For Whom the Clock Ticks: Clinical Chronobiology for Infectious Diseases.

The host defense against pathogens varies among individuals. Among the factors influencing host response, those associated with circadian disruptions are emerging. These latter depend on molecular clocks, which control the two partners of host defense: microbes and immune system. There is some evidence that infections are closely related to circadian rhythms in terms of susceptibility, clinical presentation and severity. In this review, we overview what is known about circadian rhythms in infectious diseases and update the knowledge about circadian rhythms in immune system, pathogens and vectors. This heuristic approach opens a new fascinating field of time-based personalized treatment of infected patients.

Variation in melatonin receptors (Mel(1a) and Mel(1b)) and androgen receptor (AR) expression in the spleen of a seasonally breeding bird, Perdicula asiatica.

Daily variation in the peripheral level of melatonin plays a major role in integrating reproduction and environmental information for seasonally breeding birds. However, the variation in immunity and reproduction has never been assessed in any avian species on a 24 h time scale. Therefore, to understand the relationship between immune function and reproductive phases in a seasonally breeding bird, Perdicula asiatica, the Indian jungle bush quail, we studied the daily variation of melatonin and testosterone levels along with expression of their receptors Mel(1a), Mel(1b), and androgen receptor in the spleen during the reproductively active phase. Immunocytochemistry for the melatonin receptors Mel(1a) and Mel(1b) presented a differential distribution pattern. Western blot of splenic protein suggested a daily rhythm of melatonin receptors, while acrophases for the two melatonin receptors Mel(1a) and Mel(1b) differed by 4 h, suggesting that the expression of the receptors may peak at different times, causing more of either Mel(1a) or Mel(1b) to be available at a particular time to mediate function. The circulatory melatonin level correlated with percentage stimulation ratio of splenocytes and plasma interleukin-2 level, but did not correlate with testosterone or androgen receptor, suggesting that melatonin could be a major hormone imparting a time-of-day effect on the modulation of immune function in a seasonally breeding bird during the reproductively active phase.

Changes in endometrial natural killer cell expression of CD94, CD158a and CD158b are associated with infertility.

PROBLEM: Cycle-dependent fluctuations in natural killer (NK) cell populations in endometrium and circulation may differ, contributing to unexplained infertility. METHOD OF STUDY: NK cell phenotypes were determined by flow cytometry in endometrial biopsies and matched blood samples. RESULTS: While circulating and endometrial T cell populations remained constant throughout the menstrual cycle in fertile and infertile women, circulating NK cells in infertile women increased during the secretory phase. However, increased expression of CD94, CD158b (secretory phase), and CD158a (proliferative phase) by endometrial NK cells from infertile women was observed. These changes were not reflected in the circulation. CONCLUSION: In infertile women, changes in circulating NK cell percentages are found exclusively during the secretory phase and not in endometrium; cycle-related changes in NK receptor expression are observed only in infertile endometrium. While having exciting implications for understanding NK cell function in fertility, our data emphasize the difficulty in attaching diagnostic or prognostic significance to NK cell analyses in individual patients.

Cows milk-dependent exercise-induced anaphylaxis under the condition of a premenstrual or ovulatory phase following skin sensitization.

BACKGROUND: A 24 year-old woman with atopic dermatitis occasionally developed symptoms, including dyspnea and generalized urticaria, following ingestion of food containing cows milk. Similar episodes had continued, and had been treated empirically since the age of 16 years. CASE SUMMARY: Although a skin test and IgE RAST showed positive reactions to cows milk, a provocation test with cows milk alone did not induce any symptoms. Therefore, food-dependent exercise-induced anaphylaxis (FDEIA) was suspected, but examination using various combinations of cows milk, aspirin and exercise failed to elicit any symptoms. Finally, a provocation test during the ovulatory phase with cows milk followed by aspirin and exercise evoked systemic urticaria, dyspnea and hypotension. DISCUSSION: The symptoms against cows milk began when she took baths with bath salts containing cows milk as its main ingredient for one year at the age 15 years. Sensitization to cows milk through eczematous skin is indicated from this history. Hormonal change during a premenstrual or ovulatory phase is also an important factor for the development of FDEIA in this case.

Gender- and menstrual phase dependent regulation of inflammatory gene expression in response to aerobic exercise.

The immunological reaction to exercise has been investigated with increasing intensity in the last 10-20 years, with most human studies performed in male subjects. Recently, gender-specific aspects have received growing attention, but studies carefully monitoring the influence of gender including the menstrual cycle, are rare. Here, we report gene expression patterns in response to a run at 93% of the individual anaerobic threshold of 9 women with regular menstrual cycles and no use of oral contraceptives who ran both at day 10 (follicular phase, F) and at day 25 (luteal phase, L) of their cycle. 12 male subjects (M) served as controls. The mRNA was pooled group wise and processed on a gene expression microarray encompassing 789 genes, including major genes of the inflammatory and anti-inflammatory reaction. The differences of gene expression between time points to (before run) and t1 (after run) were analyzed. Females in L showed a higher extent of regulation than females in F or men. Among those genes which were up-regulated above 1.5 fold change (log2) pro-inflammatory genes were significantly enriched (p = 0.033, after Bonferroni correction) in L, while this was not the case in F or M. Conversely, women in L showed a strong trend towards downregulation of anti-inflammatory genes. Some prominent genes like IL6 (coding for interleukin-6), and IL1RN (also termed IL1RA, coding for interleukin-1 receptor antagonist) were clearly regulated in opposite directions in L as opposed to F and M. In conclusion, women in L showed a distinctly different pattern of gene regulation in response to exercise, compared with women in F or M. The overall direction of gene expression changes of women in L is clearly pro-inflammatory. This finding accentuates a need for careful consideration of the female cyclic phase when investigating women in exercise immunology studies. Our results may also have implications relevant to other forms of stress in females.

[The chronobiological aspects of changes in the level of serum immunoglobulins in healthy people]. / Khronobiologicheskie aspekty izmenenii soderzhaniia syvorotochnykh immunoglobulinov u zdorovykh lits.

The results of the determination of the concentration of immunoglobulins (Ig) in the blood of 540 donors, carried out at the period of 1989-1990, are analyzed. The presence of annual biorhythms in the content of IgA, IgG and IgM has been established, the biorhythmic curves of IgG and IgM practically coinciding and the biorhythmic curve of IgA shifting with respect to the curves of IgG and IgM by about 3 months. As revealed by this analysis, a decrease in the concentration of IgG and IgM correlates with an increase in the occurrence of purulent septic infections after surgical interventions. The presence of annual rhythms in the content serum should be considered in the interpretation of the results of immunological studies, as well as in planning and realization of different therapeutic and prophylactic measures.

The feedsideward of cephalo-adrenal immune interactions.

The feedsideward phenomenon is the interaction of three or more rhythmic physiological entities by a diversified spectrum of rhythms that constitute a rhythmic network. These rhythmic units are: a) the modulator, b) the actor, c) the reactor and d) the integrative unity. Rhythmic interactions are characterized by an alternating sequence of algorithmically predictable effects of attenuation, no effect, and stimulation occurring in different frequencies. The basis of this phenomenon was determined from experimental evidence derived from cephalo-adrenal ex vivo studies. Internal phase-shift studies allow the demonstration ex vivo of a collateral hierarchy of rhythmic neuro-endocrine interactions as alpha, beta, gamma and delta rhythms. Linear least squares analyses describe and quantify circadian (alpha, beta and gamma) and infradian (delta) rhythms in the original series and the differences in responses [beta-alpha] and [gamma-delta]. These spontaneous and response rhythms reveal a collateral neuro-endocrine hierarchy and validate a pineal feedsideward phenomenon. Circadian-infradian murine rhythmic intermodulations are demonstrated in the epithelial corneal mitosis; brain neurosteroids and pineal melatonin content. A circadian rhythm in pineal melatonin content in female B6D2F1 mice and the chronomodulating action of melatonin + ACTH upon adrenal corticosterone production are confirmed. A chronopilot ex vivo study "suggests" that melatonin chronomodulates mouse aldosterone production. In a second chronopilot study, HrIL-2 chronomodulates rat corticosterone production ex vivo. Feedsidewards in vivo were seen in the chronomodulation of tumor-host balance occurring after melatonin, IL-2, cefodizime, and cyclosporine treatments that enhanced or delayed tumor growth and survival time of tumor-bearing mice.