Loma Linda University

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Denise Bellinger, PhD
Assoc Res Prof, Pathology and Human Anatomy
School of Medicine
Publications    Book Review - Scholarly Journals--Published
  • Perez SD, Kozic B, Molinaro C, ThyagaRagan S, Ghamsary M, Lubahn C, Lorton D, Bellinger DL. Chronically Lowering Sympathetic Activity Protects Sympathetic Nerves in the F344 Rat Spleen from an Age-Related Decline.  J. Neuroimmunol. Aug. 2011. Submitted.  ( 8/2011 )
  • ThyagaRajan S, Madden KS, Teruya B, Stevens SY, Felten DL, Bellinger DL. Age-associated alterations in sympathetic noradrenergic innervation of primary and secondary lymphoid organs in female Fischer 344 rats. J Neuroimmunol. 2011. 230, 85-94. ( 5/2008 - 1/2011 )
  Scholarly Journals--Submitted
  • Lorton D, Bellinger DL, Schaller JA , Osredkar T, Shewmacker E, Lubahn C. 2011. Altered Sympathetic-to-Immune Cell Signaling via Beta2-Adrenergic Receptors in Adjuvant Arthritis. Brain Behav. Immun. Submitted. ( 9/2011 )
  • Lubahn C, Schaller JA, Eric Shewmacker E, Wood C, Carter J, Bellinger DL, Byron D, Melody N, George R. Pettit GR, Lorton D. Preclinical Efficacy of Sodium Narcistatin to Reduce Inflammation and Joint Destruction in Rats with Adjuvant-Induced Arthritis. JPET.  Sept. 2011. Submitted. ( 8/2011 )
  Scholarly Journals--Published
  • ThyagaRajan S, Madden KS, Teruya B, Stevens SY, Felten DL, Bellinger DL. 2011. Age-associated alterations in sympathetic noradrenergic innervation of primary and secondary lymphoid organs in female Fischer 344 rats. J Neuroimmunol. 233, 54-64. ( 12/2010 - 12/2011 )
  • Carter JL, Lubahn C, Lorton D, Osredkar T, Der TC, Schaller J, Evelsizer S, Flowers S, Ruff N, Reese B, , Bellinger DL. Adjuvant-Induced Arthritis Induces c-Fos Chronically in Neurons in the Hippocampus. J Neuroimmunol. 2011. 230, 85-94. ( 10/2010 - 10/2011 )
  • Perez SD, Silva D, Millar AB, Molinaro CA, Carter J, Bassett K, Lorton D, Garcia P, Tan L, Gross J, Lubahn C, Thyagarajan S, Bellinger DL. Sympathetic innervation of the spleen in male Brown Norway rats: a longitudinal aging study. Brain Res. 2009 Dec 11;1302:106-17. ( 12/2009 )
  • Lee JW, Morton KR, Walters J, Bellinger DL, Butler TL, Wilson C, Walsh E, Ellison CG, McKenzie MM, Fraser GE. Cohort profile: The biopsychosocial religion  and health study (BRHS). Int J Epidemiol. 2009 Dec;38(6):1470-8. ( 12/2009 )
  • Mastroeni D, Grover A, Leonard B, Joyce JN, Coleman PD, Kozik B, Bellinger DL, Rogers J. Microglial responses to dopamine in a cell culture model of Parkinson''s disease. Neurobiol Aging. 2009 Nov;30(11):1805-17. ( 11/2009 )
  • Lorton D, Lubahn C, Sweeney S, Major A, Lindquist CA, Schaller J, Washington C, Bellinger DL. Differences in the injury/sprouting response of splenic noradrenergic nerves in Lewis rats with adjuvant-induced arthritis compared with rats treated with 6-hydroxydopamine. Brain Behav Immun. 2009 Feb;23(2):276-85. ( 2/2009 )
  • Bellinger DL, Lubahn C, Lorton D. Maternal and early life stress effects on immune function: relevance to immunotoxicology. J Immunotoxicol. 2008 Oct;5(4):419-44. ( 10/2008 )
  • Bellinger DL, Silva D, Millar AB, Molinaro C, Ghamsary M, Carter J, Perez S, Lorton D, Lubahn C, Araujoa G, Thyagarajan S. Sympathetic nervous system and lymphocyte proliferation in the Fischer 344 rat spleen: a longitudinal study. Neuroimmunomodulation. 2008;15(4-6):260-71. ( 6/2008 )
  • Bellinger DL, Millar BA, Perez S, Carter J, Wood C, ThyagaRajan S, Molinaro C, Lubahn C, Lorton D. Sympathetic modulation of immunity: relevance to disease. Cell Immunol. 2008 Mar-Apr;252(1-2):27-56. ( 3/2008 - 4/2008 )
  • Makris S, Rooney A, Bellinger DL, Kobzik L, Holliday S, Dietert RR, Yang YG. "Current issues in developmental immunotoxicology." Toxicological Sciences 100. (2007): In Press-. ( 1/2007 )
  • Bellinger DL, Millar BA, Perez S, Carter JL, Wood C, ThyagaRajan S, Molinaro C, Lubahn C, Lorton D. . "Sympathetic Modulation of Immunity: Relevane to Disease.." Cellular Immunology 247. (2007): In Press-. ( 1/2007 )
  • Lorton D, Lubahn CL, Estus C, Millar BA, Carter JL, Wood CA, Bellinger DL. 2006. Bidirectional communication between the brain and the immune system: Implications for physiological sleep and disorders with disrupted sleep. NeuroImmunoModulation 13, 357-374. ( 8/2006 ) Link...
    This review describes mechanisms of immune-to-brain and brain-to-immune signaling involved in mediating physiological sleep and altered sleep with disease. The central nervous system (CNS) modulates immune function by signaling target cells of the immune system through autonomic and neuroendocrine pathways. Neurotransmitters and hormones produced and released by these pathways interact with immune cells to alter immune functions, including cytokine production. Cytokines produced by cells of the immune and nervous systems regulate sleep. Cytokines released by immune cells, particularly interleukin-1beta and tumor necrosis factor-alpha, signal neuroendocrine, autonomic, limbic and cortical areas of the CNS to affect neural activity and modify behaviors (including sleep), hormone release and autonomic function. In this manner, immune cells function as a sense organ, informing the CNS of peripheral events related to infection and injury. Equally important, homeostatic mechanisms, involving all levels of the neuroaxis, are needed, not only to turn off the immune response after a pathogen is cleared or tissue repair is completed, but also to restore and regulate natural diurnal fluctuations in cytokine production and sleep. The immune system''s ability to affect behavior has important implications for understanding normal and pathological sleep. Sleep disorders are commonly associated with chronic inflammatory diseases and chronic age- or stress-related disorders. The best studied are rheumatoid arthritis, fibromyalgia and chronic fatigue syndromes. This article reviews our current understanding of neuroimmune interactions in normal sleep and sleep deprivation, and the influence of these interactions on selected disorders characterized by pathological sleep.
  • Bellinger DL, Wood C, ThyagaRajan S, Molinaro C, Lubahn C, Lorton D. . "Innervation of lymphoid organs: clinical implications." Clinical Neuroscience Research 6. (2006): 3-33. ( 8/2006 )
  • Lorton D, Lubahn CL, Estus C, Millar BA, Carter JL, Wood CA, Bellinger DL. "Bidirectional communication between the brain and the immune system: implications for physiological sleep and disorders with disrupted sleep." Neuroimmunomodulation 13.5-6 (2006): 357-374. ( 8/2006 )
    This review describes mechanisms of immune-to-brain and brain-to-immune signaling involved in mediating physiological sleep and altered sleep with disease. The central nervous system (CNS) modulates immune function by signaling target cells of the immune system through autonomic and neuroendocrine pathways. Neurotransmitters and hormones produced and released by these pathways interact with immune cells to alter immune functions, including cytokine production. Cytokines produced by cells of the immune and nervous systems regulate sleep. Cytokines released by immune cells, particularly interleukin-1beta and tumor necrosis factor-alpha, signal neuroendocrine, autonomic, limbic and cortical areas of the CNS to affect neural activity and modify behaviors (including sleep), hormone release and autonomic function. In this manner, immune cells function as a sense organ, informing the CNS of peripheral events related to infection and injury. Equally important, homeostatic mechanisms, involving all levels of the neuroaxis, are needed, not only to turn off the immune response after a pathogen is cleared or tissue repair is completed, but also to restore and regulate natural diurnal fluctuations in cytokine production and sleep. The immune system's ability to affect behavior has important implications for understanding normal and pathological sleep. Sleep disorders are commonly associated with chronic inflammatory diseases and chronic age- or stress-related disorders. The best studied are rheumatoid arthritis, fibromyalgia and chronic fatigue syndromes. This article reviews our current understanding of neuroimmune interactions in normal sleep and sleep deprivation, and the influence of these interactions on selected disorders characterized by pathological sleep.
  • Lorton D, Lubahn CL, Estus C, Millar BA, Carter JL, Wood C, Bellinger DL. "Bidirectional communication between the brain and the immune system: implications for physiological sleep and disorders with disrupted sleep.." NeuroImmunoModulation 13. (2006): 357-374. ( 1/2006 )
  • Lorton D, Lubahn CL, Estus C, Millr BA, Carter JL, Wood CA, Bellinger DL. "Bidirectional communication between the brain and the immune system: implications for physiological sleep and disorders with disrupted sleep." NeuroImmunoModulation 13. (2006): 357-374. ( 1/2006 ) Link...
    This review describes mechanisms of immune-to-brain and brain-to-immune signaling involved in mediating physiological sleep and altered sleep with disease. The central nervous system (CNS) modulates immune function by signaling target cells of the immune system through autonomic and neuroendocrine pathways. Neurotransmitters and hormones produced and released by these pathways interact with immune cells to alter immune functions, including cytokine production. Cytokines produced by cells of the immune and nervous systems regulate sleep. Cytokines released by immune cells, particularly interleukin-1beta and tumor necrosis factor-alpha, signal neuroendocrine, autonomic, limbic and cortical areas of the CNS to affect neural activity and modify behaviors (including sleep), hormone release and autonomic function. In this manner, immune cells function as a sense organ, informing the CNS of peripheral events related to infection and injury. Equally important, homeostatic mechanisms, involving all levels of the neuroaxis, are needed, not only to turn off the immune response after a pathogen is cleared or tissue repair is completed, but also to restore and regulate natural diurnal fluctuations in cytokine production and sleep. The immune system's ability to affect behavior has important implications for understanding normal and pathological sleep. Sleep disorders are commonly associated with chronic inflammatory diseases and chronic age- or stress-related disorders. The best studied are rheumatoid arthritis, fibromyalgia and chronic fatigue syndromes. This article reviews our current understanding of neuroimmune interactions in normal sleep and sleep deprivation, and the influence of these interactions on selected disorders characterized by pathological sleep. Copyright (c) 2006 S. Karger AG, Basel.
  • Denise L. Bellinger, Brooke A. Millar, Sam Perez, Jeff Carter, Carlo Wood, Srinivasan ThyagaRajan, Christine Molinaro, Cheri Lubahn and Dianne Lorton. "Innervation of lymphoid organs: Clinical implications ." Clinical Neuroscience Research 6.1-2 (2006): 3-33. ( 1/2006 )
    Host defense against pathogens is regulated by cross-talk between two major adaptive systems of the body?the nervous and immune systems. This bidirectional communication is essential for maintaining homeostasis. Sympathetic nerves that innervate lymphoid tissues provide one of the major outflows from the brain to regulate tissue repair and host defense. This review focuses on the role of (sympathetic nervous system) SNS in neuroimmune regulation, an area that has received much less attention than the other major immunoregulatory pathway, the hypothalamo?pituitary?adrenal (HPA) axis. Research over the past 25 years has demonstrated that norepinephrine (NE) fulfills the criteria for neurotransmission in lymphoid tissue, with both primary and secondary immune organs receiving an extensive supply of sympathetic nerves that directly contact with immunocytes. Under stimulation, NE released from terminals in secondary lymphoid organs interacts with adrenergic receptors (AR) expressed on immune cells to affect the development, trafficking, circulation, proliferation, cytokine production, and the functional activity of variety of lymphoid and myeloid cells. Our knowledge of the role of sympathetic nerves in modulating hematopoietic functions of primary lymphoid organs (bone marrow and thymus) and mucosal immunity are extremely limited. While the immune system is not absolutely dependent upon signals from the brain to function, sympathetic-immune modulation may drive host defense toward protection against, or progression toward, immune-related diseases. Additionally, signals from the (SNS) may enhance immune readiness during disease- or injury-induced ?fight-or-flight? responses. A better understanding of neural?immune interactions may foster the development of strategies for treating immune-mediated diseases, particularly where neuroimmune cross-talk may be dysregulated.
  • Lorton, D, Lubahn, CL, Zautra, AJ, and Bellinger, DL. "Proinflammatory Cytokines and Sickness Behavior in Rheumatic Diseases.." Current Pharmaceutical Design . (2006): in press-. ( 1/2006 )
  • Lorton D, Lubahn C, Lindquist CA, Schaller J, Washington C, Bellinger DL. "Changes in the density and distribution of sympathetic nerves in spleens from Lewis rats with adjuvant-induced arthritis suggest that an injury and sprouting response occurs." J Comp Neurol 489.2 (2005): 260-273. ( 8/2005 )
    Previously we demonstrated reduced norepinephrine concentrations in spleens from Lewis rats with adjuvant-induced arthritis (AA), an animal model of rheumatoid arthritis. This study extends these findings, examining the anatomical localization and density of sympathetic nerves in the spleen with disease development. Noradrenergic (NA) innervation in spleens of Lewis rats was examined 28 days following adjuvant treatment to induce arthritis or vehicle for the adjuvant by using fluorescence histochemistry for catecholamines, with morphometric analysis and immunocytochemistry for tyrosine hydroxylase. In AA rats, sympathetic nerve density in the hilar regions, where NA nerves enter the spleen, was increased twofold over that observed in vehicle-treated rats. In contrast, there was a striking twofold decline in the density of NA nerves in splenic regions distal to the hilus in arthritic rats compared with nonarthritic rats. In both treatment groups, NA nerves distributed to central arterioles, white pulp regions, trabeculae, and capsule. However, NA nerve density was reduced in the white pulp but was increased in the red pulp in AA rats compared with non-AA rats. These findings indicate an injury/sprouting response with disease development whereby NA nerves die back in distal regions and undergo a compensatory sprouting response in the hilus. The redistribution of NA nerves from white pulp to red pulp suggests that these nerves signal activated immune cells localized in the red pulp in AA. Although the mechanisms of this redistribution of NA nerves into the red pulp are not known, it may be due to migration from white pulp to red pulp of target immune cells that provide trophic support for these nerves. The redistribution of NA nerves into the red pulp may be critical in modulating immune functions that contribute to the chronic inflammatory stages of arthritis.
  • Lorton D, Lubahn CL, Zautra A, Bellinger DL.. "Proinflammatory cytokines and psychological well-being in rheumatic diseases." Curr Drug Targets . (2005): in press-. ( 2/2005 )
  • Lubahn CL, Schaller JA, Bellinger DL, Sweeney S, Lorton D. "The importance of timing of adrenergic drug delivery in relation to the induction and onset of adjuvant-induced arthritis." Brain Behav Immun 18.6 (2004): 563-571. ( 11/2004 ) Link...
    Stressful events often precede onset and exacerbate established rheumatic diseases. There are numerous reports of abnormal autonomic function in rheumatoid arthritis (RA) patients. Targeting the sympathetic nervous system (SNS) with adrenergic receptor (AR) drugs in RA patients and animal models of the disease have revealed mixed results, with treatments inhibiting and exacerbating disease pathology. We tested the hypothesis that variability in disease outcome following adrenergic drug treatment is due to different roles played by the SNS at different disease stages. The contribution of beta2- and alpha-AR subtypes to disease pathology was studied at different disease stages in adjuvant-induced arthritis (AA), an animal model of RA. Lewis rats were given twice-daily intraperitoneal (i.p.) injections of an alpha-AR antagonist (phentolamine: 500 microg/kg) or a beta2-AR agonist (terbutaline: 1200 microg/day), initiated at adjuvant challenge or disease onset, and continued through severe disease. Both adrenergic therapies, when initiated at adjuvant challenge exacerbated disease pathology. In contrast, SH1293, an adrenergic drug that targets both alpha- and beta-AR (300 microg/day; twice-daily), initiated at adjuvant challenge did not exacerbate disease severity. Additionally, the same treatment regimen of phentolamine, terbutaline or SH1293 initiated at disease onset attenuated joint-inflammation and dramatically reduced bone destruction in the arthritic hind limbs. These data support the SNS playing different roles in disease pathology preclinically and after disease onset. Given current drug therapies are not effective in preventing bone destruction, these data support using adrenergic drugs as bone sparing treatments in RA.
  • Makris S, Rooney A, Bellinger DL, Kobzik L, Holladay S, Dietert RR, Yang YG. "Current Issues in Developmental Toxicology." Toxicological Sciences . (1969): -. (*)
  Books and Chapters
  • Lorton D, Lubahn CL, Estus C, and Bellinger DL. Bidirectional Communication between the Brain and the Immune System: Implications for Physiological Sleep and Disorders with Disrupted Sleep . Handbook of Neurochemistry and Molecular Neurobiology: Springer-Verlag Berlin Heidelberg, 2008. 3 - 38 ( 1/2008 )
  • Bellinger DL, Lubahn C, Millar BA, Carter JL, Vyas S, Perez S, Lorton D.. Age-related alterations in autonomic nervous system innervation of lymphoid tissues. In: Handbook of Neurochemistry and Molecular Neurobiology. Eds. Lajtha A, Reith MEA.. New York, NY: Springer Science + Business Media, LLC, 2007. In Press ( 1/2007 )
  • Lorton D , Lubahn CL, Estus C and Bellinger DL . Bidirectional Communication Between the Brain and the Immune System: Implications for Physiological Sleep and Disorders with Disrupted Sleep. Neuroimmunology of Sleep; Eds. SR Pandi-Perumal, DP Cardinali, and GP Chrousos: , 2006. in press ( 1/2006 )
  • Bellinger DL, ThyagaRajan S, Damjanovic AK, Millar B, Lubahn C, and Lorton D. Immunotoxicology and Immunopharmacology, Third Edition. An Overview of Neural-Immune Communication in Development, Adulthood, and Aging: CRC Press, 2006. 490 - 507 ( 1/2006 )
  • Bellinger DL, Lubahn CL, and Lorton D. Age-Related Alterations in Autonomic Nervous System Innervation of Lymphoid Tissue . Handbook of Neurochemistry and Molecular Neurobiology, Third Edition, Ed. A. Lajtha.: Springer, 2006. in press ( 1/2006 )
  • Bellinger D.L, ThyagaRajan S, Damjanovic AK, Millar B, Lubahn C, Lorton D.. An Overview of Neural-Immune Communication in Development, Adulthood, and Aging. In: Immunopharmacology & Immunotoxicology, 3rd Edition, R Luebke, R House and I Kimber (Eds).. Asterdam: Elsevier, 2005. in press ( 7/2005 )
  • Bellinger DL, Madden KS, Lorton D. Age-related alterations in autonomic nervous innervation. In: The Neuroendocrine Immune Network in Ageing: RH Straub, E Mocchegiani (Eds.). Elsevier: Amsterdam, 2004. 233 - 255 ( 10/2004 )
  • Bellinger, D. L., ThyagaRajan, S.,Damjanovic, A. K., Millar, B., Lubahn, C. and Lorton, D. An Overview of Neural-Immune Communication in Development, Adulthood, and Aging.Third Ed. Immunotoxicology & Immunopharmacology, Ed. Robert Leubke. : Elsevier, . in press (*)