Carrington

Mary N. Carrington, Ph.D.

Lab Info:

Principal Investigator: Mary N. Carrington, Ph.D.

Lab Staff: 3 scientists, 3 technicians, 5 postdocs, 1 Ph.D. Student

Office/Location: Frederick, MD

Phone: (301) 846-1390

Email: carringt@ncifcrf.gov

Category: Members

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 appointments at the Frederick National Laboratory for Cancer Research, Leidos Biomedical Research at the National Cancer Institute, and the Ragon Institute, she was a faculty member in the Immunology Department at Duke University.

 

Extensive genetic polymorphism is a primary characteristic of the human major histocompatibility complex (MHC) HLA class I and class II loci, which encode products that present antigenic peptides to T cells, initiating an adaptive immune response and clearance of foreign material. Variation within these loci is concentrated primarily, but not solely, at positions that alter amino acid sequences and determines specificity for foreign peptides.  We have shown that variation within and around these genes also affects level of their expression, which has a strong effect on HIV disease that is independent of individual allelic effects involved in peptide binding.  Differential expression levels of HLA class I also has an influence on risk of inflammatory disease.  These data underscore the importance of variation within/near to the HLA genes in determining their function and impact on human disease pathogenesis.

 

Apart from their role in the acquired immune response, HLA class I molecules participate in innate immunity as ligands for the killer immunoglobulin-like receptors (KIR). KIR molecules are expressed on natural killer (NK) cells, critical components of the innate immune system that are directly involved in the anti-viral/anti-tumor immune response. Upon binding of HLA ligand, KIR molecules regulate cytotoxicity and cytokine production through balanced control of activation and inhibition of NK cells. KIR are expressed on a subset of T cells as well, affirming their role in both innate and adaptive immunity, but they are distinct from other NK cell receptors in that they are exceptionally diverse and rapidly evolving (characteristics they share with the HLA molecules). The HLA and KIR loci are located on different chromosomes (6p and 19q, respectively), so they segregate independently. Thus 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. Given the extensive diversity of the HLA class I and KIR gene loci and the central role of their interactions in modulating both the innate and adaptive immune response, variation at these loci likely influences the risk of disease pathogenesis; it also indicates the necessity for co-evolution of these two sets of genes in order to maintain an appropriate level of functional interaction that is beneficial to the individual.

 

The main goal of my laboratory is to understand the genetic basis for resistance or susceptibility to disease conferred by HLA, KIR, and other loci involved in the immune response. Our approach involves direct testing for genetic effects of polymorphic genes within the MHC, as well as functionally relevant combinations of HLA class I alleles and KIR genes, on specific disease outcomes. We have detected novel associations between specific KIR/HLA genotypes that are known to behave as receptor-ligand pairs and disease outcomes to infection (HIV and hepatitis C virus [HCV]), cancer (nasopharyngeal carcinoma [NPC] and cervical neoplasia), autoimmune disease (psoriatic arthritis), inflammatory disease (Crohn’s and ulcerative colitis), and maternal-fetal disease (pre-eclampsia, miscarriage, and fetal growth restriction). Upon identification of genetic variants that associate with a given disease outcome, we are committed to assisting collaborators whose expertise allows direct testing for the functional significance of that genetic finding. These collaborative studies have been exceptionally fruitful, specifically for HIV-1 and HCV disease, in that they explain and confirm the genetic data, and thereby provide solid information for potential use in therapeutic development.

 

A greater understanding of the evolutionary and molecular genetic characteristics of the MHC and KIR gene cluster 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 HLA genes and the KIR genes exemplify, because it is a significant aid in identifying the actual disease locus amongst multiple logical candidates. In both the MHC and the KIR gene cluster, we have defined patterns of linkage disequilibrium (LD), studied the effects of meiotic recombination on KIR haplotypes, and identified patterns of association between the unlinked KIR and HLA 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.

 

Lab Members

 

Selected Publications

Apps, R., Qi, Y., Carlson, J.M., Gao, X., Thomas, R., Yuki, Y., Del Prete, G., Goulder, P., Brumme, Z.L., Brumme, C.J., John, M., Mallal, S., Nelson, G., Bosch, R., Heckerman, D., Stein, J.L., Soderberg, K.A., Moody, M.A., Denny, T.N., Moffett, A., Goedert, J.J., Buchbinder, S., Kirk, G.D., Fellay, J., McLaren, P., Deeks, S.G., Pereyra, F., Walker, B., Michael, N.L., Weintrob, A., Wolinsky, S., and Carrington, M.:  Influence of HLA-C expression level on HIV control.  Science, In Press, 2013.

 

Duggal, P., Thio, C.L., Wojcik, G.L., Goedert, J.J., Mangia, A., Latanich, R., Kim, A.Y., Lauer, G.M., Chung, R.T., Peters, M.G., Kirk, G.D., Mehta, S.H., Cox, A.L., Khakoo, S.I., Alric, L., Cramp, M.E., Donfield, S.M., Edlin, B.R., Tobler, L.H., Busch, M.P., Alexander, G., Rosen, H.R., Gao, X., Abdel-Hamid, M., Apps, R., Carrington, M., and Thomas, D.L.:  Genome wide association study of spontaneous resolution of hepatitis C virus infection.  Ann. Intern. Med., In Press, 2013.

 

Shea, P.R., Shianna, K.V., Carrington, M., and Goldstein, D.B.: Host genetics of HIV acquisition and viral control.  Annu. Rev. Med., 64:203-217, 2013.

 

Fadda, L., Korner, C., Kumar, S., van Teijlingen, N.H., Piechocka-Trocha, A., Carrington, M., and Altfeld, M.: HLA-Cw*0102-restricted HIV-1 p24 epitope variants can modulate the binding of the inhibitory KIR2DL2 receptor and primary NK cell function.  PLoS Pathog., 8:e1002805, 2012.

 

Thomas, R., Thio, C.L., Apps, R., Qi, Y., Gao, X., Marti, D., Stein, J.L., Soderberg, K.A., Moody, M.A., Goedert, J.J., Kirk, G.D., Hoots, W.K., Wolinsky, S., and Carrington, M.:  A novel variant marking HLA-DP expression levels predicts recovery from hepatitis B virus infection.  J. Virol., 86:6979-6985, 2012.

 

Carrington, M. and Walker, B.D.: Immunogenetics of spontaneous control of HIV.  Annu. Rev. Med., 63:131-145, 2012.

 

O’hUigin, C., Kulkarni, S., Xu, Y., Deng, Z., Kidd, J., Kidd, K., Gao, X., and Carrington, M:  The molecular origin and consequences of escape from miRNA regulation by HLA-C alleles.  Am. J. Hum Genet., 89:424-431, 2011.

 

Kulkarni, S., Savan, R., Qi, Y., Gao, X., Yuhi, Y., Bass, S.E., Martin, M.P., Hunt, P., Deeks, S.G., Telenti, A., Pereyra, F., Goldstein, D., Wolinsky, S., Walker, B., Young, H.A., and Carrington, M.:  Differential microRNA regulation of HLA-C expression and its association with HIV control.  Nature.  472:495-498, 2011.

 

Bashirova, A., Thomas, R., and Carrington, M.:  HLA/KIR restraint of HIV: Surviving the Fittest.  Annu. Rev. Immunol.  29:295-317, 2011.

 

Julg, B., Moodley, E.S., Qi, Y., Ramduth, D., Reddy, S., Mncube, Z., Gao, X., Goulder, P., Detels, R., Ndung’u, T., Walker, B.D., and Carrington, M.:  Possession of HLA class II DRB1*1303 associates with reduced viral loads in chronic HIV-1 clade C and B infection.  J. Infect Dis., 203:803-809, 2011.

 

The International HIV Controllers Study:  The major genetic determinants influencing HIV-1 control map to discrete amino acids involved in HLA class I peptide presentation.  Science, 330:1551-1557, 2010.

 

Kuniholm, M.H., Kovacs, A., Gao, X., Xue, X., Marti, D., Thio, C.L., Peters, M.G., Terrault, N.A., Greenblatt, R.M., Goedert, J.J., Cohen, M.H., Minkoff, H., Gange, S.J., Anastos, K., Fazzari, M., Harris, T.G., Young, M.A., Strickler, H.D., and Carrington, M.: Specific human leukocyte antigen class I and II alleles associated with hepatitis C virus viremia.  Hepatology, 51:1514-1522, 2010.

 

O’Connor, S.L., Lhost, J.J., Becker, E.A., Detmer, A.M., Johnson, R.C., MacNair, C.E., Wiseman, R.W., Karl, J.A., Greene, J.M., Burwitz, B.J., Bimber, B.N., Lank, S.M., Tuscher, J.J., Mee, E.T., Rose, N.J., Desrosiers, R.C., Hughes, A.L., Friedrich, T.C., Carrington, M., and O’Connor, D.H.:  MHC heterozygote advantage in simian immunodeficiency virus-infected Mauritian cynomolgus macaques.  Sci. Transl. Med., 2:22ra18, 2010.

 

Thomas, R., Apps, R., Qi, Y., Gao, X., Male, V., O’hUigin, C., O’Connor, G., Ge, D., Fellay, J., Martin, J.N., Margolick, J., Goedert, J.J., Buchbinder, S., Kirk, G.D., Martin, M.P., Telenti, A., Deeks, S.G., Walker, B.D., Goldstein, D., McVicar, D.W., Moffett, A., and Carrington, M.:  HLA-C cell surface expression and control of HIV/AIDS correlate with a variant upstream of HLA-C.  Nat. Genet.  41:1290-1294, 2009.

 

Thomas, D.L., Thio, C.L., Martin, M.P., Qi, Y., Ge, D., O’hUigin, C., Kidd, J., Kidd, K., Khakoo, S.I., Alexander, G., Goedert, J.J., Kirk, G.D., Donfield, S.M., Rosen, H.R., Tobler, L.H., Busch, M.P., McHutchison, J.G., Goldstein, D.L., and Carrington, M.:  Genetic variation in IL28B and spontaneous clearance of hepatitis C virus.  Nature, 461:798-801, 2009.