肝脏固有免疫系统对肠源性感染的免疫应答与免疫耐受机制

肝特殊的解剖结构及生理特征使其成为暴露肠源性抗原的主要器官。由于肝具有独特的固有免疫系统,在正常情况下,肝分布多种致耐受的抗原提呈细胞,对持续性表达或递呈于肝的肠源性抗原物质,诱发针对该抗原的系统性免疫耐受,避免肝受到不必要的免疫损伤。当炎症发生及肝脏固有免疫系统活化时,则通过免疫效应细胞及免疫效应因子对肠源性病原体发挥强烈地免疫应答以控制感染。该过程形成机制的研究对肝功能的理解及肝性疾病的预防与治疗至关重要。本文就肝固有免疫系统对肠源性感染的免疫应答与免疫耐受形成机制作一综述。     

妊娠期和哺乳期双酚A暴露对幼年子代小鼠焦虑和抑郁行为的影响

双酚A(bisphenol-A,BPA)对脑和行为发育的低剂量效应已引起广泛关注。本研究分别于妊娠最后2周和分娩后前2周母鼠灌胃BPA(0.4和4 mg/kg.d),然后以旷场、高架十字迷宫、明暗箱、镜子迷宫、强迫游泳和被动回避箱等模型,分别测试幼年期(生后21～28 d)子代小鼠的行为,探讨围生期不同阶段的BPA暴露对幼年仔鼠自发活动、探究、焦虑、抑郁和被动回避记忆等行为的影响。结果表明,围生期不同阶段的BPA暴露对这些行为的影响不同,主要表现为:妊娠期BPA暴露促进幼年仔鼠的活动性,减弱其焦虑状态,提高雄性仔鼠的探究能力,促进雌性仔鼠的被动回避记忆;哺乳期BPA暴露减少幼年仔鼠的活动性,但对其焦虑行为的影响相对较弱,不影响仔鼠的探究能力和被动回避记忆;而妊娠期和哺乳期BPA暴露均加剧幼年仔鼠的抑郁行为。以上结果提示,妊娠期和哺乳期BPA暴露均可影响幼年仔鼠的焦虑、抑郁、被动回避记忆等多种行为,而妊娠期可能是BPA影响的更敏感时期。     

A Strong Immune Response in Young Adult Honeybees Masks Their Increased Susceptibility to Infection Compared to Older Bees

Honeybees, Apis mellifera, show age-related division of labor in which young adults perform maintenance (“housekeeping”) tasks inside the colony before switching to outside foraging at approximately 23 days old. Disease resistance is an important feature of honeybee biology, but little is known about the interaction of pathogens and age-related division of labor. We tested a hypothesis that older forager bees and younger “house” bees differ in susceptibility to infection. We coupled an infection bioassay with a functional analysis of gene expression in individual bees using a whole genome microarray. Forager bees treated with the entomopathogenic fungus Metarhizium anisopliae s.l. survived for significantly longer than house bees. This was concomitant with substantial differences in gene expression including genes associated with immune function. In house bees, infection was associated with differential expression of 35 candidate immune genes contrasted with differential expression of only two candidate immune genes in forager bees. For control bees (i.e. not treated with M. anisopliae) the development from the house to the forager stage was associated with differential expression of 49 candidate immune genes, including up-regulation of the antimicrobial peptide gene abaecin, plus major components of the Toll pathway, serine proteases, and serpins. We infer that reduced pathogen susceptibility in forager bees was associated with age-related activation of specific immune system pathways. Our findings contrast with the view that the immunocompetence in social insects declines with the onset of foraging as a result of a trade-off in the allocation of resources for foraging. The up-regulation of immune-related genes in young adult bees in response to M. anisopliae infection was an indicator of disease susceptibility; this also challenges previous research in social insects, in which an elevated immune status has been used as a marker of increased disease resistance and fitness without considering the effects of age-related development.     

Low Dose Antigen Exposure for a Finite Period in Newborn Rats Prevents Induction of Mucosal Tolerance

Background

In adult rats, initial exposure to antigens by a mucosal route triggers tolerance such that any subsequent re-exposure, even by a systemic route, results in suppression of immunity. The newborn’s gut is semi-permeable for a finite period to allow maternal antibodies to enter the newborn’s circulation. We propose that antigens introduced in extreme early life can readily traverse the gut wall and therefore circumvent induction of mucosal tolerance.

Methodology/Principle Findings

Rat pups were gavaged with low-doses of ovalbumin (OVA; oral exposure group) or saline (parenteral control group) every second day for several weeks followed by an intraperitoneal (i.p.) injection at 1 month of age. When gavage was initiated the day after birth, newborn oral exposure pups responded with significantly higher anti-OVA IgA, IgM, IgG2a, and IgG1 titres in their serum and anti-OVA IgA, IgG2a and IgG1 titres in their lungs compared to negative control pups. Oral exposure alone failed to induce immunity. Pups exposed to the same treatment regimen starting at 14 days of age showed induction of mucosal tolerance after i.p. immunization. Newborn oral exposure groups subjected to secondary i.p. immunization responded with significantly increased humoral immunity in lung and sera suggesting that once antigen-specific mucosal tolerance if circumvented, it persists. Lymphocytes derived from mesenteric lymph node cells re-simulated with OVA ex vivo, from newborn oral exposure pups exposed to secondary immunization produced significantly higher IFN-γ expression and lymphocyte proliferation relative to control pups indicating prevention of tolerance in the cell-mediated immune system.

Conclusions/Significance

This work demonstrates that newborns may be uniquely qualified to prevent induction of mucosal tolerance to oral antigens. These results should be further explored to establish whether prevention of tolerance by early life oral vaccination can be exploited to prime for mucosal as well as systemic immunity and thus protect this susceptible population against infectious diseases.     

Effect of Chronic Administration of Low Dose Rapamycin on Development and Immunity in Young Rats

Mammalian target of rapamycin (mTOR) regulates cell growth, cell differentiation and protein synthesis. Rapamycin, an inhibitor of mTOR, has been widely used as an immunosuppressant and anti-cancer drug. Recently, mTOR inhibitors have also been reported to be a potential anti-epileptic drug, which may be effective when used in young patients with genetic epilepsy. Thus, a suitable dose of rapamycin which can maintain the normal function of mTOR and has fewer side effects ideally should be identified. In the present study, we first detected changes in marker proteins of mTOR signaling pathway during development. Then we determined the dose of rapamycin by treating rats of 2 weeks of age with different doses of rapamycin for 3 days and detected its effect on mTOR pathway. Young rats were then treated with a suitable dose of rapamycin for 4 weeks and the effect of rapamycin on mTOR, development and immunity were investigated. We found that the expression of the marker proteins of mTOR pathway was changed during development in brain hippocampus and neocortex. After 3 days of treanent, 0.03 mg/kg rapamycin had no effect on phospho-S6, whereas 0.1, 0.3, 1.0 and 3.0 mg/kg rapamycin inhibited phospho-S6 in a dose-dependent manner. However, only 1.0 mg/kg and 3.0 mg/kg rapamycin inhibited phospho-S6 after 4 weeks treatment of rapamycin. Parallel to this result, rats treated with 0.1 and 0.3 mg/kg rapamycin had no obvious adverse effects, whereas rats treated with 1.0 and 3.0 mg/kg rapamycin showed significant decreases in body, spleen and thymus weight. Additionally, rats treated with 1.0 and 3.0 mg/kg rapamycin exhibited cognitive impairment and anxiety as evident by maze and open field experiments. Furthermore, the content of IL-1β, IL-2, IFN-γ, TNF-α in serum and cerebral cortex were significantly decreased in 1.0 and 3.0 mg/kg rapamycin-treated rats. The expression of DCX was also significantly decreased in 1.0 and 3.0 mg/kg rapamycin-treated rats. However, rats treated with 1.0 mg/ kg rapamycin exhibited fewer and milder side effects than those treated with 3.0 mg/kg. In summary, all these data suggest that there is not a rapamycin dose that can inhibit mTOR for epilepsy without causing any side effects, but 1 mg /kg may be the optimal dose for young rats for suppressing mTOR with relatively few side effects.     

In Vitro Analysis of Myd88-mediated Cellular Immune Response to West Nile Virus Mutant Strain Infection

An attenuated West Nile virus (WNV), a nonstructural (NS) 4B-P38G mutant, induced higher innate cytokine and T cell responses than the wild-type WNV in mice. Recently, myeloid differentiation factor 88 (MyD88) signaling was shown to be important for initial T cell priming and memory T cell development during WNV NS4B-P38G mutant infection. In this study, two flow cytometry-based methods – an in vitro T cell priming assay and an intracellular cytokine staining (ICS) – were utilized to assess dendritic cells (DCs) and T cell functions. In the T cell priming assay, cell proliferation was analyzed by flow cytometry following co-culture of DCs from both groups of mice with carboxyfluorescein succinimidyl ester (CFSE) - labeled CD4⁺ T cells of OTII transgenic mice. This approach provided an accurate determination of the percentage of proliferating CD4⁺ T cells with significantly improved overall sensitivity than the traditional assays with radioactive reagents. A microcentrifuge tube system was used in both cell culture and cytokine staining procedures of the ICS protocol. Compared to the traditional tissue culture plate-based system, this modified procedure was easier to perform at biosafety level (BL) 3 facilities. Moreover, WNV- infected cells were treated with paraformaldehyde in both assays, which enabled further analysis outside BL3 facilities. Overall, these in vitro immunological assays can be used to efficiently assess cell-mediated immune responses during WNV infection.     

Impact of Low Dose Prenatal Ethanol Exposure on Glucose Homeostasis in Sprague-Dawley Rats Aged up to Eight Months

Excessive exposure to alcohol prenatally has a myriad of detrimental effects on the health and well-being of the offspring. It is unknown whether chronic low-moderate exposure of alcohol prenatally has similar and lasting effects on the adult offspring’s health. Using our recently developed Sprague-Dawley rat model of 6% chronic prenatal ethanol exposure, this study aimed to determine if this modest level of exposure adversely affects glucose homeostasis in male and female offspring aged up to eight months. Plasma glucose concentrations were measured in late fetal and postnatal life. The pancreas of 30 day old offspring was analysed for β-cell mass. Glucose handling and insulin action was measured at four months using an intraperitoneal glucose tolerance test and insulin challenge, respectively. Body composition and metabolic gene expression were measured at eight months. Despite normoglycaemia in ethanol consuming dams, ethanol-exposed fetuses were hypoglycaemic at embryonic day 20. Ethanol-exposed offspring were normoglycaemic and normoinsulinaemic under basal fasting conditions and had normal pancreatic β-cell mass at postnatal day 30. However, during a glucose tolerance test, male ethanol-exposed offspring were hyperinsulinaemic with increased first phase insulin secretion. Female ethanol-exposed offspring displayed enhanced glucose clearance during an insulin challenge. Body composition and hepatic, muscle and adipose tissue metabolic gene expression levels at eight months were not altered by prenatal ethanol exposure. Low-moderate chronic prenatal ethanol exposure has subtle, sex specific effects on glucose homeostasis in the young adult rat. As aging is associated with glucose dysregulation, further studies will clarify the long lasting effects of prenatal ethanol exposure.     

Simulation and Prediction of the Adaptive Immune Response to Influenza A Virus Infection

The cellular immune response to primary influenza virus infection is complex, involving multiple cell types and anatomical compartments, and is difficult to measure directly. Here we develop a two-compartment model that quantifies the interplay between viral replication and adaptive immunity. The fidelity of the model is demonstrated by accurately confirming the role of CD4 help for antibody persistence and the consequences of immune depletion experiments. The model predicts that drugs to limit viral infection and/or production must be administered within 2 days of infection, with a benefit of combination therapy when administered early, and cytotoxic CD8 T cells in the lung are as effective for viral clearance as neutralizing antibodies when present at the time of challenge. The model can be used to investigate explicit biological scenarios and generate experimentally testable hypotheses. For example, when the adaptive response depends on cellular immune cell priming, regulation of antigen presentation has greater influence on the kinetics of viral clearance than the efficiency of virus neutralization or cellular cytotoxicity. These findings suggest that the modulation of antigen presentation or the number of lung resident cytotoxic cells and the combination drug intervention are strategies to combat highly virulent influenza viruses. We further compared alternative model structures, for example, B-cell activation directly by the virus versus that through professional antigen-presenting cells or dendritic cell licensing of CD8 T cells.Understanding how the immune system combats influenza virus infection and how the virus can affect the immune system is crucial to predicting and designing prophylactic and therapeutic strategies against the infection (58). Antigenic shift and antigenic drift alter the degree to which preexisting immunity can control the virus. These factors also influence whether different arms of the adaptive immune system can cross-react against new strains of the virus. For example, shifts of the hemagglutinin (HA) and neuraminidase (NA) protein sequences limit the ability of antibodies to neutralize new variants of the virus and may make cross-reactive T-cell responses to conserved viral proteins more important. Other viral proteins, such as NS1, affect both the induction of type I interferon as well as the susceptibility of infected cells to interferon-mediated inhibition of viral gene expression (43). The efficiencies of viral replication and cell-to-cell viral spread are altered by mutations in the viral matrix and polymerase genes, while the survival of infected cells can be altered by the viral PB1-F2 protein. These attributes are influenced by mutations in the viral matrix (50, 51) and polymerase (30, 69) genes, while the survival of infected cells can be altered by the viral PB1-F2 protein (17). The multigenic aspect of influenza virus pathogenesis makes experimental prediction difficult and time-consuming. Computer simulation tools would be useful to independently dissect the potential contribution and relative importance of each factor or to investigate unexpected scenarios that are difficult to replicate experimentally.Mathematical models and computer simulations have been widely used to study viral dynamics and immune responses to viral infections, such as human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency viruses (SIV), lymphocytic choriomeningitis virus (19, 55, 60, 61), and influenza A virus (3, 7, 8, 13, 34, 35, 52). More complex compartmental models of the immune system (4, 23) and models incorporating differential delay equations (21, 48, 68) have been used to better reflect the time that cells reside in a particular compartment or the duration of transit between compartments. In this study, we sought to develop a two-compartment mathematical model to assess the individual contributions of antigen presentation and activation of naïve T and B cells by antigen-presenting cells (APC), CD4 T-cell help, CD8 T-cell-mediated cytotoxicity, B cells, and antibody to control influenza A virus (IAV) infection and to explore the influence of anatomical location. We developed a model which represented published experimental findings on primary influenza virus infection. More importantly, the model was used to explore alternative structures for interactions between virus and immune cells, for example, comparing virus kinetics when antigen delivery and immune cell priming occurred through direct interaction of virus and immune cells or through a cellular intermediate. The model predicts that, under some circumstances, changes affecting antigen presentation more strongly impacted viral kinetics than other viral or immune factors (28, 73, 75, 78). This model highlights the importance of the assumptions used to synthesize a model and gaps in our understanding of the immune response regulating primary influenza virus infection. We discuss the implications of these findings for future influenza virus research and theories of influenza virus virulence based on influenza virus-immune system interactions.     

Vitamin A Supplementation in Early Life Enhances the Intestinal Immune Response of Rats with Gestational Vitamin A Deficiency by Increasing the Number of Immune Cells

Vitamin A is a critical micronutrient for regulating immunity in many organisms. Our previous study demonstrated that gestational or early-life vitamin A deficiency decreases the number of immune cells in offspring. The present study aims to test whether vitamin A supplementation can restore lymphocyte pools in vitamin A-deficient rats and thereby improve the function of their intestinal mucosa; furthermore, the study aimed to identify the best time frame for vitamin A supplementation. Vitamin A-deficient pregnant rats or their offspring were administered a low-dose of vitamin A daily for 7 days starting on gestational day 14 or postnatal day 1, day 14 or day 28. Serum retinol concentrations increased significantly in all four groups that received vitamin A supplementation, as determined by high-performance liquid chromatography. The intestinal levels of secretory immunoglobulin A and polymeric immunoglobulin receptor increased significantly with lipopolysaccharide challenge in the rats that received vitamin A supplementation starting on postnatal day 1. The rats in this group had higher numbers of CD8⁺ intestinal intraepithelial lymphocytes, CD11_C ⁺ dendritic cells in the Peyer''s patches and CD4⁺CD25⁺ T cells in the spleen compared with the vitamin A-deficient rats; flow cytometric analysis also demonstrated that vitamin A supplementation decreased the number of B cells in the mesenteric lymph nodes. Additionally, vitamin A supplementation during late gestation increased the numbers of CD8⁺ intestinal intraepithelial lymphocytes and decreased the numbers of B lymphocytes in the mesenteric lymph nodes. However, no significant differences in lymphocyte levels were found between the rats in the other two vitamin A supplement groups and the vitamin A-deficient group. In conclusion, the best recovery of a subset of lymphocytes in the offspring of gestational vitamin A-deficient rats and the greatest improvement in the intestinal mucosal immune response are achieved when vitamin A supplementation occurs during the early postnatal period.     

Effects of Cranial Exposure to 170-MeV Proton Radiation at a Dose of 5 Gy on the Visual Behavior and Optomotor Response of Adults Rats

Biology Bulletin - In this experiment, the optomotor reflex and visual behavior were evaluated in rats exposed to protons at a dose of 5 Gy. To evaluate the visual function, equipment including a...     

七味白术散联合蒙脱石散对腹泻幼鼠肠道菌群及免疫功能影响的研究

摘要 目的：探讨七味白术散联合蒙脱石散对腹泻幼鼠肠道菌群及免疫功能影响的研究。方法：选择SD雄性幼鼠30只,随机分为对照组、模型组、七味白术散组、蒙脱石散组、七味白术散联合蒙脱石散组,对照组与模型组灌胃给予0.2 mL/10生理盐水,七味白术散组给予0.2 mL/10 g七味白术散,蒙脱石散组给予0.2 mL/10 g蒙脱石散,七味白术散联合蒙脱石散组给予0.2 mL/10 g七味白术散+0.2 mL/10 g蒙脱石散,5组每天定时灌胃一次,均连续给药7天。对比腹泻指数、平均稀便级、稀便率、脾重、胸腺重指数、血清淀粉酶、血清D-木糖水平、回肠、结肠、空肠黏膜厚度及小肠内容物细菌增殖。结果：与对照组相比,其他组脾重、胸腺重指数、血清淀粉酶及D-木糖水平、双歧杆菌、乳酸杆菌数量较低,腹泻指数、平均稀便级、稀便率、回肠、结肠、空肠黏膜厚度、大肠杆菌较高（P<0.05）;与模型组相比,蒙脱石散组、七味白术散组、七味白术散联合蒙脱石散组的脾重、胸腺重指数、血清淀粉酶及D-木糖水平、双歧杆菌、乳酸杆菌数量较高,腹泻指数、平均稀便级、稀便率、回肠、结肠、空肠黏膜厚度、大肠杆菌较低（P<0.05）;与蒙脱石散组相比,七味白术散组、七味白术散联合蒙脱石散组的脾重、胸腺重指数、血清淀粉酶及D-木糖水平、双歧杆菌、乳酸杆菌数量较高,腹泻指数、平均稀便级、稀便率、回肠、结肠、空肠黏膜厚度、大肠杆菌较低（P<0.05）;与七味白术散组相比,七味白术散联合蒙脱石散组的脾重、胸腺重指数、血清淀粉酶、D-木糖水平、双歧杆菌、乳酸杆菌数量明显较高,腹泻指数、平均稀便级、稀便率、回肠、结肠、空肠黏膜厚度、大肠杆菌较低（P<0.05）。结论：七味白术散联合蒙脱石散可明显改善腹泻幼鼠的腹泻症状,可能与其可调整腹泻幼鼠肠道菌群及免疫功能有关。     

Species Heterogeneity Between Gerbils and Rats: Quinolinate Production by Microglia and Astrocytes and Accumulations in Response to Ischemic Brain Injury and Systemic Immune Activation

Abstract: Quinolinic acid is an excitotoxic kynurenine pathway metabolite, the concentration of which increases in human brain during immune activation. The present study compared quinolinate responses to systemic and brain immune activation in gerbils and rats. Global cerebral ischemia in gerbils, but not rats, increased hippocampus indoleamine-2,3-dioxygenase activity and quinolinate levels 4 days postinjury. In a rat focal ischemia model, small increases in quinolinate concentrations occurred in infarcted regions on days 1, 3, and 7, although concentrations remained below serum values. In gerbils, systemic immune activation by an intraperitoneal injection of endotoxin (1 mg/kg of body weight) increased quinolinate levels in brain, blood, lung, liver, and spleen, with proportional increases in lung indoleamine-2,3-dioxygenase activity at 24 h postinjection. In rats, however, no significant quinolinate content changes occurred, whereas lung indoleamine-2,3-dioxygenase activity increased slightly. Gerbil, but not rat, brain microglia and peritoneal monocytes produced large quantities of [¹³C₆]-quinolinate from l -[¹³C₆]tryptophan. Gerbil astrocytes produced relatively small quantities of quinolinate, whereas rat astrocytes produced no detectable amounts. These results demonstrate that the limited capacity of rats to replicate elevations in brain and blood quinolinic acid levels in response to immune activation is attributable to blunted increases in local indoleamine-2,3-dioxygenase activity and a low capacity of microglia, astrocytes, and macrophages to convert l -tryptophan to quinolinate.     

枇杷幼果PLD和LOX对低温胁迫的响应

以3年生枇杷品种‘早钟6号’(Eriobotrya japonica‘Zaozhong No.6’)容器嫁接苗为试材,于0℃、-1℃、-3℃人工气候室内进行低温胁迫处理,探讨枇杷幼果细胞膜磷脂及相关酶对低温胁迫的响应机制。结果显示,在不同温度胁迫过程中,枇杷幼果磷脂酶D(PLD,EC 3.1.4.4)和脂氧合酶(LOX,EC 1.13.11.12)活性均呈上升趋势;质膜磷脂酰胆碱(PC)和磷脂酰肌醇(PI)含量因逐渐被降解而呈下降趋势,磷脂酸(PA)含量出现积累、增加,而膜结合Ca2+含量有不同程度的降低。随处理时间的延长和处理温度的降低,枇杷幼果细胞PLD和LOX活性增幅加大,从而加速了膜PC和PI的降解和PA的积累。低温胁迫过程中幼果细胞膜PC含量的降幅大于PI,膜结合Ca2+含量的变化与PLD和LOX活性变化呈负相关。低温胁迫下枇杷幼果细胞膜结合Ca2+含量的减少诱导了膜脂降解酶PLD和LOX活性的提高,并导致膜结构稳定性下降,加剧了低温胁迫对膜脂的降解和脂质过氧化伤害,其中尤以-3℃胁迫处理4~6 h对幼果细胞质膜的伤害最严重。表明低温胁迫下Ca2+·Ca M信使系统可能参与枇杷幼果细胞膜PLD和LOX活性的调控。     

具免疫应答和细胞内部时滞的HIV-1感染模型的稳定性分析

考虑了CTLs免疫应答和细胞内部时滞建立HIV-1感染的数学模型.对模型的无感染平衡点全局稳定性进行了分析,对CTLs未激活和CTLs已激活的感染平衡点给出了局部稳定的充分条件.数值模拟支持了得到的理论结果.     

The Lectin Pathway of Complement Activation Is a Critical Component of the Innate Immune Response to Pneumococcal Infection

The complement system plays a key role in host defense against pneumococcal infection. Three different pathways, the classical, alternative and lectin pathways, mediate complement activation. While there is limited information available on the roles of the classical and the alternative activation pathways of complement in fighting streptococcal infection, little is known about the role of the lectin pathway, mainly due to the lack of appropriate experimental models of lectin pathway deficiency. We have recently established a mouse strain deficient of the lectin pathway effector enzyme mannan-binding lectin associated serine protease-2 (MASP-2) and shown that this mouse strain is unable to form the lectin pathway specific C3 and C5 convertases. Here we report that MASP-2 deficient mice (which can still activate complement via the classical pathway and the alternative pathway) are highly susceptible to pneumococcal infection and fail to opsonize Streptococcus pneumoniae in the none-immune host. This defect in complement opsonisation severely compromises pathogen clearance in the lectin pathway deficient host. Using sera from mice and humans with defined complement deficiencies, we demonstrate that mouse ficolin A, human L-ficolin, and collectin 11 in both species, but not mannan-binding lectin (MBL), are the pattern recognition molecules that drive lectin pathway activation on the surface of S. pneumoniae. We further show that pneumococcal opsonisation via the lectin pathway can proceed in the absence of C4. This study corroborates the essential function of MASP-2 in the lectin pathway and highlights the importance of MBL-independent lectin pathway activation in the host defense against pneumococci.     

Immune Response to and Histopathology of Campylobacter jejuni Infection in Ferrets (Mustela putorius furo)

Campylobacter jejuni is 1 of the most common enteric bacterial pathogens worldwide. The mechanisms of pathogenesis remain obscure, in part because of limitations of small animal models. Young ferrets develop diarrhea when fed C. jejuni, but their pathology and the immune response after infection have not been examined in detail. In the present study, we examined the pathogenesis of C. jejuni CG8421 and associated immune responses in ferrets. After oral infection with C. jejuni CG8421, 86.7% of the animals developed diarrhea and inflammatory responses that were similar to those seen in human infection. Pronounced histopathologic changes in the colonic mucosa of infected animals were observed during the acute phase (days 1 through 3) of infection. Electron micrographs of colonic epithelium revealed disruption of the villi and internalized bacteria that were not within membrane vacuoles. During the acute phase, C. jejuni was isolated from the livers of 7 of 9 (78%) animals, and bacteria were visualized immunohistochemically in the livers from 5 of the 7 animals (71%) from which C. jejuni was isolated. A vigorous systemic and mucosal immune response to Campylobacter antigens was elicited after infection of ferrets. The data presented contribute to the current knowledge of the pathogenicity of and immunologic response to C. jejuni CG8421 in ferrets and better understanding of this model.Abbreviation: ASC, antibody-secreting cellsCampylobacter jejuni are gram-negative, spiral, microaerophilic, motile bacteria and 1 of the most common enteric bacterial pathogens globally.^15,20 The annual incidence of C. jejuni diarrheal disease varies geographically, ranging from sporadic infections in young adults in developed countries²⁸ to as frequent as 40,000 per 100,000 among children living in hyperendemic regions.¹⁵ In addition, C. jejuni is the primary cause of ‘traveler''s diarrhea’ in various regions of the world.^39,41,44 The clinical disease of C. jejuni infection has a wide spectrum of symptoms, varying from a mild, transient watery diarrhea to a bloody diarrhea with severe abdominal cramps and fever. C. jejuni infection also is associated with development of Guillain–Barré syndrome.⁵¹ Most strains of C. jejuni contain lipooligosaccharides that mimic human gangliosides structurally. Antibodies against these lipooligosaccharide structures lead to an autoimmune response, resulting in Guillain–Barré syndrome.⁵²Despite extensive study, little is understood about the mechanism by which C. jejuni causes diarrheal disease. Various Campylobacter small animal models have been reported, but these require surgical manipulation,^13,46 administration of chemicals or antibiotics (or both),^17,26,30 or inoculation by an unnatural route.⁵ None of these published models incorporate the natural route of infection. Although several immunodeficient mouse models have been reported,^35,36,49 the applicability of these models for studying the pathogenesis and immune response of natural infection is limited. An adult mouse lung model has been described that may be useful for studying pathogenesis and inflammatory response and acquired immunity, but the route of infection is not the same as that in humans.^1,5 Unlike other small animals, naïve ferrets (younger than 11 wk) intragastrically inoculated with C. jejuni developed mild to moderate diarrhea with mucus, fecal leukocytes or frank blood that lasted for as long as 3 d and remained colonized for as long as 8 d.^9,10,18 Moreover, on rechallenge with the homologous bacterial strain, ferrets asymptomatically excreted C. jejuni in their stools.¹⁰ The observation of resistance to disease, but not to infection, is similar to findings from human studies, in which protection against disease developed before colonization resistance.¹¹ Ferrets have been used to evaluate vaccines against C. jejuni¹⁴ and in molecular pathogenesis studies using strain 81-176 to confirm a role in virulence for capsular polysaccharide and flagellar glycans.^3,21 However, we evaluated the histopathology and immune response after C. jejuni infection in ferrets in more detail in the present study.C. jejuni CG8421 was isolated from a case of dysentery in Thailand. It has an lipooligosaccharide core that, as shown by chemical analyses, lacks all ganglioside mimicry.³⁸ The absence of ganglioside mimicry is predicted to reduce the risk of Guillain–Barré syndrome. We selected strain CG8421 for the current studies as part of an evaluation of a potential strain for use in future human vaccine challenge studies. Here we report the pathogenesis, histopathology, inflammatory, and immune responses after oral infection of ferrets with C. jejuni strain CG8421.     

Biochemical Modifications and Neuronal Damage in Brain of Young and Adult Rats After Long-Term Exposure to Mobile Phone Radiations

This study investigated the effect of exposure to mobile phone radiations on oxidative stress and apoptosis in brain of rats. Rats were allocated into six groups (three young and three adult). Groups 1 and 4 were not subjected to the radiation source and served as control groups. In groups 2 and 5, the mobile phones were only connected to the global system for mobile communication, while in groups 3 and 6, the option of calling was in use. Microwaves were generated by a mobile test phone (SAR = 1.13 W/kg) during 60 days (2 h/day). Significant increments in conjugated dienes, protein carbonyls, total oxidant status, and oxidative stress index along with a significant reduction of total antioxidant capacity levels were evident after exposure. Bax/Bcl-2 ratio, caspase-3 activity, and tumor necrosis factor-alpha level were enhanced, whereas no DNA fragmentation was detected. The relative brain weight of young rats was greatly affected, and histopathological examination reinforced the neuronal damage. The study highlights the detrimental effects of mobile phone radiations on brain during young and adult ages. The interaction of these radiations with brain is via dissipating its antioxidant status and/or triggering apoptotic cell death.