糖化血红蛋白与2型糖尿病患者免疫功能改变的相关性分析

目的：糖化血红蛋白与2型糖尿病患者免疫功能改变的相关性。方法：分析2011年1月至2014年1月在我院接受治疗的2型糖尿病患者的临床资料（观察组）,并纳入健康体检者作为对照组。结果：共纳入研究对象75例,其中观察组45例,对照组30例。观察组糖化血红蛋白水平显著高于对照组,差异具有统计学意义（8.12±3.45 vs 4.87±1.65;t＝4.472, P＜0.001）。观察组患者CD4/CD8值显著低于对照组（1.57±0.41 vs 1.82±0.52;t＝2.104,P＝0.039）。观察组IgM水平（1.39±0.46 vs 2.21±0.65;t＝5.978,P＜0.001）及IgA水平（1.62±0.41 vs 2.33±0.71;t＝4.948,P＜0.001）均显著低于对照组。相关性分析显示,观察组糖化血红蛋白（HbA1c）与IgM（r＝-0.418,P＝0.004）及IgA（r＝-0.573,P＜0.001）呈现显著正相关;而与CD4/CD8呈现显著负相关（ r＝-0.507,P＜0.001）。结论：2型糖尿病患者的免疫功能存在缺陷,且与患者血糖控制情况密切相关。     

Serum granulysin is a marker for Th1 type immunity in pre-eclampsia

Recent studies suggest that pre-eclampsia is associated with a Th1 predominant state and may be considered a failure of tolerance. Granulysin is a cytotoxic granule protein of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Recently, we developed an enzyme-linked immunosorbent assay (ELISA) system for detecting serum granulysin, and reported that serum granulysin is a useful marker to evaluate the cell-mediated immunity. In this study, we show that the serum levels of granulysin were significantly elevated in pre-eclamptic patients compared with those in normal pregnancy subjects. In addition, the serum granulysin levels in pre-eclamptic patients were well associated with mean blood pressure, percentage of peripheral blood Th1 cells and Th1/Th2 ratios. The present results suggest that the serum granulysin levels would be a useful and novel serum marker to evaluate the Th1/Th2 balance, especially Th1 type immunity in pre-eclampsia.     

BCG-induced trained immunity in macrophage: reprograming of glucose metabolism

Abstract

Memory is no longer a privilege of adaptive immunity. Innate immune cells can exhibit a long-term immune activation after infection or vaccination, which is called “trained immunity.” In addition to defense against mycobacterial infection, BCG-induced trained immunity can also exert nonspecific protection, which is regulated by metabolic rewiring and epigenetic reprograming. Enhanced glycolysis and glutamine-driven tricarboxylic acid cycle have been proven to be important metabolic pathways for trained immunity induced by BCG, which is dependent on Akt/mTOR pathway.     

Lessons in type 2 immunity: Neutrophils in Helminth infections

Neutrophils constitute the body’s first line of defense against invading pathogens. Equipped with a large array of tools, these immune cells are highly efficient in eliminating bacterial and viral infections, yet their activity can at the same time be detrimental to the host itself - this is the broad consensus on these granulocytes. However, the last decade has proven that neutrophils are a much more sophisticated cell type with unexpected and underappreciated functions in health and disease. In this review, we look at the latest discoveries in neutrophil biology with a focus on their role during the hallmark setting of type 2 immunity – helminth infection. We discuss the involvement of neutrophils in various helminth infection models and summarize the latest findings regarding neutrophil regulation and effector function. We will show that neutrophils have much more to offer than previously thought and while studies of neutrophils in helminth infections are still in its infancy, recent discoveries highlight more than ever that these cells are a key cog of the immune system, even during type 2 responses.     

Inherent maternal type 2 immunity: Consequences for maternal and offspring health

An inherent elevation in type 2 immunity is a feature of maternal and offspring immune systems. This has diverse implications for maternal and offspring biology including influencing success of pregnancy, offspring immune development and maternal and offspring ability to control infection and diseases such as allergies. In this review we provide a broad insight into how this immunological feature of pregnancy and early life impacts both maternal and offspring biology. We also suggest how understanding of this axis of immune influence is and may be utilised to improve maternal and offspring health.     

Remote regulation of type 2 immunity by intestinal parasites

The intestinal tract is the target organ of most parasitic infections, including those by helminths and protozoa. These parasites elicit prototypical type 2 immune activation in the host’s immune system with striking impact on the local tissue microenvironment. Despite local containment of these parasites within the intestinal tract, parasitic infections also mediate immune adaptation in peripheral organs. In this review, we summarize the current knowledge on how such gut-tissue axes influence important immune-mediated resistance and disease tolerance in the context of coinfections, and elaborate on the implications of parasite-regulated gut-lung and gut-brain axes on the development and severity of airway inflammation and central nervous system diseases.     

Metabolic control of the Treg/Th17 axis

The interplay of the immune system with other aspects of physiology is continually being revealed and in some cases studied in considerable mechanistic detail. A prime example is the influence of metabolic cues on immune responses. It is well appreciated that upon activation, T cells take on a metabolic profile profoundly distinct from that of their quiescent and anergic counterparts; however, a number of recent breakthroughs have greatly expanded our knowledge of how aspects of cellular metabolism can shape a T-cell response. Particularly important are findings that certain environmental cues can tilt the delicate balance between inflammation and immune tolerance by skewing T-cell fate decisions toward either the T-helper 17 (Th17) or T-regulatory (Treg) cell lineage. Recognizing the unappreciated immune-modifying potential of metabolic factors and particularly those involved in the generation of these functionally opposing T-cell subsets will likely add new and potent therapies to our repertoire for treating immune mediated pathologies. In this review, we summarize and discuss recent findings linking certain metabolic pathways, enzymes, and by-products to shifts in the balance between Th17 and Treg cell populations. These advances highlight numerous opportunities for immune modulation.     

葡萄糖代谢调控T细胞功能的研究进展

T细胞接受复杂的信号后激活、增殖和分化成不同的细胞亚型.研究表明,葡萄糖代谢可影响T细胞的激活、分化和免疫功能.因此,了解T细胞葡萄糖代谢特点和部分调控葡萄糖代谢的信号分子,探讨葡萄糖代谢的改变如何影响T细胞功能很有必要,深入探索T细胞的葡萄糖代谢特点和调控机制,有助于研究炎症条件下T细胞的功能,从而为炎症的治疗提供新的方法和思路.     

T cell immunity in neonates

Typically, neonates exhibit decreased or aberrant cellular immune responses when compared to adults, resulting in increased susceptibility to infection. However, it is clear that newborns are able to generate adult-like protective T cell responses under certain conditions. The focus of our research is to understand the deficiencies within the neonatal immune system that lead to improper cellular responses and how priming conditions can be altered to elicit the appropriate T cell response necessary to protect against development of pathogen-induced disease. With these goals in mind, we are exploring the attributes of neonatal T cells and their development, as well as the conditions during priming that influence the resulting response to immune challenge during the neonatal period.     

Innate and adaptive type 2 immunity in lung allergic inflammation

Allergic inflammation is a type 2 immune disorder classically characterized by high levels of immunoglobulin E (IgE) and the development of Th2 cells. Asthma is a pulmonary allergic inflammatory disease resulting in bronchial hyper-reactivity. Atopic asthma is defined by IgE antibody-mediated mast cell degranulation, while in non-atopic asthma there is no allergen-specific IgE and more involvement of innate immune cells, such as basophils, group 2 innate lymphoid cells (ILC2), and eosinophils. Recently, protease allergens were shown to cause asthmatic responses in the absence of Th2 cells, suggesting that an innate cell network (IL-33/TSLP-basophil-ILC2-IL-5/IL-13 axis) can facilitate the sensitization phase of type 2 inflammatory responses. Recent evidence also indicates that in the chronic phase, these innate immune cells directly or indirectly contribute to the adaptive Th2 cell responses. In this review, we discuss the role of Th2 cytokines (IL-4 and IL-13) and innate immune cells (mast cells, basophils, ILC2s, and dendritic cells) in the cross-talk between innate and adaptive inflammatory responses.     

Innate type 2 immunity controls hair follicle commensalism by Demodex mites

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Basophils in antihelminth immunity

It has been appreciated that basophilia is a common feature of helminth infections for approximately 50 years. The ability of basophils to secrete IL-4 and other type 2 cytokines has supported the prevailing notion that basophils contribute to antihelminth immunity by promoting optimal type 2 T helper (Th2) cell responses. While this appears to be the case in several helminth infections, emerging studies are also revealing that the effector functions of basophils are extremely diverse and parasite-specific. Further, new reports now suggest that basophils can restrict type 2 inflammation in a manner that preserves the integrity of helminth-affected tissue. Finally, exciting data has also demonstrated that basophils can regulate inflammation by participating in neuro-immune interactions. This article will review the current state of basophil biology and describe how recent studies are transforming our understanding of the role basophils play in the context of helminth infections.     

Phenytoin promotes Th2 type immune response in mice

The effects of chronic administration of phenytoin, a common anticonvulsive drug, on immune responses were studied in mice. Anti-keyhole limpet haemocyanin (KLH) IgE antibody response after KLH-immunization was enhanced in phenytoin-treated mice. Proliferative responses of spleen cells induced with KLH, concanavalin A (ConA), lipopolysaccharide and anti-CD3 antibody were reduced in phenytoin-treated mice. Accessory function of spleen adherent cells on ConA-induced T cell proliferative response was reduced in phenytoin-treated mice. KLH-induced IL-4 production of spleen cells was enhanced, while IFN-gamma production was reduced in phenytoin-treated mice. In addition, production of IL-1 alpha, but not IL-6 and IL-12 by spleen adherent cells from phenytoin-treated mice was reduced. Natural killer cell activity was reduced in phenytoin-treated mice. These results suggest that phenytoin treatment preferentially induces a Th2 type response. We also observed that plasma ACTH and corticosterone levels were increased in phenytoin-treated mice, and speculated that phenytoin might act directly and indirectly, through HPA axis activation, on the immune system to modulate Th1/Th2 balance.     

Metabolic inventory of Streptococcus pneumoniae growing in a chemical defined environment

The Gram-positive bacterium Streptococcus pneumoniae can cause a broad range of severe diseases including pneumonia and septicemia. The pneumococcal pathophysiology is highly dependent on host nutrients such as purines, pyrimidines, amino acids and carbon sources. Therefore, we aimed to decipher the metabolome with a metabolomics approach that allows for the investigation of the basic metabolic characteristics during growth in a chemical defined medium composed of typical host metabolites. By using a combination of ¹H-NMR, HPLC–MS and GC–MS methods we monitored extracellular uptake and secretion of metabolites as well as the intracellular metabolic composition. Employing our validated protocol for the pneumococcal intracellular metabolome analysis, a time resolved snapshot of the primary metabolism of pneumococci was obtained. The intracellular metabolic profile indicates a high glycolytic flux and displays high concentrated precursors of peptidoglycan synthesis probably to fuel cell‐wall‐metabolism in growing cells. Furthermore, our data reflect the biochemical dependency for S. pneumoniae on external host derived nutrients such as nucleosides. These essential pathways may serve as new targets in the drug development against S. pneumoniae.     

Blocking induction of T helper type 2 responses prevents development of disease in a model of childhood asthma

Early-life respiratory viral infections are linked to subsequent development of allergic asthma in children. We assessed the underlying immunological mechanisms in a novel model of the induction phase of childhood asthma. BALB/c mice were infected neonatally with pneumonia virus of mice, then sensitized intranasally with ovalbumin following recovery. Animals were challenged with low levels of aerosolized ovalbumin for 4 weeks to induce changes of chronic asthma, then received a single moderate-level challenge to elicit mild acute allergic inflammation. To inhibit the initial induction of a T helper type 2 (Th2) response, we administered neutralizing antibodies against interleukin (IL)-4 or IL-25, then assessed development of airway inflammation and remodelling. Anti-IL-4 administered during chronic challenge prevented development of chronic and acute allergic inflammation, as well as goblet cell hyperplasia/metaplasia, but features of remodelling such as subepithelial fibrosis and epithelial hypertrophy were unaffected. In contrast, anti-IL-25 had limited effects on the airway inflammatory response but prevented key changes of remodelling, although it had no effect on goblet cells. Both antibodies suppressed development of a Th2 response, while anti-IL-25 also promoted a Th17 response. In further experiments, anti-IL-25 was administered in early life alone, and again had limited effects on airway inflammation, but prevented development of airway wall remodelling. We conclude that in this murine model of childhood asthma, administration of anti-IL-4 or anti-IL-25 prevents development of some key features of asthma, suggesting that suppression of development of a Th2 response during the neonatal period or later in childhood could be effective for primary prevention.     

Metabolic regulation of innate and adaptive lymphocyte effector responses

Innate and adaptive lymphocytes employ diverse effector programs that provide optimal immunity to pathogens and orchestrate tissue homeostasis, or conversely can become dysregulated to drive progression of chronic inflammatory diseases. Emerging evidence suggests that CD4⁺ T helper cell subsets and their innate counterparts, the innate lymphoid cell family, accomplish these complex biological roles by selectively programming their cellular metabolism in order to instruct distinct modules of lymphocyte differentiation, proliferation, and cytokine production. Further, these metabolic pathways are significantly influenced by tissue microenvironments and disease states. Here, we summarize our current knowledge on how cell-intrinsic metabolic factors modulate the context-dependent bioenergetic pathways that govern innate and adaptive lymphocytes. Further, we propose that a greater understanding of these pathways may lead to the identification of unique features in each population and provoke the development of novel therapeutic strategies to modulate lymphocytes in health and disease.     

Direct and indirect role of Toll-like receptors in T cell mediated immunity

Toll-like receptors (TLR) are pathogen-associated molecular patterns (PAMPs) recognition receptors that playan important role in protective immunity against infection and inflammation.They act as central integrators ofa wide variety of signals,responding to diverse agonists of microbial products.Stimulation of Toll-like receptorsby microbial products leads to signaling pathways that activate not only innate,but also adaptive immunity byAPC dependent or independent mechanisms.Recent evidence revealed that TLR signals played a determiningrole in the skewing of na(?)ve T cells towards either Th1 or Th2 responses.Activation of Toll-like receptors alsodirectly or indirectly influences regulatory T cell functions.Therefore,TLRs are required in both immuneactivation and immune regulation.Study of TLRs has significantly enhanced our understanding of innate andadaptive immune responses and provides novel therapeutic approaches against infectious and inflammatorydiseases.Cellular & Molecular Immunology.2004;1(4):239-246.     

CD40-CD154: A perspective from type 2 immunity

The interaction between CD40 and CD154 (CD40 ligand) is central in immunology, participating in CD4⁺ T cell priming by dendritic cells (DC), CD4⁺ T cell help to B cells and classical macrophage activation by CD4⁺ T cells. However, its role in the Th2 side of immunology including helminth infection remains incompletely understood. Contrary to viral and bacterial stimuli, helminth products usually do not cause CD40 up-regulation in DC, and exogenous CD40 ligation drives Th2-biased systems towards Th1. On the other hand, CD40 and CD154 are necessary for induction of most Th2 responses. We attempt to reconcile these observations, mainly by proposing that (i) CD40 up-regulation in DC in Th2 systems is mostly induced by alarmins, (ii) the Th2 to Th1 shift induced by exogenous CD40 ligation is related to the capacity of such ligation to enhance IL-12 production by myeloid cells, and (iii) signals elicited by endogenous CD154 available in Th2 contexts and by exogenous CD40 ligation are probably different. We stress that CD40-CD154 is important beyond cognate cellular interactions. In such a context, we argue that the proliferation response of B-cells to IL-4 plus CD154 reflects a Th2-specific mechanism for polyclonal B-cell amplification and IgE production at infection sites. Finally, we argue that CD154 is a general immune activation signal across immune polarization including Th2, and propose that competition for CD154 at tissue sites may provide negative feedback on response induction at each site.     

Metabolic effects of L-citrulline in type 2 diabetes

The prevalence of type 2 diabetes (T2D) is increasing worldwide. Decreased nitric oxide (NO) bioavailability is involved in the pathophysiology of T2D and its complications. L -citrulline (Cit), a precursor of NO production, has been suggested as a novel therapeutic agent for T2D. Available data from human and animal studies indicate that Cit supplementation in T2D increases circulating levels of Cit and L -arginine while decreasing circulating glucose and free fatty acids and improving dyslipidemia. The underlying mechanisms for these beneficial effects of Cit include increased insulin secretion from the pancreatic β cells, increased glucose uptake by the skeletal muscle, as well as increased lipolysis and β-oxidation, and decreased glyceroneogenesis in the adipose tissue. Thus, Cit has antihyperglycemic, antidyslipidemic, and antioxidant effects and has the potential to be used as a new therapeutic agent in the management of T2D. This review summarizes available literature from human and animal studies to explore the effects of Cit on metabolic parameters in T2D. It also discusses the possible mechanisms underlying Cit-induced improved metabolic parameters in T2D.     

Development of protective immunity against cutaneous leishmaniasis is dependent on STAT1-mediated IFN signaling pathway

Although STAT1-dependent signaling mediates biological functions of IFN-alpha/beta and IFN-gamma, recent reports indicate that STAT1-independent IFN signaling also regulates expression of several genes. To determine the roles of STAT1-dependent and -independent IFN signaling in the regulation of immunity during cutaneous leishmaniasis, we studied the course of Leishmania major infection in resistant C57BL/6 mice lacking the STAT1 gene. While L. major-infected STAT1(+/+) mice resolved their lesions, STAT1(-/-) mice developed large lesions containing significantly more parasites. Moreover, the inability of STAT1(-/-) mice to control L. major infection was due to the lack of Th1 development associated with reduced production of IL-12, IFN-gamma and nitric oxide. Although STAT1(-/-) mice produced more IL-4 and total IgE than STAT1(+/+) mice later during infection, these differences were not significant. Nevertheless, at these time points lymph node cells from STAT1(-/-) mice produced significantly more IL-10. Finally, STAT1(-/-) mice were also susceptible to low dose L. major infection. Thesefindings demonstrate that STAT1-mediated IFN signaling is indispensable for the development of protective immunity against cutaneous L. major infection. Moreover, they also suggest that the protective role of STAT1-mediated signaling is due to its ability to induce Th1 development during infection with this parasite.