Jan A. Moynihan

Does programmed cell death (apoptosis) play a role in the development of multiple organ dysfunction in critically ill patients? a review and a theoretical framework.

Objectives: To critically review the current understanding of the pathophysiologic events leading to the development of secondary multiple organ dysfunction (MODS) in critical illness and to examine the role of apoptosis (programmed cell death) as a mechanism involved in the progression of MODS. Data Sources: Research and review articles published since 1982 on the pathophysiology of MODS, particularly the role of cytokines, reactive oxygen species, heat shock proteins, and apoptosis. Research and review articles on the physiology of apoptosis. Articles include human/animal and in vitro/in vivo studies. Data Extraction: The most prevalent mediating factors of MODS were examined for their potential to induce apoptosis, as reported in the literature. The combination of several of the above factors was also examined in terms of apoptosis‐triggering potential. Data Synthesis: Specific pathophysiologic conditions related to the onset of MODS have been shown to affect apoptotic rates in organ tissue cells and their respective endothelial cells in animal and in vitro models. These conditions include the following: a) increased release of inflammation‐related cytokines; b) increased production of oxygen free radicals associated with ischemia/reperfusion injury and states of low tissue perfusion; c) expression and release of heat shock proteins from tissue cells and the liver; d) elevated glucocorticoid concentrations after adrenal cortex activation; and e) release of bacterial products into the systemic circulation. Conclusion: The most important MODS‐related pathophysiologic conditions known to date have been shown to affect programmed cell death rates in almost all cell types. Organ‐specific cell death involving both parenchymal and microvasculature endothelial cells is conceivably underlying organ dysfunction. The hypothesis that increased apoptotic rates are involved in organ dysfunction may provide a unifying theory for the pathophysiology of MODS.

Sympathetic nervous system modulation of the immune system. III. Alterations in T and B cell proliferation and differentiation in vitro following chemical sympathectomy

Functional changes in lymph node (LN) and spleen lymphocytes were examined following sympathetic denervation of adult mice with 6-hydroxydopamine (6-OHDA). Sympathectomy reduced in vitro proliferation to concanavalin A (ConA) by LN cells and decreased LN Thy-1+ and CD4+ T cells. At the same time, ConA-induced interferon-gamma (IFN-gamma) production was increased, but interleukin-2 (IL-2) production was not altered. After sympathectomy, lipopolysaccharide (LPS)-stimulated proliferation of LN B cells was enhanced, in parallel with an increase in the proportion of sIgM+ cells. LPS-induced polyclonal IgM secretion was decreased, whereas polyclonal IgG secretion was dramatically enhanced. In the spleen, ConA and LPS responsiveness was reduced after sympathectomy, as was IL-2 and IFN-gamma production. The decreased proliferation was not associated with changes in splenic T and B cell populations. The uptake blocker desipramine prevented the 6-OHDA-induced changes in spleen and LN, indicating that these alterations were dependent upon neuronal destruction. These results provide evidence for heterogeneity of sympathetic nervous system regulation of T and B lymphocyte function and for organ-specific influences on immune function.

Mechanisms of stress-induced modulation of immunity

The purpose of this chapter is to discuss the wealth of animal studies of stress-induced modulation of immunity, and to relate our understanding of stress and immunity to clinical populations, particularly cancer patients.

Exposure to conspecific alarm chemosignals alters immune responses in BALB/c mice

Male BALB/cJ mice were exposed for 24 h to odors from donor mice that were either footshocked or undisturbed. Mice exposed to odors from footshocked donors had suppressed splenic IL-2 production following in vitro concanavalin A (Con A) stimulation compared to home cage or apparatus controls. Stress odor exposure also resulted in reduced natural killer (NK) cell cytotoxicity against YAC-1 tumor target cells compared to controls. Stress odor exposure 24 h after intraperitoneal injection of keyhole limpet hemocyanin (KLH) increased IgM and IgG antibody titers relative to the response of home cage or apparatus control animals. These results demonstrate that exposure to olfactory cues from stressed rodents alters both cellular and humoral immune responses. This paradigm may provide an ethnologically appropriate model of psychosocial stress in rodents.

The associations between psychosocial stress and the frequency of illness, and innate and adaptive immune function in children

OBJECTIVE Family processes have a substantial impact on childrens social and emotional well-being, but little is known about the effects of family stress on childrens physical health. To begin to identify potential links between family stress and health in children, we examined associations between specific aspects of family psychosocial stress and the frequency of illnesses in children, measures of innate and adaptive immune function, and human herpesvirus 6 (HHV-6) reactivation. STUDY DESIGN Prospective study of 169 ambulatory school-age children and parents. Parents completed multiple assessments of stress at 7 sequential six-month visits and maintained weekly illness diaries for their children over three years using a thermometer to record fever. Children had blood obtained for HHV-6 and immune function studies at each visit including natural killer (NK) cell function and the percentage of CD4 and CD8 cells associated with immune control of cytomegalovirus (CMV). RESULTS Parental psychiatric symptoms were associated with a higher frequency of illnesses: for each 1 U increase in symptom score children had an increased 1-year rate of total illnesses of 40% (rate ratio, 1.40; 95% CI, 1.06-1.85) and febrile illnesses of 77% (rate ratio, 1.77, 95% CI, 1.00-3.13). Parental psychiatric symptom scores were also associated with enhanced NK cell function (estimate, 0.15; 95% CI, 0.05-0.26) and increased percentages of CD8+CD28-CD57+ cells in the blood of CMV seropositive children (estimate, 2.57; 95% CI, 0.36-4.79). HHV-6 reactivation was not detected. CONCLUSIONS There is an association between specific psychosocial stress exposure and rates of illness and immune function in normally developing children.

Mindfulness-Based Stress Reduction for Older Adults: Effects on Executive Function, Frontal Alpha Asymmetry and Immune Function

Background/Aims: Mindfulness-based stress reduction (MBSR) has enhanced cognition, positive emotion, and immunity in younger and middle-aged samples; its benefits are less well known for older persons. Here we report on a randomized controlled trial of MBSR for older adults and its effects on executive function, left frontal asymmetry of the EEG alpha band, and antibody response. Methods: Older adults (n = 201) were randomized to MBSR or waiting list control. The outcome measures were: the Trail Making Test part B/A (Trails B/A) ratio, a measure of executive function; changes in left frontal alpha asymmetry, an indicator of positive emotions or approach motivation; depression, mindfulness, and perceived stress scores, and the immunoglobulin G response to a protein antigen, a measure of adaptive immunity. Results: MBSR participants had a lower Trails B/A ratio immediately after intervention (p < 0.05); reduced shift to rightward frontal alpha activation after intervention (p = 0.03); higher baseline antibody levels after intervention (p < 0.01), but lower antibody responses 24 weeks after antigen challenge (p < 0.04), and improved mindfulness after intervention (p = 0.023) and at 21 weeks of follow-up (p = 0.006). Conclusions: MBSR produced small but significant changes in executive function, mindfulness, and sustained left frontal alpha asymmetry. The antibody findings at follow-up were unexpected. Further study of the effects of MBSR on immune function should assess changes in antibody responses in comparison to T-cell-mediated effector functions, which decline as a function of age.

Big 5 personality traits and interleukin-6: Evidence for “healthy Neuroticism” in a US population sample

The current study investigated if the Big 5 personality traits predicted interleukin-6 (IL-6) levels in a national sample over the course of 5years. In addition, interactions among the Big 5 were tested to provide a more accurate understanding of how personality traits may influence an inflammatory biomarker. Data included 1054 participants in the Midlife Development in the U.S. (MIDUS) biomarkers subproject. The Big 5 personality traits were assessed in 2005-2006 as part of the main MIDUS survey. Medication use, comorbid conditions, smoking behavior, alcohol use, body mass index, and serum levels of IL-6 were assessed in 2005-2009 as part of the biomarkers subproject. Linear regression analyses examined personality associations with IL-6. A significant Conscientiousness*Neuroticism interaction revealed that those high in both Conscientiousness and Neuroticism had lower circulating IL-6 levels than people with all other configurations of Conscientiousness and Neuroticism. Adjustment for health behaviors diminished the magnitude of this association but did not eliminate it, suggesting that lower comorbid conditions and obesity may partly explain the lower inflammation of those high in both Conscientiousness and Neuroticism. Our findings suggest, consistent with prior speculation, that average to higher levels of Neuroticism can in some cases be associated with health benefits - in this case when it is accompanied by high Conscientiousness. Using personality to identify those at risk may lead to greater personalization in the prevention and remediation of chronic inflammation.

THE ROLE OF THE SYMPATHETIC NERVOUS SYSTEM IN THE MODULATION OF IMMUNE RESPONSES

Publisher Summary Studies of the effects of sympathectomy on immune responses invariably suggest that norepinephrine (NE) and the sympathetic nervous system have important roles in modulation of immune responses. Lymphoid organs, both primary and secondary, are innervated by NE-containing postganglionic sympathetic nerve fibers, as well as a variety of peptidergic fibers. At the light microscopic level, much of the innervation appears to be associated with the vasculature in these organs, although there are always fibers that appear to have no anatomic relationship to blood vessels. Immunocytochemistry of the rodent spleen at the ultrastructural level, using antibodies for tyrosine hydroxylase, has revealed that, in addition to abundant blood vessel and trabecular smooth-muscle innervation, there is direct contact between tyrosine hydroxylase-positive nerve terminals and both lymphocytes and macrophages. The presence of sympathetic nerve terminals near, or in direct contact with, lymphocytes in lymphoid organs, including thymus, spleen, lymph nodes, and bone marrow, and the presence of adrenergic receptors on lymphocytes suggest that sympathetic innervation and the transmitter NE may be important in the modulation of immune responses. Not only does NE affect cytokine production, but it is also likely that some cytokines also regulate NE release both via central nervous system sympathetic responses to circulating cytokines and by interactions with local noradrenergic nerve terminals innervating lymphoid organs and other peripheral target sites where inflammation or immune responses take place.

Decreased herpes simplex viral immunity and enhanced pathogenesis following stressor administration in mice

Mild electric footshock stress was delivered during the dark portion of a 12:12 h light:dark cycle to C57BL/6 female mice that were infected with herpes simplex virus-type 1 (HSV). The studies were designed to correlate viral titer with both humoral and cell-mediated immune responses to HSV infection. Footshock was observed to result in decreased HSV-specific immunity. The numbers of leukocytes in spleens and draining popliteal lymph nodes of footshocked mice were depressed compared to both apparatus control and home cage control mice. A significant suppression of the HSV-specific cytotoxic T lymphocyte (CTL) response was observed in both the spleen and popliteal lymph nodes of footshocked mice. Serum IgM anti-HSV antibody titers were also depressed in footshocked mice. These changes were shown to be correlated with significantly increased viral titers in footshocked mice compared to control mice. These data demonstrate that administration of a relatively mild stressor is associated with depressed HSV-specific cellular and humoral immunity and is associated with increased pathogenicity.

The effects of stress on the development of immunological memory following low-dose antigen priming in mice

Observable stress effects on immune responses may be a function of the quantitative and qualitative characteristics of the stressor, and the outcome measurement of immunity. Further, the effects of stress on humoral immunity, in particular, may be sensitive to the concentrations of antigen used to elicit a response. We have studied the effects of footshock stress during the time of priming with low concentrations of antigen on the secondary response to another low dose of antigen. The secondary humoral immune response of C3H/HeJ mice to the protein antigen keyhole limpet hemocyanin was examined following footshock, exposure to the apparatus without shock, or exposure to the home cage. Footshock reproducibly depressed the IgG anti-KLH response, and the effect on the IgM response was sporadic. Initially, footshock was administered for 7 days before and 7 days after priming with low amounts of antigen. Subsequent studies demonstrated that a single footshock session delivered 24 h after priming could suppress the IgG anti-KLH response.