Biologic Rhythms in the Immune System

In all of its components, the immune system shows regularly recurring, rhythmic variations in numerous frequencies; the circadian (about 24h) rhythms are the best explored. The circadian variations in immunocompetent cells circulating in the peripheral blood are of a magnitude to require attention in medical diagnostics. Both the humoral arm and the delayed (cellular) arm of the immune system function in a rhythmic manner. The response of the immune system to introduction of an antigen and to challenge of the sensitized organism varies in extent in the circadian frequency range and also in lower frequencies, for example, of about a week (circaseptan) or seasonally (circannual). The medical application of the biologic rhythms of the immune system extends to diagnostic measures, as well as treatment.     

Biologic Rhythms in the Immune System

In all of its components, the immune system shows regularly recurring, rhythmic variations in numerous frequencies; the circadian (about 24h) rhythms are the best explored. The circadian variations in immunocompetent cells circulating in the peripheral blood are of a magnitude to require attention in medical diagnostics. Both the humoral arm and the delayed (cellular) arm of the immune system function in a rhythmic manner. The response of the immune system to introduction of an antigen and to challenge of the sensitized organism varies in extent in the circadian frequency range and also in lower frequencies, for example, of about a week (circaseptan) or seasonally (circannual). The medical application of the biologic rhythms of the immune system extends to diagnostic measures, as well as treatment.     

Circadian variation of the response of T cells to antigen

Circadian clocks regulate many important aspects of physiology, and their disturbance leads to various medical conditions. Circadian variations have been found in immune system variables, including daily rhythms in circulating WBC numbers and serum concentration of cytokines. However, control of immune functional responses by the circadian clock has remained relatively unexplored. In this study, we show that mouse lymph nodes exhibit rhythmic clock gene expression. T cells from lymph nodes collected over 24 h show a circadian variation in proliferation after stimulation via the TCR, which is blunted in Clock gene mutant mice. The tyrosine kinase ZAP70, which is just downstream of the TCR in the T cell activation pathway and crucial for T cell function, exhibits rhythmic protein expression. Lastly, mice immunized with OVA peptide-loaded dendritic cells in the day show a stronger specific T cell response than mice immunized at night. These data reveal circadian control of the Ag-specific immune response and a novel regulatory mode of T cell proliferation, and may provide clues for more efficient vaccination strategies.     

Chronobiology in hematology and immunology

The hematopoietic and the immune systems in all their components are characterized by a multifrequency time structure with prominent rhythms in cell proliferation and cell function in the circadian, infradian, and rhythms in cell proliferation and cell function in the circadian, infradian, and circannual frequency ranges. The circulating formed elements in the peripheral blood show highly reproducible circadian rhythms. The timing and the extent of these rhythms were established in a clinically healthy human population and are shown as chronograms, cosinor summaries and, for some high-amplitude rhythms, as time-qualified reference ranges (chronodesms). Not only the number but also the reactivity of circulating blood cells varies predictably as a function of time as shown for the circadian rhythm in responsiveness of human and murine lymphocytes in vitro to lectin mitogens (phytohemagglutinin and pokeweed mitogen). Some circadian rhythms of hematologic functions appear to be innate and are presumably genetically determined but are modulated and adjusted in their timing by environmental factors, so-called synchronizers. Phase alterations in the circadian rhythms of hematologic parameters of human subjects and of mice by manipulation of the activity-rest or light-dark schedule and/or of the time of food uptake are presented. Characteristically these functions do not change their timing immediately after a shift in synchronizer phase but adapt over several and in some instances over many transient cycles. The circadian rhythm of cell proliferation in the mammalian bone marrow and lymphoid system as shown in mice in vivo and in vitro may lend itself to timed treatment with cell-cycle-specific and nonspecific agents in an attempt to maximize the desired and to minimize the undesired treatment effects upon the marrow. Differences in response, and susceptibility of cells and tissues at different stages of their circadian and circaseptan (about 7-day) rhythms and presumably of cyclic variations in other frequencies are expected to lead to the development of a chronopharmacology of the hematopoietic and immune system. Infradian rhythms of several frequencies have been described for numerous hematologic and immune functions. Some of these, i.e., in the circaseptan frequency range, seem to be of importance for humoral and for cell mediated immune functions including allograft rejection. Infradian rhythms with periods of 19 to 22 days seem to occur in some hematologic functions and are very prominent in cyclic neutropenia and (with shorter periods) in its animal model, the grey collie syndrome.(ABSTRACT TRUNCATED AT 400 WORDS)     

Role of mast cells in health: daily rhythmic variations in their number, exocytotic activity, histamine and serotonin content in the rat thyroid gland.

A chronobiologic transverse study on rat thyroid has been carried out to investigate whether mast cells and their content in biogenic amines normally undergo daily variations and whether these are related to circadian activity of the gland. The mean number of mast cells per microscopic field presents daily variations ranging from 10.9 +/- 3 to 14.6 +/- 3.8 in males and from 8.4 +/- 1.9 to 14.8 +/- 3 in females: these variations show a circadian trend in both sexes, with a 12 hrs period and two peaks at about 11:10/23:10. The mean percentage of degranulated mast cells per microscopic fields shows daily variations ranging from 51 +/- 11 to 60.4 +/- 14.2 in males and from 49.8 +/- 12.5 to 58.3 +/- 13.6 in females; these variations present a circadian rhythm with a 24 hrs period and a mean peak at 02:00. The histamine content of the gland varies in 24 hrs from 20.93 +/- 1.19 micrograms/g w w to 38.08 +/- 1.7 micrograms/g w w, without any sex-related difference: these variations show a rhythmic trend with a 12 hrs period and two peaks at 09:10/21:10. Serotonin content of thyroid presents circadian variations from 15.98 +/- 0.83 to 23.23 +/- 0.61 micrograms/g w w, with a 12 hrs period and two peaks at 04:20/16:20. Whereas the variations of mast cell exocytosis and of serotonin content seem to be chronobiologically linked to circadian variations of gland activity, evaluated on the basis of free and total tetraiodothyronine serum levels, the variations of mast cell number appear to be related to those of thyroid and blood histamine. The present data support the hypothesis that mast cell activity should not be considered as only linked to inflammation or allergic responses.     

Circadian rhythmicity in leukocytes immune responses in the freshwater snake,Natrix piscator

Circadian rhythm is observed in most of the physiological functions including immune response. The use of animal models other than mammals is useful in understanding how the vertebrate circadian system is organized and how this biological clock has changed throughout the vertebrate evolution. The present study was aimed to examine the circadian variability in the innate immune responses of leukocytes in the freshwater snake, Natrix piscator. Leukocytes were isolated and processed for total and differential leukocyte count, leukocyte phagocytosis, NBT reduction, nitrite production, and lymphocyte proliferation. Experiments were conducted for seven time points at 24, 4, 8, 12, 16, 20, and 24 h in three seasons – summer, winter, and spring. Cosinor analysis revealed that among leukocytes, only lymphocyte count showed circadian variation in summer. Percent phagocytosis and phagocytic index had significant rhythm of 24 h in winter and summer season, respectively. The acrophase of NBT reduction and nitrite release were coming during the evening hours in summer and during morning hours in winter and had circadian rhythmicity. A significant phase shift in nitrite release was observed with a trend of delayed phase shift from winter to summer. Circadian rhythm was also observed in lymphocyte proliferation (basal and concanavalin A stimulated). It is evident from the present study that animals synchronize their immune activity according to the time of the day and season. Enhancement of immune function helps the individual cope with seasonal stressors that would otherwise jeopardize the survival of animal.     

分子佐剂C3d的研究进展

C3d是补体C3不可再被酶解的最小片段,在抗原特异性免疫建立之前,C3d可识别非已抗原并与之共价结合,增强了抗原递呈细胞的递呈能力、降低了B细胞的活化阈、提高特异性抗体的滴度、促进抗体亲和力成熟等。近年来研究显示,C3d还可以促进抗原特异性细胞免疫应答水平并改变机体免疫应答模式。所以,C3d是连接固有性免疫和获得性免疫的桥梁。本文对C3d的分子生物学特征、生物学功能以及作为分子佐剂可能的分子机制进行了简要总结。     

Photoperiodic control of melatonin synthesis in fish pineal and retina

Melatonin is the time-keeping molecule of vertebrates. The daily and annual variations of its rhythmic production allow synchronizing physiological functions and behaviours to the variations of the environment. In fish, melatonin is produced by the photoreceptor cells of the retina and pineal organ. It is also synthesized by other retinal cell types of the inner nuclear and ganglion cell layers. In most of the species investigated, the melatonin rhythm displays a high-at-night profile, resulting from the circadian control of the arylalkylamine N-acetyltranferase (AANAT) activity; AANAT is the penultimate enzyme in the melatonin biosynthesis pathway. Some fish species escape the high-at-night rule in the retina, and the rhythm displays a high-at-day profile, intermediate situations being sometimes observed. This review summarizes our current knowledge on the molecular and cellular mechanisms of the rhythmic control of production of an important circadian clock messenger, underlying their plasticity.     

KCTD10 Biology: An Adaptor for the Ubiquitin E3 Complex Meets Multiple Substrates

Protein ubiquitination constitutes a post-translational modification mediated by ubiquitin ligases whereby ubiquitinated substrates are degraded through the proteasomal or lysosomal pathways, or acquire novel molecular functions according to their “ubiquitin codes.” Dysfunction of the ubiquitination process in cells causes various diseases such as cancers along with neurodegenerative, auto-immune/inflammatory, and metabolic diseases. KCTD10 functions as a substrate recognition receptor for cullin-3 (CUL3), a scaffold protein in RING-type ubiquitin ligase complexes. Recently, studies by ourselves and others have identified new substrates that are ubiquitinated by the CUL3/KCTD10 ubiquitin ligase complex. Moreover, the type of polyubiquitination (e.g., K27-, K48-, or K63-chain) of various substrates (e.g., RhoB, CEP97, EIF3D, and TRIF) mediated by KCTD10 underlies its divergent roles in endothelial barrier formation, primary cilium formation, plasma membrane dynamics, cell proliferation, and immune response. Here, the physiological functions of KCTD10 are summarized and potential mechanisms are proposed.     

A role for the thermal environment in defining co-stimulation requirements for CD4+ T cell activation

Maintenance of normal core body temperature is vigorously defended by long conserved, neurovascular homeostatic mechanisms that assist in heat dissipation during prolonged, heat generating exercise or exposure to warm environments. Moreover, during febrile episodes, body temperature can be significantly elevated for at least several hours at a time. Thus, as blood cells circulate throughout the body, physiologically relevant variations in surrounding tissue temperature can occur; moreover, shifts in core temperature occur during daily circadian cycles. This study has addressed the fundamental question of whether the threshold of stimulation needed to activate lymphocytes is influenced by temperature increases associated with physiologically relevant increases in temperature. We report that the need for co-stimulation of CD4+ T cells via CD28 ligation for the production of IL-2 is significantly reduced when cells are exposed to fever-range temperature. Moreover, even in the presence of sufficient CD28 ligation, provision of extra heat further increases IL-2 production. Additional in vivo and in vitro data (using both thermal and chemical modulation of membrane fluidity) support the hypothesis that the mechanism by which temperature modulates co-stimulation is linked to increases in membrane fluidity and membrane macromolecular clustering in the plasma membrane. Thermally-regulated changes in plasma membrane organization in response to physiological increases in temperature may assist in the geographical control of lymphocyte activation, i.e., stimulating activation in lymph nodes rather than in cooler surface regions, and further, may temporarily and reversibly enable CD4+ T cells to become more quickly and easily activated during times of infection during fever.     

七鳃鳗Lja-SHP2分子鉴定、重组表达及免疫学研究

高等脊椎动物的蛋白酪氨酸磷酸酶SHP2(SH2 domain-containing protein-tyrosine phosphatase-2)由ptpn11基因编码,催化酪氨酸残基去磷酸化,与其他能催化酪氨酸磷酸化的蛋白酪氨酸激酶共同调节机体内多种信号通路的信号传导。以往研究表明,SHP2在高等脊椎动物T细胞和B细胞的激活与信号转导过程中起着重要作用。为了研究无颌类脊椎动物日本七鳃鳗(Lampetra japonica)中与SHP2同源的分子——Lja-SHP2在免疫应答反应中的作用,本研究通过PCR扩增获取其Lja-SHP2开放阅读框序列,并构建到原核表达载体pET-32a中,成功在大肠杆菌中实现重组蛋白表达并制备了其兔源多克隆抗体。用混合菌免疫刺激日本七鳃鳗后,通过实时荧光定量PCR和免疫印迹方法检测了Lja-SHP2在日本七鳃鳗免疫相关组织中mRNA和蛋白水平表达谱。结果显示,混合菌免疫刺激后,Lja-SHP2 mRNA和蛋白表达在外周血白细胞和髓样小体中无显著变化,而在鳃组织中显著性上调(P<0.05),说明Lja-SHP2在混合菌刺激后主要参与了鳃组织的免疫应答反应。为了进一步探究Lja-SHP2与淋巴细胞亚群免疫应答反应的相关性,本研究分别使用B细胞有丝分裂原脂多糖(lipopolysaccharide,LPS)和T细胞的有丝分裂原植物凝集素(phytohemagglutinin,PHA)免疫刺激日本七鳃鳗。经LPS免疫刺激后,与对照组相比,白细胞中Lja-SHP2蛋白表达显著上调,鳃组织和髓样小体没有显著性差异表达;但经PHA免疫刺激后,与对照组相比,白细胞、鳃组织和髓样小体3种组织中Lja-SHP2均有上调,尤其在白细胞中上调最为显著,大约是对照组的2.5倍,说明Lja-SHP2参与了日本七鳃鳗由PHA介导的免疫应答反应。由于PHA能刺激日本七鳃鳗鳃组织中VLRA+淋巴细胞的活化,这表明Lja-SHP2可能参与了PHA介导的VLRA+淋巴细胞亚群的免疫应答反应。上述研究结果为进一步探索Lja-SHP2在七鳃鳗免疫应答过程中的功能奠定了基础,也为揭示SHP2分子家族的系统发生及探索高等脊椎动物适应性免疫系统的早期发生及其进化历程提供一定的线索。     

Circadian rhythms of granzyme B, perforin, IFN-gamma, and NK cell cytolytic activity in the spleen: effects of chronic ethanol

Recent studies show that alterations in the body's biological rhythms can lead to serious pathologies, including cancer. Acute and chronic ethanol consumption impairs the immune system by causing specific defects in the cellular components of the innate immune response and by creating increased risk and susceptibility to infections and cancer. NK cells are critical for immune surveillance against infected and malignant cells. To assess whether NK cell function follows a circadian trend and to determine ethanol effects on this rhythm, we measured, over a 24-h period, mRNA and protein levels of granzyme B, perforin, and the cytokine IFN-gamma, as well as NK cell activity, in the splenocytes of ad libitum-fed, pair-fed, and ethanol-fed Sprague Dawley male rats. Circadian rhythms were found in mRNA and protein levels of granzyme B, perforin, and IFN-gamma. A circadian pattern was also detected in NK cell cytolytic activity. Our data further demonstrated how chronic ethanol suppressed NK cell activity by directly disrupting the circadian rhythms of granzyme B, perforin, and IFN-gamma. These findings identify the circadian functions of splenic NK cells and show the vulnerability of these rhythms to chronic ethanol.     

Role of chemokines,innate and adaptive immunity

Polycystic Kidney Disease (PKD) triggers a robust immune system response including changes in both innate and adaptive immunity. These changes involve immune cells (e.g., macrophages and T cells) as well as cytokines and chemokines (e.g., MCP-1) that regulate the production, differentiation, homing, and various functions of these cells. This review is focused on the role of the immune system and its associated factors in the pathogenesis of PKDs as evidenced by data from cell-based systems, animal models, and PKD patients. It also highlights relevant pre-clinical and clinical studies that point to specific immune system components as promising candidates for the development of prognostic biomarkers and therapeutic strategies to improve PKD outcomes.     

Alterations in mitochondrial morphology as a key driver of immunity and host defence

Mitochondria are dynamic organelles whose architecture changes depending on the cell’s energy requirements and other signalling events. These structural changes are collectively known as mitochondrial dynamics. Mitochondrial dynamics are crucial for cellular functions such as differentiation, energy production and cell death. Importantly, it has become clear in recent years that mitochondrial dynamics are a critical control point for immune cell function. Mitochondrial remodelling allows quiescent immune cells to rapidly change their metabolism and become activated, producing mediators, such as cytokines, chemokines and even metabolites to execute an effective immune response. The importance of mitochondrial dynamics in immunity is evident, as numerous pathogens have evolved mechanisms to manipulate host cell mitochondrial remodelling in order to promote their own survival. In this review, we comprehensively address the roles of mitochondrial dynamics in immune cell function, along with modulation of host cell mitochondrial morphology during viral and bacterial infections to facilitate either pathogen survival or host immunity. We also speculate on what the future may hold in terms of therapies targeting mitochondrial morphology for bacterial and viral control.     

Immunosuppressive domains of retroviruses: Cell mechanisms of the effect on the human immune system

Immunosuppressive domains (ISDs) of viral envelope glycoproteins provide highly pathogenic phenotypes to various retroviruses. The ISD interaction with immune cells leads to an inhibition of the response. As was shown in the 1980s, a 17-amino acid residue of ISD fragment (known as CKS-17) is responsible for this immune modulation. However, the underlying mechanisms were unknown. Thorough research identified activation of signal transduction via the Ras-Raf-MEK-MAPK and PI3K-AKT-mTOR cell pathways as a result of the ISD interaction with immune cells. The result is the decrease in the secretion of stimulatory cytokines (e.g., IL-12) and increase of inhibitory and anti-inflammatory cytokines (e.g., IL-10). One of the receptor tyrosine kinases that triggers signal transduction in these pathways acts as a primary ISD target, while other key regulators, cAMP and diacylglycerol (DAG), act as secondary messengers. Immunosuppressive-like domains are not restricted to retroviruses; an ISD present in Ebola virus envelope glycoproteins determines an extremely severe clinical course of virus-induced hemorrhagic fever. A number of retrovirus-originating ISD-coding regions are found in the human genome. The regions are expressed as parts of the syncytin genes in the placenta, helping to render the mother’s immune system tolerant of the placenta and embryo. The review considers the molecular aspects of the retroviral ISD-induced modulation of the host immune system.