Stress‐Induced Neuroendocrine Modulation of Viral Pathogenesis and Immunity^a

Abstract

Physical restraint (RST) was used to examine the interactions among the hypothalamic-pituitaryadrenal (HFA) axis, sympathetic nervous system, and the immune response to infection. In these studies, mice were infected with either herpes simplex virus (HSV) or influenza A/PR8 virus so that the impact of neuroendocrine activation could be assessed on disease pathophysiology and anti-viral immunity. RST suppressed lymphadenopathy in draining lymph nodes, reduced mononuclear cellular infiltration in the lungs, and suppressed virus-specific cytokine and cytolytic T-cell responses. Blockade of type II glucocorticoid receptors (by RU486) restored cellularity and cytokine responses to both organs in restraint-stressed, infected mice. Thus, the HPA axis modulated cell trafficking and T-cell cytokine responses. However, RU486 treatment failed to restore cytolytic Tcell responses. Blockade of β-adrenergic receptors (by nadolol), in combination with RU486 treatment, fully restored cytolytic T-cell responses, suggesting that catecholamines were involved in suppressing the virus-specific CD8 + cytolytic T-cell response. RST also modulated the local development or expression of antibody-secreting cells (ASC) in the lungs draining lymph nodes, and spleen following infection of restrained mice. RST significantly suppressed the number of virusspecific ASC (IgM, IgG and subclasses IgG1 and IgG2a) in the lungs, mediastinal (MLN) lymph nodes and spleen, while it enhanced the responses in the superficial cervical (SCV) lymph nodes. This observation of differential modulation of ASC responses in the MLN and SCV lymph nodes supports the concept of tissue-specific immunoregulation in response to stress. The host's response to a viral infection is designed to limit the initial spread of the pathogen and then terminate its replication. Innate host mechanisms, such as natural killer (NK) cell activity and proinflammatory cytokines (IL-1, IL-6, and TNF), along with the α and β interferons, function in the early hours of infection to limit the spread of virus. These noncognate responses, however, usually are not sufficient to end viral replication. Therefore, adaptive host responses occur that take days to weeks to mature. These adaptive responses promote the entry of antigen-specific lymphocytes into the cell cycle and result in clonal selection, proliferation, and maturation to the effector stage. Because many viruses are tropic to and replicate in nonlymphoid tissues, effector cells must traffic to the site of virus replication to effectively eliminate the pathogen.

Sympathetic nervous system control of anti-influenza CD8+T cell responses

“…As described by van Endert and colleagues (23), peptide determinants are rapidly liberated from the fusion protein by Ub-hydrolases and behave like cytosolic minigene products. 6-OHDA treatment increased the primary T CD8ϩ response to Ova 257-264 and to the immunodominant VV determinant B8R [20][21][22][23][24][25][26][27] (Fig. 2B).…”

“…Previous studies by Sheridan et al have clearly demonstrated that the nervous system can have an impact on IAV responses (reviewed in ref. 20). In the present study, we address the role of the SNS in the generation of CD8 ϩ T cell (T CD8ϩ ) responses to viruses by investigating the effects of 6-OHDA treatment on well-defined mouse T CD8ϩ responses to viral and tumor antigens.…”

Stress, ageing and their influence on functional, cellular and molecular aspects of the immune system

“…Similar results were obtained after exposing rats to chronic restraint stress, whereas the administration of propanolol, a β-blocker, diminishes this effect (Hara et al 2013). Finally, the mutual action of GC and catecholamines (CA) during chronic restraint stress will simultaneously affect migration of mononuclear cells in the peripheral blood of a specific mouse strain (Hermann et al 1995), largely reduce cytokine expression from the lymph nodes and spleen (Dobbs et al 1996), delay cytokine gene transcription in the lungs and lymph nodes (Sheridan et al 1998), as well as diminish activation of cytotoxic T lymphocytes in the lymph nodes (Dobbs et al 1993;Sheridan et al 1998). However, it was also shown that chronic stressinduced changes in the concentrations of GC alone can have different effects on different pro-inflammatory cytokines, TNF-α, IL-1β and IL-6 (DeRijk et al 1997).…”

Lymphocyte reduction induced by hindlimb unloading: distinct mechanisms in the spleen and thymus

“…Numerous studies have shown that exhausting physical activity and severe environmental and/or psychological stress have strong suppressive effects on the immune system [12]. Such suppression has significant implications for the susceptibility onset, course, and outcome of diseases such as cancer [13][14][15], autoimmunity [15,16] and infections [15,17].…”

“…The immuosuppression resulting from chronic stress is due in part to a reduction in lymphocyte numbers [20][21][22]. Consequently, stress-induced lymphopenia has been observed in surgical patients [23], over-exercised athletes [24], persons under various psychological stresses [25,26], and animals subjected to physical restraint [15,27]. While several immune effects have been shown to be associated with stress, the exact mechanisms remain to be elucidated, especially in different organs of the immune system.…”