MHC Restriction and IR genes

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MHC Restriction and IR genes

• January 15, 2007

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1-1. McDevitt, H.O. and Chinitz, A. Genetic
control of the antibody response Relationship
between immune response and histocompatibility
(H-2) type. Science 1631207-1208. (1969).
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It all began with some rabbits
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and some antigens
Synthetic polypeptide antigens -branched
multichain synthetic polypeptides -not defined
structures -(T,G)-A-L (H,G)-A-L (P,G)-A-L
Rpoly (tyrosine,glutamine acid poly
(histidine,glutamic acid) poly
(proline,glutamic acid)
R
R
R
Poly-D,L -alanine
Poly-L -lysine
R
R
Michael Sela-Weissman Institute for Sciences,
Rehovot, Israel
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People and Places

• John Humphrey-Mill Hill, UK
• Early pioneer in modern immunology with wide
  interests
• Brigette(Ita) Askonas-Mill Hill, UK
• Emils postdoctoral advisor
• Don Shreffler-Wash U-Genetics
• H-2 Immunogeneticist
• Jan Klein-US/Germany/US
• Immunogeneticist, prolific author, iconoclast

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It all began with some rabbits
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Inbred Mouse Strains
The genetic theory of tumor transplantation
stimulated the development of inbred mouse
strains, which in turn were invaluable in many
areas of biomedical research.
Produced by repetitive matings of siblings for 20
generations. Pet fanciers collected rare
variants of mice Ancient China Europe
U.S
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Common inbred mouse strains
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Genealogy of inbred mouse strains
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MHC Congenic Mouse Strains
1948- George Snell (The Jackson Laboratory)

• Using skin transplantation he examined what he
  termed histocompatibility genes H genes
• The H gene for antigen II was designated H2,
  later changed to H-2
• He realized that the first step in the genetic
  analysis of histocompatibility was the separation
  and identification of individual genes.
• He therefore generated congenic mouse stains
• Identified 2 types of loci
• Major (strong) H-2
• Minor (weak) non-H2
• i.e. H-1, H-4, H-Y
• Nomenclature- STRAIN.LOCUS (i.e. B10.H-2a or
  B10.A)

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Generation of congenic mouse strains
Backcross generations (n) Probability of homozygosity (p)
4 0.875
8 0.992
12 0.999
Speed congenics decrease the number
of backcross generations by typing each
chromosome for background strain alleles and
selecting mice to breed which have the highest
number of background genes.
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H-2 Congenic mouse strains
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Intra-H-2 recombinant congenic mouse strains
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Table 1
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Figure 1
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Table 2
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The forgotten guinea pig
Inbred stains of guinea pigs -strain 2 and
strain 13 -differ at the I region of MHC
Benacerraf (1963) - Guinea Pigs Strain
2 Strain 13 PLL(poly L-lysine)
GT(glutamic acid/ tyrosine)

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MHC restriction was first shown a year prior to
Zinkernagel and Dohertys study
JEM 138194,1973
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MHC Restriction
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1-2. Zinkernagel, R.M. and Doherty, P.C.
Immunological surveillance against altered self
components by sensitised T lymphocytes in
lymphocytic choriomeningitis. Nature
251547-548. (1974).
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People and Places

• Rolf Zinkernagel
• M.D. Switzerland -
• Cerottini Brunner- developed the 51Cr-release
  assay
• Ph.D. Australian National University (ANU)
• Canberra headed by Gordon Ada
• Asst. Professor - Scripps
• Professor -U. of Zurich
• Peter Doherty
• Veterinarian
• Postdoc-Scotland
• ANU
• Wistar, ANU, St. Judes
• Australia

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Table 1
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Table 2
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Figure 1
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1-3. Babbitt, B.P., Allen, P.M., Matsueda, G.,
Haber, E., and Unanue, E.R. Binding of
immunogenic peptides to Ia histocompatibility
molecules. Nature 317359-361. (1985).
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Ir Genes

• How to explain lack of a response
• Hole in the repertoire
• T cells do not exist that are able to respond,
  involving thymic selection
• Determinant Selection
• MHC molecules select which determinants they can
  present

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Wheres Bruce?
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Numerous groups had completely failed to find any
evidence that antigen associated directly with
MHC molecules
JI 1332067(84)
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Identification of the HEL(46-61)/I-Ak epitope
A single HEL tryptic fragment stimulates HEL
specific T cells
Stimulatory fragment identified as 46-61
Allen, Strydom, and Unanue, PNAS 1984
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Figure 1
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Figure 2
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Figure 3