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FRISC: The Faculty Research Interests Science Comparator |
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Professor, Center for Immunology and Department of Microbiology
Investigator, Howard Hughes Medical Institute
Genetics and
Development
Immunology
Office: (214) 648-5007
FAX: (214) 648-5453
Email: kfl@chop.swmed.edu
Histocompatibility (H) antigens form a barrier to the free exchange of
tissues between individuals. Based on the strength of the rejection they elicit, they have
been classified as major and minor. The major histocompatibility complex (MHC) encodes
cell surface glycoproteins that present foreign antigens to the immune system. Class I MHC
molecules bind small peptides, derived from proteins synthesized within the cell, and
present them on the surface to T killer lymphocytes. If a virus infects the cell, the T
killer cells will recognize the foreign viral antigens and eliminate the infected cell.
Because the presentation mechanism cannot distinguish between foreign and endogenous
proteins, the latter are also processed and presented as peptides on the cell surface.
When cells are grafted to another individual who happens to have a different allelic form
of any one of these peptides, it acts as a minor H antigens, and the cells will be
rejected as foreign.
Our laboratory has long studied Mta, a maternally transmitted H antigen
of the mouse, which I discovered. We have cloned or sequenced all three genes necessary
for expression of Mta and studied their polymorphism. Mtf is the first minor H
antigen to be defined in molecular terms. It is the amino-terminus of one of the
mitochondrially encoded subunits of NADH-dehydrogenase. We have since found several other
mitochondrially encoded peptides that act as minor H antigens in mice or rats. H2-M3
encodes a class I MHC molecule that noncovalently associates with b 2 -microglobulin, encoded by B2m ,
and forms an unusual binding pocket for N -formylated peptides, which come from
mitochondria or bacteria.
We have constructed a detailed map of the chromosomal region surrounding
H2-M3 at the end of the mouse MHC, which we are cloning in yeast and bacterial
artificial chromosomes in a contig that now covers more than 5 Mb; the aim is to clone and
sequence the entire MHC. We found ten new class I genes, several olfactory receptor genes,
and a variety of other genes, all of them worth further analysis. The genetic analysis of H2-M3
led to the isolation of several MHC chromosomes from wild mice that show an unusually high
frequency of recombination. We are mapping these recombinational hot spots; the goal is to
characterize them and learn what makes recombination happen in hot spots.
Selected Publications:
Loveland B, Wang C-R, Hermel E, Yonekawa H, and Fischer Lindahl K (1990)
Maternally transmitted mouse histocompatibility antigen: a hydrophobic peptide from a
mitochondrially encoded protein. Cell 60:971-980
Wang C-R, Loveland BE, and Fischer Lindahl K (1991) H-2M3 encodes
the MHC class I molecule presenting the maternally transmitted antigen of the mouse. Cell
62:335-345
Fischer Lindahl K (1991) His and hers recombinational hotspots. Trends
Genet 7:273-276
Jones EP, Xiao H, Schultz RA, Flaherty L, Trachtulec Z, Vincek V, Larin
Z, Lehrach H, and Fischer Lindahl K (1995) MHC class I gene organization in > 1.5 Mb
YAC contigs from H2-M region. Genomics 27:298-305
Wang C-R, Castaņo AR, Peterson PA, Slaughter C, Fischer Lindahl K, and
Deisenhofer J (1995) Nonclassical binding of formylated peptide in crystal structure of
MHC class Ib molecule, H2-M3. Cell 82:655-664
Fischer Lindahl K, Byers D, Dabhi VM, Hovik R, Jones EP, Smith GP, Wang
C-R, Xiao H, and Yoshino M (1997) H2-M3, a full-service class Ib histocompatibility
antigen. Annu Rev Immunol 15:851-879
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Last Updated: 17 Nov 2000
Extraction Method: Expand using Medical Synonyms-
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