Does exposure to parasites modify relationships between diurnal cortisol and leukocytes among Honduran women?

BACKGROUND: Altered hypothalamic-pituitary-adrenal (HPA) function and related changes in circulating glucocorticoids have been implicated in the pathogenesis of numerous diseases that involve dysregulated immune function. Glucocorticoid hormones have both direct and indirect modulatory effects on both pro- and anti-inflammatory aspects of the immune system, including granulocytic and lymphocytic leukocyte subsets. However, past findings are complicated by inconsistencies across studies in how glucocorticoids and immune markers interact and relate to disease risk. Some incongruencies are likely due to an overreliance on single-unit (e.g., HPA or one immune marker) measures, and a failure to consider ecological exposures that may shape the base levels or correspondence between these systems. Here, we test single-unit and diurnal measures of HPA axis and immune system interactions in a less-industrial ecological setting with relatively high parasite loads. METHODS: In a sample of 114 Honduran women (mean age = 36 years), morning and evening blood samples were analyzed to quantify granulocytes, lymphocytes, and immunoglobulin-E (IgE). Saliva was collected over 2 days (8 samples per woman) to measure peak cortisol, cumulative cortisol, and slope of decline. These repeated measures of saliva and venous blood were used to investigate associations between single-point and diurnal salivary cortisol and leukocytes, under variable levels of past parasite exposure (proxied by IgE). RESULTS: Individuals with less of a decline in cortisol (i.e., "flatter" decline) show less of an increase in lymphocytes (2.27% increase in cells/µL/hr; 95% CI: 0.91-7.29; p = .01) across the day compared to those with steeper cortisol decline (7.5% increase in lymphocytes; 95% CI: 5.79-9.34; p < .001). IgE levels did not modify this association. Interestingly, IgE did moderate relationships between measures of cortisol and granulocytes: diurnal cortisol was positively associated with granulocytes, only in individuals with high previous exposure to parasites. There were no consistent relationships between single-unit measures of cortisol, lymphocytes or granulocytes, regardless of past parasite exposure. DISCUSSION: Results demonstrate that the relationship between HPA function and immune modulation cannot be fully understood without an understanding of local disease ecology. These results highlight the importance of research that seeks to identify etiologies of disease across environmental contexts.

Differences in Diurnal Variation of Immune Responses in Microglia and Macrophages: Review and Perspectives.

Biological rhythms, especially those that last close to 24 h, better known as circadian rhythms, are highly regulated phenomena, maintained throughout evolution in various organisms which allow organisms to predict, prepare for, and adapt to environmental changes. One of these phenomena that exhibit biological rhythms is the immune response to external agents. Immune cells (neutrophils, lymphocytes, macrophages, among others), as well as their mediators such as cytokines and chemokines, undergo variations in tissue and blood concentrations during the day. These rhythms are still being elucidated in microglia, the resident macrophages of the central nervous system, but since these cells share a common origin with peripheral macrophages, they are expected to behave similarly. In this review, we will discuss the possible differences in the responses between peripheral macrophages and microglia, their relationship with the circadian clock, and whether these rhythms can influence therapeutic choices.

Variability in gut mucosal secretory IgA in mice along a working day.

OBJECTIVE: To assess the variability of secretory immunoglobulin A (S-IgA) in the lumen and feces of mice along a working day. RESULTS: Mice were maintained under a 12 h light-dark cycle, light period starting at 8 AM. S-IgA was determined in feces and intestinal content (after one or three washes) at three points along the day: at the beginning, in the middle and at the end of the light period (ELP). Significant reduction in the content of S-IgA in the small intestine fluid and in feces was observed at the end of the light cycle, which coincides with the end of a regular working day (8 PM) in any given animal facility. It was also observed that three washes of the small intestine were more effective than one flush to recover a significant higher amount of S-IgA, with the smallest coefficient of variation observed by the ELP. A smaller CV would imply a reduced number of animals needed to achieve the same meaningful results. The results may be useful when designing animal trials for the selection of probiotic candidates based on their capacity of activating S-IgA, since it would imply a more rational use of experimental animals.

Air Travel, Circadian Rhythms/Hormones, and Autoimmunity.

Biological rhythms are fundamental for homeostasis and have recently been involved in the regulatory processes of various organs and systems. Circadian cycle proteins and hormones have a direct effect on the inflammatory response and have shown pro- or anti-inflammatory effects in animal models of autoimmune diseases. The cells of the immune system have their own circadian rhythm, and the light-dark cycle directly influences the inflammatory response. On the other hand, patients with autoimmune diseases characteristically have sleep disorders and fatigue, and in certain disease, such as rheumatoid arthritis (RA), a frank periodicity in the signs and symptoms is recognized. The joint symptoms predominate in the morning, and apparently, subjects with RA have relative adrenal insufficiency, with a cortisol peak unable to control the late night load of pro-inflammatory cytokines. Transatlantic flights represent a challenge in the adjustment of biological rhythms, since they imply sleep deprivation, time zone changes, and potential difficulties for drug administration. In patients with autoimmune diseases, the use of DMARDs and prednisone at night is probably best suited to lessen morning symptoms. It is also essential to sleep during the trip to improve adaptation to the new time zone and to avoid, as far as possible, works involving flexible or nocturnal shifts. The study of proteins and hormones related to biological rhythms will demonstrate new pathophysiological pathways of autoimmune diseases, which will emphasize the use of general measures for sleep respect and methods for drug administration at key daily times to optimize their anti-inflammatory and immune modulatory effects.

Diurnal variation in endotoxin-induced mortality in mice: correlation with proinflammatory factors.

Many immune parameters exhibit daily and circadian oscillations, including the number of circulating cells and levels of cytokines in the blood. Mice also have a differential susceptibility to lipopolysaccharide (LPS or endotoxin)-induced endotoxic shock, depending on the administration time in the 24 h light-dark (LD) cycle. We replicated these results in LD, but we did not find temporal differences in LPS-induced mortality in constant darkness (DD). Animals challenged with LPS showed only transient effects on their wheel locomotor activity rhythm without modification of circadian period and phase. Levels of several key factors involved in the pathology of sepsis and septic shock were tested in LD. We found that LPS-induced levels of interleukin (IL)-1beta, IL-6, JE (MCP-1), and MIP1alpha were significantly higher at zeitgeber time (ZT) 11 (time of increased mortality) than at ZT19 (ZT12 = time of lights-off in the animal quarters for the 12L:12D condition). Our results indicate that the differences found in mortality that are dependent on the time of LPS-challenge are not directly related to an endogenous circadian clock, and that some relevant immune factors in the development of sepsis are highly induced at ZT11, the time of higher LPS-induced mortality, compared to ZT19.

Circadian cardiac autonomic function in perinatally HIV-infected preschool children.

The 24-h heart rate variability and QT-interval adaptation was investigated in perinatally HIV-infected preschool children classified according to immunological status in order to assess autonomic function at early stages of infection. Thirty-five perinatally HIV-infected and clinically stable children (4.8 +/- 0.3 years) were enrolled after approval of the study by the University Hospital Pedro Ernesto Ethics Committee and written informed parental consent was obtained. The children were classified according to peripheral CD4+ count (cells/microL) as follows: group 1, N = 11 (>or=1000); group 2, N = 7 (>or=500 and <1000); group 3, N = 17 (<500). Left ventricular ejection fraction (>55%), 24-h RR interval variability (RRV) indexes (NN, SDANN, SDNN index, r-MSSD) and 24-h QT and Bazett-corrected QT (QTc) were determined, and groups were matched for age, body surface area, and left ventricular ejection fraction, reducing biases in RRV. The peak differences () between the highest and lowest RRV and QT indexes were extracted from nocturnal (1 am-6 am) and daytime (1 pm-6 pm) hourly assessed segments, respectively. Pearsons correlation (r) and Kruskal-Wallis ANOVA were used to compare groups. CD4+ count correlated positively with NN (r = 0.45; P = 0.003). There were no significant differences in daytime NN among groups. Nighttime SDNN index (P = 0.01), nighttime r-MSSD (P = 0.003), NN (P = 0.01), SDNN index (P = 0.03) and r-MSSD (P = 0.004) were significantly lower in group 3 than in the other groups. Expected nighttime QTc-interval lengthening was not observed in all groups. In perinatally HIV-infected preschool children with preserved left ventricular systolic function, parasympathetic-mediated autonomic dysfunction parallels immune status, impairing both RRV and circadian QTc interval adaptation.

Circadian cardiac autonomic function in perinatally HIV-infected preschool children

The 24-h heart rate variability and QT-interval adaptation was investigated in perinatally HIV-infected preschool children classified according to immunological status in order to assess autonomic function at early stages of infection. Thirty-five perinatally HIV-infected and clinically stable children (4.8 ± 0.3 years) were enrolled after approval of the study by the University Hospital Pedro Ernesto Ethics Committee and written informed parental consent was obtained. The children were classified according to peripheral CD4+ count (cells/µL) as follows: group 1, N = 11 (≥1000); group 2, N = 7 (≥500 and <1000); group 3, N = 17 (<500). Left ventricular ejection fraction (>55%), 24-h RR interval variability (RRV) indexes (NN, SDANN, SDNN index, r-MSSD) and 24-h QT and Bazett-corrected QT (QTc) were determined, and groups were matched for age, body surface area, and left ventricular ejection fraction, reducing biases in RRV. The peak differences (∆) between the highest and lowest RRV and QT indexes were extracted from nocturnal (1 am-6 am) and daytime (1 pm-6 pm) hourly assessed segments, respectively. Pearson’s correlation (r) and Kruskal-Wallis ANOVA were used to compare groups. CD4+ count correlated positively with ∆NN (r = 0.45; P = 0.003). There were no significant differences in daytime NN among groups. Nighttime SDNN index (P = 0.01), nighttime r-MSSD (P = 0.003), ∆NN (P = 0.01), ∆SDNN index (P = 0.03) and ∆r-MSSD (P = 0.004) were significantly lower in group 3 than in the other groups. Expected nighttime QTc-interval lengthening was not observed in all groups. In perinatally HIV-infected preschool children with preserved left ventricular systolic function, parasympathetic-mediated autonomic dysfunction parallels immune status, impairing both RRV and circadian QTc interval adaptation.

Circadian responses to endotoxin treatment in mice.

We tested the ability of Escherichia coli lipopolysaccharide (LPS) to phase-shift the activity circadian rhythm in C57Bl/6J mice. Intraperitoneal administration of 25 microg/kg LPS induced photic-like phase delays (-43+/-10 min) during the early subjective night. These delays were non-additive to those induced by light at CT 15, and were reduced by the previous administration of sulfasalazine, a NF-kappaB activation inhibitor. At CT 15, LPS induced c-Fos expression in the dorsal area of the suprachiasmatic nuclei (SCN). Our results suggest that the activation of the immune system should be considered an entraining signal for the murine circadian clock.

Melatonin role in experimental arthritis.

Our perception of the function of the pineal gland and its hormone melatonin has attained a new dimension during the last decade. Through melatonin, the pineal becomes a principal organ present in vertebrates involved in the control of rhythmic adaptations to daily and seasonal cycles. Melatonin is synthesized and secreted during the dark period of the light/dark cycle. The rhythmic nocturnal melatonin secretion is directly generated by the circadian clock and is entrained to a 24-hour period by the light-dark cycle. The periodic secretion of melatonin may be used as a circadian mediator to any system than can "read" the message. Melatonin acts as an arm of the circadian clock, giving a time-related signal to a number of body functions; one of them is the circadian organization of the immune response. This review discusses melatonin role in rheumatoid arthritis. Animal studies employing Freund's complete mycobacterial adjuvant (FCA) as a model of rheumatoid arthritis are described. Immune and neuroendocrine circadian rhythms were examined in FCA-injected rats, both in the preclinical phase of arthritis (2-3 days after FCA injection) as well as in the acute phase of the disease (18 days after FCA injection). In arthritic rats, the 24-h organization of immune and neuroendocrine responses becomes altered. Significant effects of immune response on diurnal rhythmicity of adenohypophysial and hypophysiotropic hormones occurred in arthritic rats. Melatonin treatment prevented alteration of 24-h rhythms of serum ACTH, prolactin and luteinizing hormone in rats injected with FCA. In addition, melatonin treatment prevented alteration of the 24-h variation in hypothalamic monoamine transmitter turnover during the preclinical phase of Freund's adjuvant arthritis in rats. A comparison between the inflammatory and immune responses elicited by physiological and pharmacological doses of melatonin in FCA arthritis is reported. Pinealectomized rats exhibited a significantly less pronounced inflammatory response, which was restored to normal by a low melatonin dose (0.3 microg/ml of drinking water), whereas a high melatonin dose (30 microg/ml) that resulted in a 50-60-fold increase in plasma melatonin, augmented the inflammatory and immune response. These results should be considered in the light of recent reports that rheumatoid arthritis patients have increased nocturnal plasma levels of melatonin and that their synovial macrophages respond to melatonin with an increased cytokine production.

Melatonin as a time-meaningful signal in circadian organization of immune response.

Melatonin is synthesized and secreted during the dark period of the light/dark cycle. The rhythmic nocturnal melatonin secretion is directly generated by the circadian clock, located within the suprachiasmatic nuclei in mammals and is entrained to a 24-hour period by the light-dark cycle. The periodic secretion of melatonin may be used as a circadian mediator to any system that can 'read' the message. Melatonin seems to act as an arm of the circadian clock, giving a time-related signal to a number of body functions; one of these, the circadian organization of the defense of the organism, is discussed in some detail as an example.