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Social stress enhances sympathetic innervation of primate lymph nodes: Mechanisms and implications for viral pathogenesis

Department of Psychology, University of California, Davis, Davis, California, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 09/2007; 27(33):8857-65. DOI: 10.1523/JNEUROSCI.1247-07.2007
Source: PubMed

ABSTRACT Behavioral processes regulate immune system function in part via direct sympathetic innervation of lymphoid organs, but little is known about the factors that regulate the architecture of neural fibers in lymphoid tissues. In the present study, we find that experimentally imposed social stress can enhance the density of catecholaminergic neural fibers within axillary lymph nodes from adult rhesus macaques. This effect is linked to increased transcription of the key sympathetic neurotrophin nerve growth factor and occurs predominately in extrafollicular regions of the paracortex that contain T-lymphocytes and macrophages. Functional consequences of stress-induced increases in innervation density include reduced type I interferon response to viral infection and increased replication of the simian immunodeficiency virus. These data reveal a surprising degree of behaviorally induced plasticity in the structure of lymphoid innervation and define a novel pathway by which social factors can modulate immune response and viral pathogenesis.

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    • "For example, recent studies have found that both a general tendency to be unsociable and exposure to 3 weeks of social instability upregulate expression of the gene that codes for nerve growth factor beta (NGF) in rhesus macaque lymph nodes (Sloan et al., 2007; Sloan et al., 2008). This is critical because upregulated NGF expression has been associated with reduced antiviral immune response gene expression in leukocytes , which increases an organism's vulnerability to viral infection (Collado-Hidalgo et al., 2006; Sloan et al., 2007). These dynamics have also been shown to trigger increased arborization of sympathetic nervous system fibers in the lymph node, which expands the regulatory pipeline from the brain to the immune system, making local leukocyte immune response gene and NGF transcription increasingly sensitive to social-environmental input. "
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    • "Figure 6 provides a theoretical model that integrates existing results from human clinical studies relating SNS activity to indicators of HIV-1 pathogenesis (Ironson et al., in press), in vitro analyses of catecholamine effects on HIV- 1 replication (Cole et al., 1998; Cole et al., 1999; Collado et al., 2006;), and experimental analyses of the SIV lymphoid tissue model in vivo (Sloan et al., 2007). SNS activity is hypothesized to enhance viral replication by inhibiting the activity of Type I interferons (Collado et al., 2006; Sloan et al., 2007;), which increases viral replication through multiple mechanisms including impaired resistance to viral gene expression (via inhibition of the interferon-mediated antiviral state) (Collado et al., 2006) and enhanced cellular vulnerability to infection (via disinhibited expression of the viral coreceptors CCR5 and CXCR4, which occurs under physiologic conditions (Zang et al., 2001), but not in artificially stimulated cells (Yang et al., 2001). In conjunction with immune activation (e.g., via proinflammatory cytokines or ligation of the T cell receptor), these factors. "
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    • "At the level of gene regulation, the CTRA profile underscores the fact that stress is not broadly immunosuppressive, but instead selectively suppresses some groups of immune response genes (e.g., Type I interferons and some immunoglobulin genes) while simultaneously activating others (e.g., pro-inflammatory cytokines) (Irwin and Cole, 2011). Adverse social conditions can also regulate gene expression in a wide variety of other tissues besides circulating leukocytes, including the central nervous system (Karelina et al., 2009; Karssen et al., 2007; Weaver et al., 2006) and peripheral lymphoid organs such as the lymph nodes and spleen (Cole et al., 2010; Sloan et al., 2007). Given the much smaller number of social genomics analyses targeting solid tissues, and the relative difficulty in ascertaining the functional significance of specific transcriptional alterations outside the well-charted territories of immune response, it is not yet clear what specific ''gene programs'' are being activated in these other tissue contexts (e.g., are these tissue ''defensive programs'' analogous to the leukocyte CTRA, or do they represent some other type of functional adaptation specific to the organ system involved?). "
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