The role of innate immunity in diabetic nephropathy and their therapeutic consequences

Diabetic nephropathy (DN) is an enduring condition that leads to inflammation and affects a substantial number of individuals with diabetes worldwide. A gradual reduction in glomerular filtration and emergence of proteins in the urine are typical aspects of DN, ultimately resulting in renal failure. Mounting evidence suggests that immunological and inflammatory factors are crucial for the development of DN. Therefore, the activation of innate immunity by resident renal and immune cells is critical for initiating and perpetuating inflammation. Toll-like receptors (TLRs) are an important group of receptors that identify patterns and activate immune responses and inflammation. Meanwhile, inflammatory responses in the liver, pancreatic islets, and kidneys involve inflammasomes and chemokines that generate pro-inflammatory cytokines. Moreover, the activation of the complement cascade can be triggered by glycated proteins. This review highlights recent findings elucidating how the innate immune system contributes to tissue fibrosis and organ dysfunction, ultimately leading to renal failure. This review also discusses innovative approaches that can be utilized to modulate the innate immune responses in DN for therapeutic purposes.

Pharmacological Investigation on the Qi-Invigorating Action of Schisandrin B: Effects on Mitochondrial ATP Generation in Multiple Tissues and Innate/Adaptive Immunity in Mice

Schisandrae Fructus, containing schisandrin B (Sch B) as its main active component, is recognized in traditional Chinese medicine (TCM) for its Qi-invigorating properties in the five visceral organs. Our laboratory has shown that the Qi-invigorating action of Chinese tonifying herbs is linked to increased mitochondrial ATP generation and an enhancement in mitochondrial glutathione redox status. To explore whether Sch B can exert Qi-invigorating actions across various tissues, we investigated the effects of Sch B treatment on mitochondrial ATP generation and glutathione redox status in multiple mouse tissues ex vivo. In line with TCM theory, which posits that Zheng Qi generation relies on the Qi function of the visceral organs, we also examined Sch B’s impact on natural killer cell activity and antigen-induced splenocyte proliferation, both serving as indirect measures of Zheng Qi. Our findings revealed that Sch B treatment consistently enhanced mitochondrial ATP generation and improved mitochondrial glutathione redox status in mouse tissues. This boost in mitochondrial function was associated with stimulated innate and adaptive immune responses, marked by increased natural killer cell activity and antigen-induced T/B cell proliferation, potentially through the increased generation of Zheng Qi.

MEKK1, MKK1/MKK2 and MPK4 function together in a mitogen-activated protein kinase cascade to regulate innate immunity in plants

Mitogen-activated protein kinase （MAPK） cascades play important roles in regulating plant innate immune responses. In a genetic screen to search for mutants with constitutive defense responses, we identified multiple alleles of mpk4 and mekkl that exhibit cell death and constitutive defense responses. Bimolecular fluorescence complemen- tation （BiFC） analysis showed that both MPK4 and MEKK1 interact with MKK1 and MKK2, two closely related MAPK kinases, mkkl and mkk2 single mutant plants do not have obvious mutant phenotypes. To test whether MKK1 and MKK2 function redundantly, mkkl mkk2 double mutants were generated. The mkkl mkk2 double mutant plants die at seedling stage and the seedling-lethality phenotype is temperature-dependent. Similar to the mpk4 and mekkl mutants, the mkkl mkk2 double mutant seedlings accumulate high levels of H202, display spontaneous cell death, constitutively express Pathogenesis Related （PR） genes and exhibit pathogen resistance. In addition, activation of MPK4 by fig22 is impaired in the mkkl mkk2 double mutants, suggesting that MKK1 and MKK2 function together with MPK4 and MEKK1 in a MAP kinase cascade to negatively regulate innate immune responses in plants.

Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy

AIM To study the innate immune function in ulcerative colitis(UC) patients who fail to respond to anti-tumor necrosis factor(TNF) therapy.METHODS Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell(PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor(TLR) expression and cytokine production post TLR stimulation was assessed in UC "responders"(n = 12) and "non-responders"(n = 12) and compared to healthy controls(n = 12). Erythrocyte sedimentation rate(ESR) and C-reactive protein(CRP) levels were measured in blood to assess disease severity/activity and inflammation. Pro-inflammatory(TNF, IL-1β, IL-6), immuno-regulatory(IL-10), Th1(IL-12, IFNγ) and Th2(IL-9, IL-13, IL-17A) cytokine expression was measured with enzyme-linked immunosorbent assay while TLR cellular composition and intracellular signalling was assessed with FACS.RESULTS Prior to anti-TNF therapy, responders and nonresponders had similar level of disease severity and activity. PBMC's ability to respond to TLR stimulation was not affected by TNF therapy, patient's severity of the disease and inflammation or their medication use. At baseline, non-responders had elevated innate but not adaptive immune responses compared to responders(P < 0.05). Following TLR stimulation, nonresponders had consistently reduced innate cytokine responses to all TLRs compared to healthy controls(P < 0.01) and diminished TNF(P < 0.001) and IL-1β(P < 0.01) production compared to responders. This innate immune dysfunction was associated with reduced number of circulating plasmacytoid dendritic cells(p DCs)(P < 0.01) but increased number of CD4+ regulatory T cells(Tregs)(P = 0.03) as well as intracellular accumulation of IRAK4 in non-responders following TLR-2,-4 and-7 activation(P < 0.001). CONCLUSION Reduced innate immunity in non-responders may explain reduced efficacy to anti-TNF therapy. These serological markers may prove useful in predicting the outcome of costly anti-TNF therapy.

Regulation of microRNA by hepatitis B virus infection and their possible association with control of innate immunity

Hepatitis B virus(HBV)chronically infects more than350 million people worldwide.HBV causes acute and chronic hepatitis,and is one of the major causes of cirrhosis and hepatocellular carcinoma.There exist complex interactions between HBV and the immune system including adaptive and innate immunity.Tolllike receptors(TLRs)and TLR-signaling pathways are important parts of the innate immune response in HBV infections.It is well known that TLR-ligands could suppress HBV replication and that TLRs play important roles in anti-viral defense.Previous immunological studies demonstrated that HBV e antigen(HBeAg)is more efficient at eliciting T-cell tolerance,including production of specific cytokines IL-2 and interferon gamma,than HBV core antigen.HBeAg downregulates cytokine production in hepatocytes by the inhibition of MAPK or NF-κB activation through the interaction with receptor-interacting serine/threonine protein kinase.MicroRNAs(miRNAs)are also able to regulate various biological processes such as the innate immune response.When the expressions of approximately 1000 miRNAs were compared between human hepatoma cells HepG2 and HepG2.2.15,which could produce HBV virion that infects chimpanzees,using real-time RT-PCR,we observed several different expression levels in miRNAs related to TLRs.Although we and others have shown that HBV modulates the host immune response,several of the miRNAs seem to be involved in the TLR signaling pathways.The possibility that alteration of these miRNAs during HBV infection might play a critical role in innate immunity against HBV infection should be considered.This article is intended to comprehensively review the association between HBV and innate immunity,and to discuss the role of miRNAs in the innate immune response to HBV infection.

Tetrahedral Framework Nucleic Acid-Based Delivery of Resveratrol Alleviates Insulin Resistance:From Innate to Adaptive Immunity

Obesity-induced insulin resistance is the hallmark of metabolic syndrome,and chronic,low-grade tissue inflammation links obesity to insulin resistance through the activation of tissue-infiltrating immune cells.Current therapeutic approaches lack efficacy and immunomodulatory capacity.Thus,a new therapeutic approach is needed to prevent chronic inflammation and alleviate insulin resistance.Here,we synthesized a tetrahedral framework nucleic acid(tFNA)nanoparticle that carried resveratrol(RSV)to inhibit tissue inflammation and improve insulin sensitivity in obese mice.The prepared nanoparticles,namely tFNAs-RSV,possessed the characteristics of simple synthesis,stable properties,good water solubility,and superior biocompatibility.The tFNA-based delivery ameliorated the lability of RSV and enhanced its therapeutic efficacy.In high-fat diet(HFD)-fed mice,the administration of tFNAs-RSV ameliorated insulin resistance by alleviating inflammation status.tFNAs-RSV could reverse M1 phenotype macrophages in tissues to M2 phenotype macrophages.As for adaptive immunity,the prepared nanoparticles could repress the activation of Th1 and Th17 and promote Th2 and Treg,leading to the alleviation of insulin resistance.Furthermore,this study is the first to demonstrate that tFNAs,a nucleic acid material,possess immunomodulatory capacity.Collectively,our findings demonstrate that tFNAs-RSV alleviate insulin resistance and ameliorate inflammation in HFD mice,suggesting that nucleic acid materials or nucleic acid-based delivery systems may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.

Crosstalk between innate and adaptive immunity in hepatitis B virus infection

Hepatitis B virus(HBV) infection is a major public healthproblem worldwide. HBV is not directly cytotoxic to infected hepatocytes; the clinical outcome of infection results from complicated interactions between the virus and the host immune system. In acute HBV infection, initiation of a broad, vigorous immune response is res-ponsible for viral clearance and self-limited inflammatory liver disease. Effective and coordinated innate and adaptive immune responses are critical for viral clearance and the development of long-lasting immunity. Chronic hepatitis B patients fail to mount efficient innate and adaptive immune responses to the virus. In particular, HBV-specific cytotoxic T cells, which are crucial for HBV clearance, are hyporesponsiveness to HBV infection. Accumulating experimental evidence obtained from the development of animal and cell line models has highlighted the importance of innate immunity in the early control of HBV spread. The virus has evolved immune escape strategies, with higher HBV loads and HBV protein concentrations associated with increasing impairment of immune function. Therefore, treatment of HBV infection requires inhibition of HBV replication and protein expression to restore the suppressed host immunity. Complicated interactions exist not only between innate and adaptive responses, but also among innate immune cells and different components of adaptive responses. Improved insight into these complex interactions are important in designing new therapeutic strategies for the treatment HBV infection. In this review, we summarize the current knowledge regarding the cross-talk between the innate and adaptive immune responses and among different immunocytes in HBV infection.

Role of innate immunity in the development of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the most common form of liver cancer worldwide.It is caused by a variety of risk factors,most common ones being infection with hepatitis viruses,alcohol,and obesity.HCC often develops in the background of underlying cirrhosis,and even though a number of interventional treatment methods are currently in use,recurrence is fairly common among patients who have had a resection.Therefore,whole liver transplantation remains the most practical treatment option for HCC.Due to the growing incidence of HCC,intense research efforts are being made to understand cellular and molecular mechanisms of the disease so that novel therapeutic strategies can be developed to combat liver cancer.In recent years,it has become clear that innate immunity plays a critical role in the development of a number of liver diseases,including HCC.In particular,the activation of Toll-like receptor signaling results in the generation of immune responses that often results in the production of proinflammatory cytokines and chemokines,and could cause acute inflammation in the liver.In this review,the current knowledge on the role of innate immune responses in the development and progression of HCC is examined,and emerging therapeutic strategies based on molecular mechanisms of HCC are discussed.

Innate immunity and hepatocarcinoma:Can toll-likereceptors open the door to oncogenesis?

Hepatocarcinoma(HCC) is a highly prevalent cancer worldwide and its inflammatory background was established long ago.Recent studies have shown that innate immunity is closely related to the HCC carcinogenesis.An effective innate immunity response relies on the tolllike receptors(TLR) found in several different liver cells which,through different ligands and many signaling pathways can elicit,not only a pro-inflammatory but also an oncogenic or anti-oncogenic response.Our aim was to study the role of TLRs in the liver oncogenesis and as a consequence their value as potential therapeutic targets.We performed a systematic review of PubMed searching for original articles studying the relationship between HCC and TLRs until March 2015.TLR2 appears to be a fundamental stress-sensor as its absence reveals an augmented tendency to accumulate DNAdamages and to cell survival.However,pathways are still not fully understood as TLR2 up-regulation was also associated to enhanced tumorigenesis.TLR3 has a wellknown protective role influencing crucial processes like angiogenesis,cell growth or proliferation.TLR4 works as an interesting epithelial-mesenchymal transition's inducer and a promoter of cell survival probably inducing HCC carcinogenesis even though an anti-cancer role has already been observed.TLR9's influence on carcinogenesis is also controversial and despite a potential anticancer capacity,a pro-tumorigenic role is more likely.Genetic polymorphisms in some TLRs have been found and its influence on the risk of HCC has been reported.As therapeutic targets,TLRs are already in use and have a great potential.In conclusion,TLRs have been shown to be an interesting influence on the HCCs microenvironment,with TLR3 clearly determining an antitumour influence.TLR4 and TLR9 are considered to have a positive relationship with tumour development even though,in each of them anti-tumorigenic signals have been described.TLR2 presents a more ambiguous role,possibly depending on the stage of the inflammationHCC axis.

Gut epithelial barrier dysfunction in humanimmunodeficiency virus-hepatitis C virus coinfectedpatients:Influence on innate and acquired immunity

Even in cases where viral replication has been controlled by antiretroviral therapy for long periods of time, human immunodeficiency virus(HIV)-infected patients have several non-acquired immunodeficiency syndrome(AIDS) related co-morbidities, including liver disease, cardiovascular disease and neurocognitive decline, which have a clear impact on survival. It has been considered that persistent innate and acquired immune activation contributes to the pathogenesis of these non-AIDS related diseases. Immune activation has been related with several conditions, remarkably with the bacterial translocation related with the intestinal barrier damage by the HIV or by hepatitis C virus(HCV)-related liver cirrhosis. Consequently, increased morbidity and mortality must be expected in HIV-HCV coinfected patients. Disrupted gut barrier lead to an increased passage of microbial products and to an activation of the mucosal immune system and secretion of inflammatory mediators, which in turn might increase barrier dysfunction. In the present review, the intestinal barrier structure, measures of intestinal barrier dysfunction and the modifications of them in HIV monoinfection and in HIV-HCV coinfection will be considered. Both pathogenesis and the consequences for the progression of liver disease secondary to gut microbial fragment leakage and immune activation will be assessed.

Hepatitis B virus-persistent infection and innate immunity defect: Cell-related or virus-related?

The outcomes of hepatitis B virus(HBV) infection are closely related to the age at which infection was acquired. Infection acquired in adult life tends to be selflimited, in contrast to perinatal acquirement, for which chronic persistence of the HBV is a general outcome. Innate immunity plays an indispensable role in early virus infection, facilitating virus clearance. However, it has been reported that HBV is under-recognized and poorly eliminated by the innate immune system in the early stages of infection, possibly explaining the long-lasting persistence of viremia afterwards. Furthermore, due to the existence of covalently closed circular DNA, chronic HBV clearance is very difficult, even when patients are given interferon-α and nucleotide/nucleoside analogs for antiviral therapy. The mechanism by which HBV evades innate immune recognition and establishes persistent infection remains a subject of debate. Besides, some researchers are becoming more interested in how to eradicate chronic HBV infection by restoring or boosting innate immunity. This review aimed to summarize the current knowledge on how intrahepatocyte signaling pathways and innate immune cells act after the onset of HBV infection and how these actions are related to the persistence of HBV. We anticipate the insights presented herein to be helpful for future development of novel immune therapeutic strategies to fight HBV infection.

Interplay of autophagy and innate immunity in Crohn's disease: A key immunobiologic feature

Crohn's disease representing a clinical phenotype of inflammatory bowel disease is a polygenic immune disorder with complex multifactor etiology. Recent genome-wide association studies of susceptibility loci have highlighted on the importance of the autophagy pathway, which previously had not been implicated in disease pathology. Autophagy represents an evolutionarily highly conserved multi-step process of cellular self-digestion due to sequestration of excessive, damaged, or aged proteins and intracellular organelles in double-membranous vesicles of autophagosomes, terminally self-digested in lysosomes. Autophagy is deeply involved in regulation of cell development and differentiation, survival and senescence, and it also fundamentally affects the inflammatory pathways, as well as the innate and adaptive arms of immune responses. Autophagy is mainly activated due to sensors of the innate immunity, i.e., by pattern recognition receptor signaling. The interplay of genes regulating immune functions is strongly influenced by the environment, especially gut resident microbiota. The basic challenge for intestinal immune recognition is the requirement of a simultaneous delicate balance between tolerance and responsiveness towards microbes. On the basis of autophagy-related risk genetic polymorphisms (ATG16L1, IRGM , NOD2 , XBP1 ) impaired sensing and handling of intracellular bacteria by innate immunity, closely interrelated with the autophagic and unfolded protein pathways seem to be the most relevant immunobiologic events. Autophagy is now widely considered as a key regulator mechanism with the capacity to integrate several aspects of Crohn's disease pathogenesis. In this review, recent advances in the exciting crosstalk of susceptibility coding variants-related autophagy and innate immunity are discussed.

Regulatory effects of dietary L-Arg supplementation on the innate immunity and antioxidant ability in broiler chickens

Here, we investigated the effect of dietary arginine（Arg） supplementation on innate immunity and the antioxidant ability of broiler chickens. The experiment was designed as a single-factorial arrangement（n=8 cages/treatment, six birds/cage）, and we used four dietary Arg concentrations（10.0, 15.0, 20.0 or 25.0 g kg–1）. On day 21, the birds were killed to obtain spleen, cecal tonsil and liver samples to determine the gene expression and antioxidant characteristics. Increasing the Arg concentration linearly decreased（P0.05） the m RNA expression of splenic interleukin-18（IL-18） and tumor necrosis factor-α（TNF-α）. Dietary Arg supplementation quadratically decreased（P0.05） the expression of interleukin-1b（IL-1b） and interferon-γ（IFN-γ） m RNA in the spleen. Increasing Arg concentrations linearly and quadratically reduced the expression of IL-18 m RNA in the spleen. Meanwhile, increasing dietary Arg supplementation linearly and quadratically increased the lymphotactin m RNA（P0.05） expression, and linearly increased the macrophage inflammatory protein-1β（MIP-1β） and toll-like receptor 15（TLR15） m RNA expression in the cecal tonsils. Dietary Arg supplementation linearly（P0.05） increased the glutathione peroxidase（GSH-Px）, catalase（CAT）, and lysozyme（LZM） activities in the liver. However, the malondialdehyde（MDA） activity in the liver was not influenced by the dietary Arg concentration（P0.05）. No significant（P0.05） effect was found on the activity of superoxide dismutase（SOD） in the liver. Thus high levels of Arg supplementation（20.0 g kg^（–1）） may potentially suppress the innate immunity of broiler chickens, and dietary Arg supplementation enhances the antioxidant activity in broiler chickens.

Innate immunity–the hallmark of Helicobacter pylori infection in pediatric chronic gastritis

BACKGROUND Innate immunity was found to be associated with both persistence of Helicobacter pylori(H.pylori)infection and increased risk of gastric cancer.AIM To identify the risk factors associated with H.pylori infection and to establish the role of TLR9 rs352140 in suppressing or promoting inflammation related to this infection in children.METHODS We performed a study of 155 children with digestive symptoms,who were divided into two groups according to the histopathological exam:Group 1–48 children with H.pylori-induced chronic gastritis,and Group 2–control group.RESULTS Rural area and poor living conditions were significantly associated with H.pylori chronic gastritis(P=0.0042/P<0.0001).Both positive immunoglobulin A anti H.pylori and the rapid urease test were significantly associated with H.pylori infection(P<0.0001).Significantly higher values of leukocytes and neutrophils within the peripheral blood were found in children with H.pylori chronic gastritis(P=0.111/P=0.284).We found a significant positive correlation between the variant TT genotype of TLR9 rs352140 polymorphism and both leucocytes and neutrophils(P=0.0225/P=0.0292).CONCLUSION Variant TT genotype carriers of the TLR9 rs352140 gene polymorphism might have a more severe degree of inflammation.

Innate immunity in inflammatory bowel disease

The human intestinal tract is home to an enormous bacterial flora. The host defense against microorganisms can be divided into innate and adaptive immunity. The former is the most immediate line of response to immunologic challenges presented by bacteria, viruses, and fungi. The mucosal immune system has evolved to balance the need to respond to pathogens while co-existing with commensal bacteria and food antigens. In inflammatory bowel disease （IBD）, this hyporesponsiveness or tolerance breaks down and inflammation supervenes driven by the intestinal microbial flora. Bacteria contain compounds and are recognized by a variety of receptors, including Toll-like receptors （TLRs） and NODs （a family of intracellular bacterial sensors） and are potent stimuli of innate immune responses. Several mutations in these receptors have been associated with development of IBD.

Dectin-1 agonist curdlan modulates innate immunity to Aspergillus fumigatus in human corneal epithelial cells

· AIM: To explore the immunomodulatory effects of curdlan on innate immune responses against Aspergillus fumigatus(A. fumigatus) in cultured human corneal epithelial cells(HCECs), and whether C-type lectin receptor Dectin-1 mediates the immunomodulatory effects of curdlan.·METHODS: The HCECs were stimulated by curdlan in different concentrations(50, 100, 200, 400 μg/m L) for various time. Then HCECs pretreated with or without laminarin(Dectin-1 blocker, 0.3 mg/m L) and curdlan were stimulated by A. fumigatus hyphae. The m RNA and protein production of tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6) were determined by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The protein level of Dectin-1 was measured by Western blot.· RESULTS: Curdlan stimulated m RNA expression of TNF-α and IL-6 in a dose and time dependent manner in HCECs. Curdlan pretreatment before A. fumigatus hyphae stimulation significantly enhanced the expression of TNF-α and IL-6 at m RNA and protein levels compared with A. fumigatus hyphae stimulation group(P 【0.05).Both curdlan and A. fumigatus hyphae up-regulated Dectin-1 protein expression in HCECs, and Dectin-1expression was elevated to 1.5- to 2-fold by curdlan pretreatment followed hyphae stimulation. The Dectin-1blocker laminarin suppressed the m RNA expression and protein production of TNF-α and IL-6 induced by curdlan and hyphae(P 【0.05).· CONCLUSION: These findings demonstrated that curdlan pretreatment enhanced the inflammatory response induced by A. fumigatus hyphae in HCECs.Dectin-1 is essential for the immunomodulatory effectsof curdlan. Curdlan may have high clinical application values in fungal keratitis treatment.

Evaluation of fatty acid metabolism and innate immunity interactions between commercial broiler, F1 layer × broiler cross and commercial layer strains selected for different growth potentials

Background： The broiler industry has undergone intense genetic selection over the past 50 yr. resulting in improvements for growth and feed efficiency, however, significant variation remains for performance and growth traits. Production improvements have been coupled with unfavourable metabolic consequences, including immunological trade-offs for growth, and excess fat deposition. To determine whether interactions between fatty acid（FA） metabolism and innate immunity may be associated with performance variations commonly seen within commercial broiler flocks, total carcass lipid %, carcass and blood FA composition, as wel as genes involved with FA metabolism, immunity and cel ular stress were investigated in male birds of a broiler strain, layer strain and F1 layer × broiler cross at d 14 post hatch. Heterophil：lymphocyte ratios, relative organ weights and bodyweight data were also compared.Results： Broiler bodyweight（n = 12） was four times that of layers（n = 12） by d 14 and had significantly higher carcass fat percentage compared to the cross（n = 6; P = 0.002） and layers（P = 0.017） which were not significantly different from each other（P = 0.523）. The carcass and whole blood FA analysis revealed differences in the FA composition between the three groups indicating altered FA metabolism, despite al being raised on the same diet. Genes associated with FA synthesis andβ-oxidation were upregulated in the broilers compared to the layers indicating a net overal increase in FA metabolism,which may be driven by the larger relative liver size as a percentage of bodyweight in the broilers. Genes involved in innate immunity such as TLR2 and TLR4, as wel as organel e stress indicators ERN1 and XBP1 were found to be nonsignificant, with the exception of high expression levels of XBP1 in layers compared to the cross and broilers. Additional y there was no difference in heterophil： lymphocytes between any of the birds.Conclusions： The results provide evidence that genetic selection may be associated with altered metabolic processes between broilers, layers and their F1 cross. Whilst there is no evidence of interactions between FA metabolism, innate immunity or cel ular stress, further investigations at later time points as growth and fat deposition increase would provide useful information as to the effects of divergent selection on key metabolic and immunological processes.

Human Milk Oligosaccharides Enhance Innate Immunity to Respiratory Syncytial Virus and Influenza <i>in Vitro</i>

Human milk oligosaccharides (HMO) contribute to innate immunity by enhancing growth of beneficial bacteria, epithelial cell maturation and mucosal barrier integrity. They have immunomodulatory effects and can block pathogen binding to host cell surface glycans or receptors. We investigated the effects of 2’-fucosyllactose (2’FL), 6’-sialyllactose (6’SL), 3’-sialyllactose (3’SL) and lacto-N-neoTetraose (LNnT) on human respiratory epithelial cell lines or peripheral blood mononuclear cells (PBMCs) following respiratory viral infectionin vitro. Expression of cytokines and viral load were monitored in infected cells. These biomarkers of innate immunity were selected since viral load and cytokine levels (IP-10, MIP-1α, IL-6, IL-8, TNF-α) have been correlated with disease severity in respiratory syncytial virus (RSV) and influenza (IAV) virus infectionin vivo. 2’FL significantly decreased RSV viral load and cytokines associated with disease severity (IL-6, IL-8, MIP-1α) and inflammation (TNF-α, MCP-1) in airway epithelial cells. LNnT and 6’SL significantly decreased IAV viral load in airway epithelial cells. 6’SL dose-dependently down-regulated IP-10 and TNF-α in RSV infected PBMCs. HMO at or below levels found in breast milk enhance innate immunity to respiratory viruses in vitro and may interact directly with cells to modulate biomarkers of innate immunity.

Effect of temperature on antioxidant defense and innate immunity in Brandt’s voles

Ambient temperature is an importa nt factor in flue ncing many physiological processes, in eluding antioxidant defense and immunity. In the present study, we tested the hypothesis that antioxidant defense and immunity are suppressed by high and low temperature treatme nt in Bran dt's voles (Lasiopodomys brandtii). Thirty male voles were randomly assigned into different temperature groups (4, 23, and 32℃, n=10 for each group), with the treatment course lasting for 27 d. Results showed that low temperature in creased gross en ergy in take (GEI) and liver, heart, and kidney mass, but decreased body fat mass and dry carcass mass. With the decline in temperature, hydrogen peroxide (H2O2) concentration, which is indicative of reactive oxyge n species (ROS) levels, in creased in the liver, decreased in the heart, and was unchanged in the kidney, testis, and small intestine. Lipid peroxidation indicated by malonaldehyde (MDA) content in the liver, heart, kidney, testis, and small intestine did not differ among groups, implying that high and low temperature did not cause oxidative damage. Similarly, superoxide dismutase (SOD) and catalase (CAT) activities and total antioxidant capacity (TAOC) in the five tissues did not respond to low or high temperature, except for elevation of CAT activity in the testis upon cold exposure. Bacteria killing capacity, which is indicative of innate immunity, was nearly suppressed in the 4℃ group in contrast to the 23℃ group, whereas spleen mass and white blood cells were un affected by temperature treatment. The levels of testosterone, but not corticostero ne, were in flue need by temperature treatment, though neither were correlated with innate immunity, H2O2 and MDA levels, or SOD, CAT, and TAOC activity in any detected tissues. Overall, these results showed that temperature had different in flue nces on oxidative stress, an tioxida nt en zymes, and immunity, which depended on the tissues and parameters tested. Up-regulation or maintenance of an tioxida nt defe nse might be an importa nt mechanism for voles to survive highly variable environmental temperatures.

Prognostic value of innate and adaptive immunity in colorectal cancer

Colorectal cancer(CRC) remains one of the major public health problems throughout the world.Originally depicted as a multi-step dynamical disease,CRC develops slowly over several years and progresses through cytologically distinct benign and malignant states,from single crypt lesions through adenoma,to malignant carcinoma with the potential for invasion and metastasis.Moving from histological observations since a long time,it has been recognized that inflammation and immunity actively participate in the pathogenesis,surveillance and progression of CRC.The advent of immunohistochemical techniques and of animal models has improved our understanding of the immune dynamical system in CRC.It is well known that immune cells have variable behavior controlled by complex interactions in the tumor microenvironment.Advances in immunology and molecular biology have shown that CRC is immunogenic and that host immune responses influence survival.Several lines of evidence support the concept that tumor stromal cells,are not merely a scaffold,but rather they influence growth,survival,and invasiveness of cancer cells,dynamically contributing to the tumor microenvironment,together with immune cells.Different types of immune cells infiltrate CRC,comprising cells of both the innate and adaptive immune system.A relevant issue is to unravel the discrepancy between the inhibitory effects on cancer growth exerted by the local immune response and the promoting effects on cancer proliferation,invasion,and dissemination induced by some types of inflammatory cells.Here,we sought to discuss the role played by innate and adaptive immune system in the local progression and metastasis of CRC,and the prognostic information that we can currently understand and exploit.