane
Cytoplasmic tail
MHC II Molecules
 Antigen presenting features
 Alpha 1 and beta 1 domains form
peptide-binding pocket
 13-18 amino acid peptides can bind to
MHC II molecule
 Alpha 2 and beta 2 interact with CD 4 on
T helper cells
Fig 7-5
MHC I – Peptide Interaction
Stable associations
Endogenously processed antigens
Up to six allelic variants
~100,000 MHC molecule variants per
cell
 ~ 100 MHC-peptide complexes
required for T cytotoxic cell
recognition
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MHC II – Peptide Interaction
 Stable associations
 Exogenously processed antigens
 Up to 12 allelic variants
MHC Diversity
 Genetically determined
 Polygenic characteristic
 Different alleles
 Genes with overlapping functions
 ~12 million haplotypes
 Diversity in HLA type
MHC I Expression
 Varies by cell type
 Lymphocytes high
 Hepatocytes low
 Regulated by cytokines
 Interferons
 TNF
 Suppressed by viruses
 Herpes family
 Hepatitis B
Inheritance of MHC(HLA) Type
 Polymorhisms
 Many allelic types within a species
 Haplotype
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The genetic loci of MHC are closely linked
Inherited as a group (haplotype)
One haplotype from each parent
Co-dominant expression
Inheritance of MHC
 Inbred mice
 Homozygous parents
 F 1 generation has MHC loci from both
(heterozygous)
 F1 generation can accept grafts from
either parent
 Neither parent can accept graft from F1
offspring
 WHY?
Inheritance of MHC
 Humans
 Heterozygous parents
 F 1 generation has MHC loci from both
(heterozygous)
 Four combinations
 F1 generation can not accept grafts from
either parent
 Neither parent can accept graft from F1
offspring
 1 in 4 F1 generation are HLA compatible