Charles B. Stephensen, Ph.D., is a Research Scientist at the
Dr. Stephensen's research focuses on the effect of nutrition on immune function, with a particular emphasis on vitamin A, vitamin D and omega-3 fatty acids. Current research projects include the following:
•• Effect of vitamin A and nutrient-binding nuclear receptors on immune function in mice. This project focuses primarily on the effect of vitamin A on T lymphocyte development and function. The approaches used include dietary manipulation of vitamin A status and the use of genetic approaches to disrupt vitamin A-mediated regulation of gene expression in T lymphocytes. The latter approach uses Cre-LoxP technology to disrupt expression of the Rxra and Rxrb genes in T lymphocytes using the promoter of the lck gene to drive expression of the enzyme Cre to disrupt gene expression only in this cell type. Since these genes are required for retinoic acid activity (retinoic acid is the principal vitamin A metabolite involved in regulation of gene expression) this approach essentially produces T lymphocytes that are "deficient" in vitamin A. This approach also affects mediation of gene expression by some other nutrients, including vitamin D. This work is being done in collaboration with Dr. Kent Lloyd of UC Davis.
•• Effect of vitamin A on immune function in Bangladeshi men with low vitamin A stores. The RDA for vitamin A was established based on prevention of night-blindness, a sign of severe vitamin A deficiency. Immune function is also impaired by vitamin A deficiency and Dr. Stephensen and collaborators have conducted a study to determine if men need higher vitamin A stores to maintain normal immune function than they do to prevent night blindness. This work examined various measures of both innate and adaptive immunity, including monocyte and granulocyte function, T-cell function and the response to immunization. This work involved collaboration with Dr. Marjorie Haskell from UC Davis and Dr.'s S.M. Ahmad and Rubhana Raqib from the International Centre for Diarrhoeal Disease Research,
•• Variation in the ALOX5 gene and response to omega-3 fatty acid supplements. Cardiovascular disease, hypertension, diabetes and related metabolic disorders are prevalent in the
•• Assessing the Contribution of Individual Sun Exposure to Vitamin D Status. African Americans are more likely to develop vitamin D deficiency or insufficiency than are other population groups in the
•• Risk Of Vitamin D Deficiency in Mothers and Infants in
•• Trial of Vitamin D Supplementation to Improve Tubular Function and Decrease Bone Turnover in Subjects with HIV Infection Being Treated with Tenofovir. Tenofovir, a nucleotide analogue reverse transcriptase inhibitor (NRTI), is commonly used as part of combination antiretroviral therapy (ART) for adolescents and adults with HIV infection. Its favorable kinetics profile allows it to be dosed once daily, an important aspect of its usefulness in the care of adolescents with HIV. Tenofovir treatment is associated with phosphate wasting in the renal tubule, which can lead to hypophosphatemia. Prolonged hypophosphatemia can lead to decrease in bone mineral density (BMD) and even osteomalacia, which has been seen in patients treated with tenofovir. Many adolescent and young adult patients receiving tenofovir are African American and are thus at risk of vitamin D insufficiency or deficiency. Dr. Stephensen and collaborators postulate that the adverse effects of tenofovir may be more severe in subjects with poor vitamin D status and this randomized, controlled trial will test this hypothesis using a vitamin D intervention. This is a Multi-Center Trial of the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) sponsored by the National Institute of Child Health and Human Development (NICHD) with co-funding from the National Institute of Drug Abuse (NIDA) and the National Institute of Mental Health (NIMH).
•• Antioxidant micronutrients in HIV infection. Antioxidants and other micronutrients with activity in the immune system can affect the progression of chronic inflammatory diseases, including HIV infection. Dr. Stephensen and collaborators conducted a cross-sectional study to evaluate the nutritional status of adolescents and young adults with and without HIV infection. Subjects were enrolled in the Reaching for Excellence in Adolescent Health (REACH) study sponsored by the National Institute of Child Health and Human Development (NICHD). Micronutrients of interest in this study included vitamins A, C, D and E, carotenoids, iron, zinc, copper and selenium. The principal collaborators on this study were Dr. Craig Wilson (
Dr. Stephensen's recent research group has demonstrated that vitamin A and other nutrients that act via the retinoid X receptor (RXR) can directly promote survival of T lymphocytes and development of Th2 memory cells, which mediate immune responses that protect against mucosal and parasitic infections. This work is represented by the following publications:
Stephensen, C.B., Rasooly, R., Jiang, X., Ceddia, M.A., Weaver, C.T., Chandraratna, R.A.S., Bucy, R.P. Vitamin A Enhances in vitro Th2 Development via Retinoid X Receptor Pathway. J Immunol 168:4495-4503, 2002.
Rasooly, R, Schuster, GU, Gregg, JP, Xiao, JH, Chandraratna, RAS, Stephensen, CB. Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Na?ve T Lymphocytes. J Immunol 175(12):7916-7929, 2005.
Stephensen CB, Borowsky AD, Lloyd KC. Disruption of Rxra gene in thymocytes and T lymphocytes modestly alters lymphocyte frequencies, proliferation, survival and T helper type 1/type 2 balance. Immunology. 2007 Apr 13; [Epub ahead of print]
Dr. Stephensen also collaborated with investigators in
Mitra, A.K., Wahed, M.A., Chowdhury, A.K., Stephensen, C.B. Urinary retinol excretion in children with acute watery diarrhoea. J Health Popul Nutr 20:12-17, 2002.
Stephensen, C.B., Franchi, L.M., Hernandez, H.,
Working with collaborators in The Gambia Dr. Stephensen found that use of locally produced dried mangoes could improve the vitamin A status of young children living in rural
Drammeh, B.S., G.S. Marquis, E. Funkhouser, C. Bates,
Dr. Stephensen and collaborators have also shown that adolescent and young adults with HIV infection have poor quality diets and low intake of many micronutrients. Intake and biochemical indicators of vitamin C status were quite good, and selenium status was good as well, but vitamin E status was suboptimal and vitamin D status was very poor in most subjects. These findings are described in the following publications:
Kruzich LA, Marquis GS, Carriquiry AL, Wilson CM, Stephensen CB.
Stephensen, CB, Marquis, GS, Jacob, RA,
Stephensen, CB, Marquis, GS,
Stephensen CB, Marquis GS, Douglas SD, Kruzich LA, Wilson CM. Glutathione, glutathione peroxidase, and selenium status in HIV-positive and HIV-negative adolescents and young adults. Am J Clin Nutr. 2007 Jan;85(1):173-81.
Zunino SJ, Parelman MA, Freytag TL, Stephensen CB, Kelley DS, Mackey BE, Woodhouse LR, Bonnel EL. Effects of dietary strawberry powder on blood lipids and inflammatory markers in obese human subjects. Br J Nutr. 2011 Nov 9:1-10. [Epub ahead of print] PubMed PMID: 22068016.
Stephensen CB, Armstrong P, Newman JW, Pedersen TL, Legault J, Schuster GU, Kelley D, Vikman S, Hartiala J, Nassir R, Seldin MF, Allayee H. ALOX5 gene variants affect eicosanoid production and response to fish oil supplementation. J Lipid Res. 2011 May;52:991-1003.
Sharkar MT, Jou MY, Hossain MB, Lonnerdal B, Stephensen CB, Raqib R. Prenatal zinc supplementation of zinc-adequate rats adversely affects immunity in offspring. J Nutr. 2011 Aug;141:1559-64.
Makhoul Z, Kristal AR, Gulati R, Luick B, Bersamin A, O'Brien D, Hopkins SE, Stephensen CB, Stanhope KL, Havel PJ, Boyer B. Associations of obesity with triglycerides and C-reactive protein are attenuated in adults with high red blood cell eicosapentaenoic and docosahexaenoic acids. Eur J Clin Nutr. 2011 Jul;65:808-17.
Hartiala J, Li D, Conti DV, Vikman S, Patel Y, Tang WH, Brennan ML, Newman JW, Stephensen CB, Armstrong P, Hazen SL, Allayee H. Genetic contribution of the leukotriene pathway to coronary artery disease. Hum Genet. 2011 Jun;129:617-27.
Liang L, Chantry C, Styne DM, Stephensen CB. Prevalence and risk factors for vitamin D deficiency among healthy infants and young children in Sacramento, California. Eur J Pediatr. 2010 Nov;169:1337-44.
Hall LM, Kimlin MG, Aronov PA, Hammock BD, Slusser JR, Woodhouse LR, Stephensen CB. Vitamin D intake needed to maintain target serum 25-hydroxyvitamin D concentrations in participants with low sun exposure and dark skin pigmentation is substantially higher than current recommendations. J Nutr. 2010 Mar;140:542-50.
Eneroth H, El Arifeen S, Persson LA, Lonnerdal B, Hossain MB, Stephensen CB, Ekstrom EC. Maternal multiple micronutrient supplementation has limited impact on micronutrient status of Bangladeshi infants compared with standard iron and folic acid supplementation. J Nutr. 2010 Mar;140:618-24.
Vikman S, Brena RM, Armstrong P, Hartiala J, Stephensen CB, Allayee H. Functional analysis of 5-lipoxygenase promoter repeat variants. Hum Mol Genet. 2009 Dec 1;18:4521-9.
Stephensen CB, Livingston KA. Vitamin supplements and vaccines: maximize benefits, evaluate potential risks. Am J Clin Nutr. 2009 Sep;90:457-8.
Maynard CL, Hatton RD, Helms WS, Oliver JR, Stephensen CB, Weaver CT. Contrasting roles for all-trans retinoic acid in TGF-beta-mediated induction of Foxp3 and Il10 genes in developing regulatory T cells. J Exp Med. 2009 Feb 16;206:343-57.
Ahmad SM, Haskell MJ, Raqib R, Stephensen CB. Markers of innate immune function are associated with vitamin a stores in men. J Nutr. 2009 Feb;139:377-85.
Ahmad SM, Haskell MJ, Raqib R, Stephensen CB. Vitamin A status is associated with T-cell responses in Bangladeshi men. Br J Nutr. 2009 Sep;102:797-802.
Schuster GU, Kenyon NJ, Stephensen CB. Vitamin A deficiency decreases and high dietary vitamin A increases disease severity in the mouse model of asthma. J Immunol. 2008 Feb 1;180:1834-42.
Aronov PA, Hall LM, Dettmer K, Stephensen CB, Hammock BD. Metabolic profiling of major vitamin D metabolites using Diels-Alder derivatization and ultra-performance liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem. 2008 Jul;391:1917-30.
Ahmad SM, Haskell MJ, Raqib R, Stephensen CB. Men with low vitamin A stores respond adequately to primary yellow fever and secondary tetanus toxoid vaccination. J Nutr. 2008 Nov;138:2276-83.