Our Science – Carrington Website

Mary N. Carrington, Ph.D.

Laboratory of Experimental Immunology Head, HLA Typing Section Senior Investigator (Contr) National Cancer Institute at Frederick Building 560, Room 21-89 Frederick, MD 21702-1201 Phone:   301-846-1390 Fax:   301-846-6771 E-Mail:   carringt@mail.ncifcrf.gov

Biography

Dr. Carrington obtained her Ph.D. at Iowa State University in the Immunobiology Department. She performed her postdoctoral studies in the departments of immunology and microbiology at Duke University and the University of North Carolina, respectively. Prior to her current appointment, she was a faculty member in the Immunology Department at Duke University.

Research

The HLA Immunogenetics Group studies host genetic effects on human disease. Our primary candidates include the HLA class I and II genes located within the human Major Histocompatibility Complex (MHC), because of their central role in the immune response. However, we also consider other regions of the genome containing loci known to participate in innate and acquired immunity, as the effects of host genetics on most human diseases are complex and involve multiple genes. A confounding factor in determining the precise disease locus (or loci) among the many candidate genes within the MHC is the non-random association between pairs of loci within the complex. Accounting for molecular genetic characteristics such as meiotic recombination rates and levels of linkage disequilibrium between pairs of loci, helps us to identify more accurately which locus is truly involved in the disease process.

Disease Association Studies

In order to determine the effects of HLA on a given disease process, we have taken several approaches:1) direct analysis of allelic and haplotypic associations between HLA and infectious diseases, including HIV-1, HBV, HCV and HPV; 2) identification of loci located outside the MHC that have an effect on outcome after exposure to the pathogen, some of which may act in an epistatic manner with HLA; 3) characterization of patterns of recombination and linkage disequilibrium between loci of the MHC. Recently, major advances have been made in understanding the role of natural killer (NK) cells in the innate immune response. The killer immunoglobulin-like receptors (KIR) on NK cells regulate inhibition and activation of NK cell responses through recognition of HLA class I molecules on target cells. We are studying the effects of HLA and KIR genes in several types of diseases including infectious diseases, autoimmune diseases, and cancer. We have found a general trend for an association of activating KIRs with a favorable outcome in infectious diseases. Conversely, in autoimmune disease and cancer, the activating KIRs are associated with an unfavorable outcome. Analyses of combinations of KIR and HLA genotypes strongly indicate that these two unlinked loci are interacting synergistically in resistance or susceptibility to disease, thus highlighting the importance of these genes in the immune response.

Recombination and Linkage Disequilibrium Across The HLA Complex

Another layer of diversity within the HLA complex is the combination of alleles at the various loci on a single chromosome known as haplotypes. About 40% of the 128 genes in this region participate in immune responses and it is likely that beneficial interactions among specific allelic products of these loci result in selective pressure to secure their close linkage relationship and maintain particular haplotypes. On the other hand, a constant, though perhaps low level shuffling of haplotypes may protect against novel human pathogens such as HIV-1. In this case, haplotypes that are particularly beneficial against a novel pathogen may arise through recombination and would not necessarily already be present in high frequencies if they were not effective against pathogens that have existed in the population over long periods of time. We have determined recombination rates across the entire HLA complex in 59 CEPH families by typing genes and microsatellites within and flanking the complex. Using single sperm typing, we have extended our knowledge of recombination within the 3.3Mb region of the MHC. Several principal characteristics of recombination in this region were observed including information regarding haplotype specificity of recombination, recombination hotspots, and sequence motifs involved in the recombination process. Comparisons of recombination and linkage disequilibrium data in this genomic segment may indicate a history of haplotypic selection between loci in the region.

Collaborators

Allan Hildesheim, DCEG, NCI
Kenneth and Judith Kidd, Yale University
Metka Ravnik-Glavac, University of Lubljana, Slovenia
John Rioux, Broad Institute, MIT
Kathy Siminovitch, University of Toronto, Canada
Rich Singleton, University of Vermont
Howard Strickler, Albert Einstein College of Medicine
Chloe Thio, Johns Hopkins University
David Thomas, Johns Hopkins University
John Trowsdale, Cambridge University, UK

This page was last updated on 6/11/2008.