Ph.D., Department of Immunology and Infectious Diseases
Johns Hopkins University School of Hygiene and Public Health
Office: 430 West Health Sciences Dr.
University of California
Davis, CA 95616
Phone: (530) 754-9266
Fax: (530) 752-5271
Charles B. Stephensen, Ph.D., is a Research Scientist at the USDA Western Human Nutrition Research Center at the University of California, Davis and an Adjunct Professor of Nutrition at U.C. Davis. Dr. Stephensen's research examines how nutrition affects immune function and the risk of infectious or inflammatory disease, and also examines how infectious diseases affect nutritional status. A principal focus of his work is to examine the role of nutrients that act via nuclear receptors (including vitamins A and D, and some fatty acids) in maintaining a healthy immune system. This work currently involves studies in transgenic mice to examine the role of the retinoid X receptor in the normal development and function of T lymphocytes, as well as human studies examining the level of vitamin A stores required for maintaining optimal immune function in humans. His work also involves human studies examining the role of vitamins in treatment or progression of infectious diseases, such as HIV infection, pneumonia and diarrhea. Recent work has examined the effect of HIV infection on nutritional status, particularly antioxidant nutrients and vitamin D. Dr. Stephensen obtained a B.S. degree in Biochemistry at the University of California, Davis, M. S. degree in Human Nutrition at Cornell University and a Ph.D. in Immunology and Infectious Diseases at the Johns Hopkins University School of Hygiene and Public Health in Baltimore, Maryland. He trained as a postdoctoral fellow in Virology at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. Dr. Stephensen was a faculty member in the Department of International Health, School of Public Health at the University of Alabama at Birmingham for 10 years and also served as acting Director of the Sparkman Center for International Public Health Education. In 1998 he moved to the USDA Western Human Nutrition Research Center. Dr. Stephensen is a consulting editor for the American Journal of Clinical Nutrition and has authored >70 scientific publications.
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, Bangladesh.
· 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 US and disproportionately affect African Americans. Inflammation is an integral component of this metabolic syndrome and is mediated, in part, by pro-inflammatory leukotrienes produced from arachadonic acid (AA) via the 5-lipoxygenase (5-LO) pathway. 5-LO is the rate-limiting enzyme in this pathway and is encoded by the gene ALOX5. Naturally occurring variants in the promoter region of the ALOX5 gene appear to cause different levels of expression of 5-LO, and may thus affect an individual’s production of leukotrienes. The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) decrease production of AA-derived leukotrienes by several mechanisms, including direct competition of EPA with AA as an alternate substrate for 5-LO. Dr. Stephensen and collaborators postulate that subjects with variants in the ALOX5 gene promoter may have different responses to dietary intake of DHA and EPA. Subjects with higher expression may have a greater need for the anti-inflammatory benefits of EPA plus DHA. In this study we will determine if subjects with one or two variant ALOX5 alleles have higher ALOX5 gene expression, higher production of AA-derived leukotrienes, and a “better” response to omega-3 supplements than do subjects homozygous for the common allele. Subjects will be African Americans 20 – 59 y of age without serious disease. The study will be a randomized controlled trial with a 6 x 2 design (6 genotypes x EPA/DHA supplement or placebo). The intervention group will receive 3.0 g/d EPA/DHA from highly refined fish oil for 6 wk. An isocaloric amount of refined olive oil will act as the placebo. The study is being done with collaborators from the University of Southern California (Dr. Hooman Allayee) and the Ethnic Health Institute of the Alta-Bates-Summit Medical Center in Oakland (Dr. Frank Staggers).
· 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 US. A principal reason for this disparity is that the skin pigment melanin blocks ultraviolet (UV) light and thus blocks UV-induced dermal synthesis of vitamin D. Subjects with high melanin content thus need more sun exposure to synthesize the same amount of vitamin D than do subjects with lower melanin content. Differences in dietary intake and behaviors affecting sun exposure may also contribute to this disparity. These observations have led to the proposal that dietary requirements for vitamin D should be adjusted for skin pigmentation and individual sun exposure. However, before making such recommendations methods must be developed and validated to quantitatively assess the contribution of sun exposure to vitamin D status in free-living individuals. Such studies have not been performed. To be useful, these methods must be quantitative (e.g., measure Joules of energy in the appropriate UV-B spectrum, 290-320 nm) and thus be able to account for differences in intensity of sunlight due to season, time of day, latitude, altitude and local environmental conditions such as cloud cover. The method must also consider skin pigmentation, use of sunscreen and the area of skin exposed to sunlight. Dr Stephensen’s group is conducting an observational study among free-living volunteers to assess such methods and to determine if assessment of UV-B exposure (using daily diary, weekly or monthly recall, or personal dosimeters) predicts vitamin D status following 4 wk or 8 wk of monitoring. Skin pigmentation and dietary vitamin D intake will also be considered in the analysis. This work is being done in collaboration with Dr. Bruce Hammock (UC Davis), Dr. Michael Kimlin (Queensland University of Technology, Brisbane) and Dr. James Slusser (Colorado State University, Fort Collins; USDA UVB Monitoring Program).
· Risk Of Vitamin D Deficiency in Mothers and Infants in Sacramento. Clinical vitamin D deficiency (rickets) has been diagnosed intermittently in infants and young children at UC Davis Medical Center in Sacramento. At UC Davis and elsewhere the majority of such cases occur in African American infants, where vitamin D status may be poor in the mother due to the inhibitory effects of skin pigmentation on vitamin D synthesis. Prolonged breastfeeding without the use of supplements is also a risk factor. Because routine surveillance for vitamin D status is not carried out in such settings, Dr. Stephensen and Dr. Caroline Chantry (UCD Department of Pediatrics) are conducting a study to determine the prevalence of vitamin D insufficiency and deficiency in infants and their mothers seen at well-baby visits at the UC Davis Department of Pediatrics.
· 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 (University of Alabama at Birmingham) and Dr. Grace Marquis (Iowa State University).
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 Naïve 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 Peru and Bangladesh to examine the interaction of vitamin A with common infectious diseases of childhood. This research found that common infections can directly induce depletion of vitamin A stores via infection-induced urinary loss, and also found that infection can impair assessment of vitamin A status using the relative dose-response test.
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., Campos, M., Colarossi, A., Gilman, R.H., Alvarez, A.O. Assessment of vitamin A status with relative dose-response test in Peruvian Children Recovering from pneumonia. Am. J. Clin. Nutr. 76:1351-7, 2002.
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 Africa, as described in the following manuscript:
Drammeh, B.S., G.S. Marquis, E. Funkhouser, C. Bates, I. Eto, C.B. Stephensen. A randomized, 4-month mango and fat supplementation trial improved vitamin A status among young Gambian children. J. Nutr. 132:3693-9, 2002.
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. U.S. youth in the early stage of HIV disease have low intakes of some micronutrients important for optimal immune function. J Am Diet Assoc. 2004; 104(7): 1095-1101.
Kruzich, LA, Marquis, GS, Wilson, CM, Stephensen, CB. HIV-infected U.S. youth are at high risk of obesity and poor dietary quality: a challenge for improving short- and long-term health outcomes. J Am Dietetics Assoc 2004 Oct; 104(10): 1554-60.
Stephensen, CB, Marquis, GS, Jacob, RA, Kruzich, LA, Douglas, SD, Wilson, CM. Vitamins C and E in Adolescents and Young Adults with HIV Infection. Am. J. Clin. Nutr. 83(4):870-9, 2006.
Stephensen, CB, Marquis, GS, Kruzich, LA, Douglas, SD, Aldrovandi, GM, Wilson, CM. Vitamins D Status in Adolescents and Young Adults with HIV Infection. Am. J. Clin. Nutr. 83(5):1135-41, 2006.
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.
Selected Articles & Patent Applications
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.