Mary N. Carrington, Ph.D.
Dr. Carrington’s group studies the influence of human leukocyte antigens (HLA) and specific KIR/HLA genotypes on risk of and outcomes to infection, cancer, autoimmune disease, and maternal-fetal disease. Recent studies have focused on the impact of HLA gene expression in disease, the molecular mechanism regulating expression levels, and the functional basis for the effect of differential expression on disease outcome.
Dr. Carrington is a senior principal scientist with Leidos Biomedical, Inc. and head of the HLA Immunogenetics Section in the Cancer and Inflammation Program. Her lab focuses on the genetic basis for resistance/susceptibility to disease conferred by immunogenetic variation.
Extensive genetic polymorphism is a primary characteristic of the human leukocyte antigen (HLA) class I and class II loci within the major histocompatibility complex (MHC), which encode products that present antigenic peptides to T cells, initiating an adaptive immune response and clearance of foreign material. Apart from their role in antigen presentation to T cells, other characteristics of the HLA genes and the molecules they encode have begun to be elucidated. Notably, HLA class I molecules serve as ligands for innate immune receptors, including the killer cell immunoglobulin-like receptors (KIR) and the leukocyte immunoglobulin-like receptors (LILR) encoded by genes located in the Leukocyte Receptor Complex (LRC). KIR molecules are expressed on natural killer (NK) cells, which are central to the anti-viral/anti-tumor innate immune response, as well as certain T cell subsets. LILR are expressed by various immune cells of the myeloid and lymphoid lineage. Both KIR and LILR genes encode inhibitory and activating molecules, which regulate immune cell activity through fine-tuned signaling pathways. The KIR genes and haplotypes are exceptionally diverse and rapidly evolving (characteristics they share with the HLA loci). Less is known about the LILR genes overall, but like KIR, some of the LILR genes are very polymorphic and the locus does have some degree of gene copy number variability. The HLA and KIR/LILR loci are located on different chromosomes (6p and 19q, respectively), so they segregate independently. Individual KIRs exhibit specificity for a given set of HLA class I molecules, so the presence of genes/alleles encoding corresponding receptor-ligand pairs is necessary for functional activity, but the presence of one without the other has no influence on effector cell activity. Certain inhibitory LILR bind essentially all HLA class I molecules, but with differing affinities that result in corresponding levels of inhibition. Due to the extensive diversity of the HLA, KIR, and LILR gene loci and their roles in both the innate and adaptive immune response, variation at these loci impacts the risk of disease pathogenesis, and co-evolution of the unlinked genes encoding these receptors and their ligands must occur in order to maintain an appropriate level of functional interaction that is beneficial to the individual.
Another more newly defined characteristic of the HLA loci is their variable level of mRNA and cell surface expression, which correlates with specific allelic types for some of the loci. This is an important modifier of the strength of the HLA-mediated immune response to cancer and infections, and diversity in expression levels appears to have been selected over time, similar to variation in the peptide-binding groove. Variants in the MHC have been shown to serve as expression quantitative trait loci (eQTL) and many of these variants that associate with expression of linked (cis) or unlinked (trans) loci are located close to HLA class I and II genes, implicating HLA in modulating expression of other genes. This novel function of HLA may explain some of the many disease associations with these loci that go beyond their classic roles in the adaptive and innate immune response.
The main goal of my laboratory is to understand the genetic basis for resistance or susceptibility to disease conferred by polymorphic immune response loci. Our approach involves direct testing for genetic effects of polymorphic immune response genes on specific disease outcomes followed by molecular or cellular biological approaches to understand the basis for the genetic association. We have detected novel immunogenetic associations with disease outcomes to infection (HIV, hepatitis C virus [HCV], hepatitis B virus [HBV]), cancer (nasopharyngeal carcinoma [NPC], leukemia, cervical neoplasia), autoimmune/inflammatory disease (psoriatic arthritis, Crohn’s), and disorders of pregnancy (pre-eclampsia, miscarriage, and fetal growth restriction). In several cases, we have uncovered at least part of the functional basis for the associations and we continue to focus on defining these mechanisms, often through collaborations.
A greater understanding of the evolutionary and molecular genetic characteristics of immune response genes is also a key objective of my laboratory. This is an especially important consideration when studying genetic loci composed of multiple homologues that share functional activity, which both the MHC and LRC exemplify, because it is a significant aid in identifying the actual disease locus amongst multiple logical candidates. We have defined patterns of linkage disequilibrium (LD), studied the effects of meiotic recombination, and identified patterns of association between unlinked, but functionally related loci that may have evolved due to selection pressures using population based approaches. These and related studies have informed our disease studies by aiding in the interpretation of the data. They also provide a basic understanding of the genetic, evolutionary, and biological properties of these highly polymorphic immune response loci.
Selected Recent Publications
Relative expression levels of the HLA class I proteins in normal and HIV-infected cells.J. Immunol. In press: 2015. [ Journal Article ]
- Blood. 124: 3996-4003, 2014. [ Journal Article ]
- PLoS Genetics. 10: e1004196, 2014. [ Journal Article ]
- Proc Natl Acad Sci U S A. 110: 20705-20710, 2013. [ Journal Article ]
- Science. 340: 87-91, 2013. [ Journal Article ]
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. Prior to her current appointment, she was a faculty member in the Immunology Department at Duke University.
|Marjan Akdag||Research Associate I (Leidos)|
|Arman Amangeldiyevna Bashirova Ph.D.||Scientist I (Leidos)|
|Xiao-jiang Gao, Ph.D.||Senior Scientist (Leidos)|
|Amir Horowitz Ph.D.||Guest Researcher (Leidos)|
|Maureen P. Martin, M.D.||Senior Scientist (Leidos)|
|Vivek Naranbhai M.D., Ph.D., DPhil||Guest Researcher (Leidos)|
|Veron Ramsuran Ph.D.||Guest Researcher (Leidos)|
|Minzhong Tang Ph.D.||Guest Researcher (Leidos)|
|Mathias Viard, Ph.D.||Scientist II (Leidos)|
|Nicolas Thierry Vince Ph.D.||Guest Researcher (Leidos)|
|Victoria Walker-Sperling||Postdoctoral Fellow (CRTA)|
|Yuko Yuki D.D.M.||Research Associate (Leidos)|