Maintenance of a proper balance between inflammatory and anti-inflammatory responses is crucial for effective immunity against infectious pathogens while repressing the development of autoimmunity. The immunoregulatory cytokines IFN-gamma and IL-10 play fundamental roles in this complex process. Studies document that levels of IFN-gamma and IL-10 are linked with susceptibility to autoimmune and infectious diseases. Those data have been confirmed in both IFN-gamma and IL-10 deficient mice. A key to understanding this delicate balance is by evaluating the molecular and biochemical mechanisms that govern the expression of these genes. Remarkably, these processes remain poorly understood. Further complicating the issue is the exciting prospect that allelic variants in the genome are likely to regulate disease susceptibility and resistance by influencing the level of expression of a particular gene or gene cluster. The identification of single nucleotide polymorphisms (SNPs) in cytokine/cytokine receptor genes is a common theme in the literature yet only a few of these SNPs have been partially characterized in function. My research is aimed at bridging the gap between genetic polymorphism and biological function. I believe this requires a bilateral approach. Accordingly, my work addresses the basic mechanisms of IFN-gamma and IL-10 gene expression and the application of these data to allelic variation.

The identification of genetic variants may serve as both markers for disease susceptibility and ultimately as targets for therapeutic intervention. There is however, a bottleneck between genetic haplotypes and the characterization of physiological/immunological mechanisms that mediate complex disease phenotypes. Thus, the broad goals of my research program include: (1) elucidating the molecular mechanisms of cell- and signal-specific IL-10 gene regulation, (2) compare and contrast the regulatory mechanisms that control IL-10 and IFN-gamma gene regulation, and (3) utilize functional genomics to investigate the translation of genetics and disease association data into a mechanistic and functional immunologic context.

cytokine, gene regulation, transgenic, polymorphism, SNP, flow cytometry, immunology, immune monitoring, inflammation

2005 & 2006 - Yang Memorial Scholar

Yao, Z, Cui, Y, Watford, W., Bream, J. H., Yamaoka, K., Hissong, B., Li, D., Durum, S., Jiang, Q., Bhandoola, A., Hennighausen, L., O’Shea, J.J. Stat5a/b are essential for normal lymphoid development and differentiation. Proceedings of the National Academy of Science 103 (4): 1000-1005, 2006.

Kouriba, B., Chevillard, C., Bream, J. H., Argiro, L., Dessein, H., Arnaud, V., Sangare, L., Dabo, A., Beavogui, A. H., Arama, C., Traoré, H. A., Doumbo, O., Dessein, A. Analysis of the 5q31-q33 locus shows an association between IL13-1055C/T IL13591A/G polymorphisms and Schistosoma haematobium infections. Journal of Immunology 174 (10): 6274-6281, 2005.

Watford, W.T., Hissong, B.D., Bream, J. H., Kanno, Y., Muul, L., O'Shea, J.J. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunological Reviews 202: 139-156, 2004.

Bream, J. H., Hodge, D. L., Gonsky, R., Morinobu, A., Krebs, S., Targan, S., O’Shea, J. J., Young, H. A. A distal region of the IFN-gamma gene is a site of chromatin remodeling and transcriptional regulation by IL-2. Journal of Biological Chemistry 279 (39): 41249-41257, 2004.

Albright, J. W., Bream, J. H., Bere, E. W., Young, H. A., Winkler-Picket, R., Ortaldo, J. R. Aging of innate immunity: Functional comparisons of NK/LAK cells obtained from bulk cultures of young and aged mouse spleen cells in high concentrations of IL-2. Experimental Gerontology 39 (1): 73-82, 2004.

Chevillard, C., Moukoko, C., Elwali, N., Bream, J. H., Kouriba, B., Argiro L., Rahoud, S., Mergani, A., Henri, S., Gaudart, J., Mohamed-Ali, Q., Young, H. A., Dessein A. J. Interferon gamma polymorphisms (IFN-gamma +2109, and IFN-gamma +3810) are associated with severe hepatic fibrosis in human Schistosomiasis (Schistosoma mansoni). Journal of Immunology 171 (10): 5596-5601, 2003.

Bream, J. H., Curiel, R. E., Yu, C. R., Egwuagu, C. E., Grusby, M. J., Aune, T. A., Young, H. A. IL-4 synergistically enhances both IL-2- and IL-12-induced IFN-gamma expression in murine NK cells. Blood 102 (1): 207-214, 2003.

Agnello, D., Lankford, C. S. R., Bream, J., Morinobu, A., Gadina, M., O’Shea, J. J., Fruct, D. M. Cytokines and transcription factors that regulate T helper cell differentiation: New players and new insights. Journal of Clinical Immunology 23 (3): 147-161, 2003.

Bream, J. H., Ping, A. Winkler, C., Zhang, X., Young, H. A. A single nucleotide polymorphism in the proximal IFN-gamma promoter alters control of gene transcription. Genes and Immunity (3): 165-169, 2002.

El-Omar, E. M., Carrington, M., Chow, W. H., McColl, K. E., Bream, J. H., Young, H. A., Herrera, J., Lissowska, J., Yuan, C. C., Rothman, N., Lanyon, G., Martin, M., Fraumeni, J. F., Rabkin, C. S. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404 (6776): 398-402, 2000.

Shin, H. D., Winkler, C., Stephens, J. C., Bream, J., Young, H. A., Goedert, J. J., O’Brien, T. R., Vlahov, D., Buchbinder, S., Giorgi, J., Rinaldo, C., Donfield, S., Willoughby, A., O’Brien, S. J., Smith, M. W. Genetic restriction of HIV-1 infection and AIDS by promoter alleles of Interleukin 10. Proceedings of the National Academy of Science 97 (26): 14467-14472, 2000.

Bream, J. H., Young, H. A., Rice, N., Martin, M.P., Smith, M.W., Carrington, M., O’Brien, S. J. CCR5 promoter alleles and specific DNA binding factors. Science 284: 223a, 1999.