Psychoneuroimmunology: the example of psoriasis.

The relationship between the central nervous system (CNS) and the endocrine system have been known for many years. Indeed some of the hormone secreting glands are actually located in the brain. The notion that the CNS and hormones are also involved in the bi-directional cross-talk with the Immune System has been the target of intense research in the recent decades. In this manner, for example, psychological states can be closely related to changes in immune mediators, and not only they may influence the evolution of human diseases, but may in the future lead to novel therapeutic interventions. This is the subject of this review, with particular emphasis on the role of psychoneuroimmunology (PNI) in psoriasis.

Moderate exercise is associated with enhanced antigen-specific cytokine, but not IgM antibody production in aged mice.

It has been suggested that moderate exercise may modulate the immune response in the elderly. We investigated whether moderate exercise had an effect on the immune response to viral infection in both young (2-4 months) and older (16-18 months) male BALB/cJ mice. Exercised (EX) mice ran on a treadmill for 8 weeks at a gradually increasing speed and duration whereas control (CON) mice were only handled briefly during each exercise session and then returned to their cages. Mice were infected with herpes simplex virus type 1 (HSV-1) 24 h post-exercise. Serum IgM anti-HSV antibody, HSV-1 specific Th1/Th2 cytokine production by spleen cells, and cytokine production by alveolar cells were measured 7 days post-infection. In the aged mice, exercise was associated with an enhanced production of the HSV-1 specific Th1-associated cytokines, interleukin (IL)-2 and interferon (IFN)-gamma, but had no effect on the Th2-associated cytokine IL-10 or IgM antibody. No effect of exercise was observed in young mice. IL-12 production was not altered by exercise, but aging was associated with altered IL-12 production in a tissue-specific manner. In conclusion, moderate exercise was associated with increased antigen-specific IL-2 and IFN-gamma production in response to viral challenge in older mice.

Immune deviation following stress odor exposure: role of endogenous opioids.

Olfactory cues can alter immune function. BALB/c mice exposed to odors produced by footshock stressed donor mice have increased antibody responses and increased splenic interleukin (IL)-4 production following immunization relative to recipients of odors from unstressed animals. Here we document that exposure to stress odors results in analgesia that is blocked by the non-selective opioid receptor antagonist naltrexone. The stress odor-induced increase in antigen-driven IL-4 and antibody is also blocked by oral administration of naltrexone. Thus, we provide evidence that immune deviation can occur following a psychosocial stressor, and that the deviation appears to be mediated by endogenous opioid production.

Alterations in interleukin-4 and antibody production following pheromone exposure: role of glucocorticoids.

We have previously shown that exposure to pheromones from footshock-stressed mice suppresses cell-mediated immunity and enhances humoral immunity. Here we show that stress odor exposure is associated with enhanced antigen-specific antibody production and interleukin (IL)-4 production in BALB/c, but not C57Bl/6, mice. Glucocorticoid receptor antagonism blocks the enhancement of IL-4, but not antibody titers. There is an apparent differential sensitivity of BALB/c and C57Bl/6 spleen cells to in vitro incubation with the synthetic glucocorticoid dexamethasone; IL-2 production by BALB/c spleen cells is more sensitive to the effects of steroid. These data suggest that C57Bl/6 mice may not respond to stress pheromones due to their relative insensitivity to endogenous steroids.

The effects of exposure to dietary nickel and zinc upon humoral and cellular immunity in SJL mice.

We are interested in potential interactions between environmental trace metal exposures and immune function. In particular, we have wondered whether dietary exposure to nickel and zinc cations can influence T and B cell proliferation and function. To study this question, we fed SJL female mice supplemental nickel and zinc sulfate from 4-8 weeks of age, and immunized the animals intraperitoneally (i.p.) with keyhole limpet hemocyanin (KLH) at 8 weeks. Eight days later, we measured antibody responses to KLH. Both IgG and IgM antibody responses to KLH were significantly depressed in vivo in the nickel fed animals (p less than 0.005). In vitro antigenic responsiveness to KLH of splenocytes from nickel fed animals was also depressed compared with control and zinc supplemented animals (p less than 0.002). This altered antigenic responsiveness persisted even after cells had been cultured for 5 days in standard media. The zinc supplemented diets did not seem to affect antibody responsiveness and proliferation. The proliferative responses of B cells to the mitogen lipopolysaccharide (LPS) were significantly depressed in Ni fed mice, but were not affected in the zinc fed animals. T cell mitogenic responses to concanavalin A were not affected in the nickel fed animals, and were enhanced in zinc fed animals. We conclude that dietary exposure to certain trace metals may induce persisting alterations in immunity in this animal model.

Chemical sympathectomy increases the innate immune response and decreases the specific immune response in the spleen to infection with Listeria monocytogenes.

Many investigators have shown that ablation of the sympathetic nervous system (SNS) with 6-hydroxydopamine (6-OHDA) can alter cell-mediated and humoral immune responses to antigenic challenge. Fewer studies have examined 6-OHDA-induced changes in natural immunity. In this study, we have examined the effect of chemical sympathectomy on the nonspecific and specific phases of the response to infection with Listeria monocytogenes. Sympathectomy decreased splenic bacterial loads 3 and 5 days post-infection and increased splenic neutrophils 3 days post-infection. Sympathectomy decreased splenocyte numbers and antigen-stimulated cytokine secretion from splenocytes. These results suggest that the SNS influences specific responses by modulating innate responses.

Sympathetic nervous system modulation of tumor metastases and host defense mechanisms.

The sympathetic nervous system can signal cells of the immune system through release of norepinephrine (NE), and may thus modulate several aspects of immune reactivity. We have examined the consequences of chemical denervation using 6-hydroxydopamine (6-OHDA) on the response of BALB/c mice to tumor cell challenge. In this study, chemical axotomy prior to the intravenous (i.v.) injection of the alveolar carcinoma line 1 significantly increased the number of pulmonary metastases. In contrast, axotomy performed after i.v. injection of tumor cells had no effect on the number of lung metastases. Line 1 tumor cells have been reported to be susceptible to lysis by natural killer (NK) cells. To examine possible mechanisms through which prior axotomy leads to increased lung metastases, we tested the effects of axotomy on in vitro and in vivo NK cell activity. No differences in NK cell activity were found between 6-OHDA- and vehicle-treated mice. Line 1 tumor cell growth in vitro was unaffected by both 6-OHDA and NE, and the tumor cells do not express beta-adrenergic receptors. Priming mice with lethally irradiated line 1 cells significantly reduced the number of lung metastases following challenge with live tumor cells; axotomy did not alter this decrease in metastases associated with priming. In summary, chemical axotomy of mice prior to injection of alveolar carcinoma cells resulted in an increased number of pulmonary metastases that was not correlated with alterations in either NK cell cytotoxicity or the putative immunological consequences of in vivo priming.

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.

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.

A monoclonal antibody against the human IL-2 receptor binds to paraformaldehyde-fixed but not viable frog (Xenopus) splenocytes.

Others have reported that a monoclonal anti-human IL-2 receptor antibody (anti-CD25) specifically binds a membrane receptor on Xenopus laevis PHA-induced and paraformaldehyde-fixed splenic blasts. In this paper, we present evidence suggesting that this binding is an artifact of membrane damage. Specifically, significant binding of anti-CD25 could only be achieved if the lymphoblasts were acid-washed and/or paraformaldehyde-fixed prior to being incubated with the fluoresceinated antibody. For example, in a representative experiment 95% of paraformaldehyde-fixed blasts, about 19% of acid-washed but not fixed blasts, but fewer than 2% of viable (untreated) blasts were positive for the CD25 epitope. Paraformaldehyde is known to alter membrane permeability. The DNA dye propidium iodide (PI) was used to demonstrate that the acid washing procedure also causes membranes to become permeable. Flow cytometric analyses of acid-washed PHA-induced splenic blasts doubly stained with the anti-CD25 antibody and PI showed that only 1.5% of the cells that were positive for CD25 did not stain with PI. Additionally, the anti-CD25 antibody, which immunoprecipitated a molecule from human lymphoblasts of between 50 and 60 kDa, did not immunoprecipitate any surface molecules from 125I-labeled Xenopus splenic blasts. Since binding of anti-CD25 to Xenopus splenic blasts appears to occur only after membrane damage, the antibody may be recognizing a cross-reactive internal epitope that is not involved in ligand binding on the cell surface.

Soluble fas levels correlate with multiple organ dysfunction severity, survival and nitrate levels, but not with cellular apoptotic markers in critically ill patients.

Apoptosis is a mode of programmed cell death (PCD). Transduction of apoptotic signals results in cellular suicide. Organ specific apoptosis has been proposed as a factor in multiple organ dysfunction syndrome (MODS). Fas is a widely occurring apoptotic signal receptor molecule expressed by almost any type of cell, which is also released in a soluble circulating form (circulating fas, sfas). In this exploratory study, we investigated the association of sfas with severity, survival, known mediators of multiple organ dysfunction, and cellular apoptotic markers on peripheral blood mononuclear cells (PBMC) in a group of 35 patients with MODS and in 35 matched controls. Critically ill patients with MODS had significantly elevated sfas levels compared to controls over time (P < .001). Increased serum concentration of circulating fas was associated with increased severity of multiple organ dysfunction. Non-survivors exhibited significantly higher sfas levels compared to survivors (P < .01) and increasing sfas was inversely associated with the likelihood of survival (P < .05). Circulating fas levels correlated highly with serum nitrate concentration, but not with fas and fasL expression on PBMC of critically ill patients. TNF-alpha and IL-6, although they appear to be mediators of both apoptosis and MODS, had no association with sfas. These results are suggestive of the need for further investigation on the role of apoptotic signaling in the development of MODS. They also suggest a potential prognostic value of sfas for SIRS/MODS clinical outcomes.

Changes in male:female ratio among newborn infants in Ireland.

Trends in the male proportion of live births in Ireland were examined by extracting the numbers of male and female live births from Registrar General's Reports (1864-1952) and Department of Health Annual Reviews (1953-1996), and subjecting them to statistical analysis. Except for 10 years (1947-1956) the proportion of male births has risen, significantly so since 1957. The global fall in male proportion of live births in recent decades has not been seen in Ireland, even though the country has undergone progressive industrialisation. It would be prudent not to assume that the same environmental factors alter sex ratio and cause pathological changes in male reproductive organs.

Prolonged exercise suppresses antigen-specific cytokine response to upper respiratory infection.

Fatiguing exercise has been associated with an increased susceptibility to infection. This study examined the antigen-specific T-helper (Th) type 1 and Th type 2 cytokine response to herpes simplex virus (HSV) infection after an acute bout of fatiguing exercise. Male BALB/cJ mice ran on a treadmill (Ex) until voluntary fatigue (approximately 2.5 h), and control mice were handled and remained next to the treadmill. Mice were infected with HSV 20 min after exercise. Mice were killed 2 or 7 days postinfection, and sera and spleens were taken for the determination of HSV-specific serum IgM, splenocyte cytokine production during culture with HSV, and splenocyte natural killer cell cytotoxicity. Both Th type 1 [interleukin (IL)-2, interferon-gamma, IL-12] and Th type 2 (IL-10) cytokine production in spleen cell cultures, as well as natural killer cell cytotoxicity, decreased in Ex on day 2 postinfection. On day 7 postinfection, there was no difference in HSV-specific serum IgM or cytokine production by cells from control and Ex mice, with the exception of decreased IL-12 in Ex mice. These findings suggest that fatiguing exercise may alter the kinetics of antigen-specific cytokine production.

Ectopic breast cancer: case report and literature review.

Ectopic breast tissue includes both supernumerary and aberrant breast tissue. The incidence of supernumerary tissue has been reported as high as 6% depending on the ethnic group studied. The incidence of aberrant breast tissue remains unknown. The development of malignancy within these anomalies is rare. In the following paper, the case report of a patient with an ectopic breast cancer and a second primary cancer of the left anatomic breast is described. A review of the world literature on ectopic breast cancer follows. Specific characteristics of ectopic breast cancer are defined and recommendations for management are made.

Quantitative differences in interleukin-2 and interleukin-4 production by antigen-stimulated splenocytes from individually- and group-housed mice.

The effects of differential housing on T-helper (TH) cell activation were investigated. BALB/c and C57Bl/6 male mice housed 1 or 4 per cage were administered three i.p. injections of keyhole limpet hemocyanin (KLH) over several weeks. Effects of differential housing on in vitro antigen-specific interleukin (IL)-2 (a TH1 cell derived cytokine) and IL-4 (a TH2 cell derived cytokine) production were observed. BALB/c mice housed alone produced significantly more IL-4 than BALB/c mice housed in groups. C57Bl/6 mice housed alone produced significantly more IL-2 than C57Bl/6 mice housed in groups. Differential housing did not influence either IL-2 production among BALB/c mice or IL-4 production among C57Bl/6 mice. These data demonstrate that environmental conditions can influence cytokine production by both TH-1 dominant (C57Bl/6) and TH-2 dominant (BALB/c) mice.

Increased pulmonary metastases and natural killer cell activity in mice following handling.

We have demonstrated that holding BALB/c female mice for two minutes per day for two weeks prior to injection of line 1, a BALB/c derived alveolar carcinoma, results in a significant increase in pulmonary metastases compared to unhandled controls. Handling did not affect splenic in vitro or in vivo natural killer (NK) cell activity but, surprisingly, was associated with increased NK cell activity in the lungs of these handled mice. These results demonstrate that a simple psychosocial manipulation may effect the metastatic process. The implications of these findings and potential mechanisms are discussed.

CO2 anesthesia facilitates a serum antibody response to orally-administered antigens.

Under most experimental circumstances, mice fed a protein antigen produce a smaller serum antibody response than the response elicited in mice that are parenterally immunized with that same antigen. In our experiments, mice fed keyhole limpet hemocyanin or herpes simplex virus type 1 had low, if any, serum IgG antibody responses regardless of whether antigen consumption was voluntary (in drinking fluids) or involuntary (force-fed by pipette). However, when force-feeding occurred during CO2 anesthesia, mice produced significantly higher serum antibody responses, which were comparable to those elicited in mice injected intraperitoneally with the same antigen. Although its mechanism of action is unclear, this potentiating effect does not appear to be mediated by possible CO2-mediated entry of the antigens into the respiratory tract, since mice fed antigen immediately before CO2 anesthesia also had a substantial antibody response.

The effects of handling on antibody production, mitogen responses, spleen cell number, and lymphocyte subpopulations.

The effects of a simple psychosocial manipulation, handling, on immune function in BALB/c.ByJ mice were studied. Handling for two minutes/day prior to immunization was shown to be associated with a decreased primary IgG antibody response to the protein antigen keyhole limpet hemocyanin. Handling was also associated with decreased T cell proliferative responses to Concanavalin A. No reliable changes in spleen cell number or lymphocyte subsets were found. These findings demonstrate that simply picking up an animal results in modulation of the immune response. These data are also of interest for their obvious methodological implications.

A presurgical psychosocial intervention for breast cancer patients. psychological distress and the immune response.

OBJECTIVE: The present study evaluated the feasibility and potential immunological benefit of a presurgical intervention for breast cancer patients. METHODS: Forty-one newly diagnosed breast cancer patients were randomized into control (standard care) and intervention groups. In addition to standard care, intervention group members received a two-session psychosocial intervention. Blood was drawn at three timepoints: (1) at preintervention; (2) at postintervention/presurgery; and (3) at postsurgery. RESULTS: Examination of the immunological data revealed evidence of suppression of interferon-gamma (IFN-gamma) in the control group over time, but not in the intervention group. Secondary findings related to psychological assessment generally paralleled the IFN-gamma results. CONCLUSION: The relevance and applicability of these findings to future breast cancer intervention research is detailed.

Voluntary consumption of cyclophosphamide by nondeprived Mrl-lpr/lpr and Mrl +/+ mice.

Cyclophosphamide dissolved in several dilutions of chocolate milk was presented for 20 hr daily to nondeprived, symptomatic, autoimmune Mrl-lpr/lpr and asymptomatic Mrl +/+ mice. In the absence of cyclophosphamide, daily consumption was inversely related to the concentration of the chocolate milk solutions and increased from the first to the fourth day of exposure. There were no effects of strain or sex on the consumption of plain chocolate milk. Consumption of 0.1 or 0.2 mg cyclophosphamide per ml of different dilutions of chocolate milk increased over days 1-4 and decreased on day 8. Consumption of 0.4 mg/ml cyclophosphamide did not change over days. Generally, consumption was inversely related to the cyclophosphamide concentration. Females consumed more cyclophosphamide than males. Autoimmune lpr/lpr mice consumed more cyclophosphamide than +/+ mice. Dilution of chocolate milk had no effect on consumption of cyclophosphamide. Lymphoproliferation and anti-ssDNA antibody titer were reduced by the consumption of cyclophosphamide-chocolate milk solutions. It is hypothesized that autoimmune lpr/lpr mice voluntarily consume more cyclophosphamide than asymptomatic +/+ mice in an effort to "correct" their immune system dysregulation.