Neuropeptide Y Is an Immunomodulatory Factor: Direct and Indirect.

Neuropeptide Y (NPY), which is widely distributed in the nervous system, is involved in regulating a variety of biological processes, including food intake, energy metabolism, and emotional expression. However, emerging evidence points to NPY also as a critical transmitter between the nervous system and immune system, as well as a mediator produced and released by immune cells. In vivo and in vitro studies based on gene-editing techniques and specific NPY receptor agonists and antagonists have demonstrated that NPY is responsible for multifarious direct modulations on immune cells by acting on NPY receptors. Moreover, via the central or peripheral nervous system, NPY is closely connected to body temperature regulation, obesity development, glucose metabolism, and emotional expression, which are all immunomodulatory factors for the immune system. In this review, we focus on the direct role of NPY in immune cells and particularly discuss its indirect impact on the immune response.

Temperature Trajectory Subphenotypes Correlate With Immune Responses in Patients With Sepsis.

OBJECTIVES: We recently found that distinct body temperature trajectories of infected patients correlated with survival. Understanding the relationship between the temperature trajectories and the host immune response to infection could allow us to immunophenotype patients at the bedside using temperature. The objective was to identify whether temperature trajectories have consistent associations with specific cytokine responses in two distinct cohorts of infected patients. DESIGN: Prospective observational study. SETTING: Large academic medical center between 2013 and 2019. SUBJECTS: Two cohorts of infected patients: 1) patients in the ICU with septic shock and 2) hospitalized patients with Staphylococcus aureus bacteremia. INTERVENTIONS: Clinical data (including body temperature) and plasma cytokine concentrations were measured. Patients were classified into four temperature trajectory subphenotypes using their temperature measurements in the first 72 hours from the onset of infection. Log-transformed cytokine levels were standardized to the mean and compared with the subphenotypes in both cohorts. MEASUREMENTS AND MAIN RESULTS: The cohorts consisted of 120 patients with septic shock (cohort 1) and 88 patients with S. aureus bacteremia (cohort 2). Patients from both cohorts were classified into one of four previously validated temperature subphenotypes: "hyperthermic, slow resolvers" (n = 19 cohort 1; n = 13 cohort 2), "hyperthermic, fast resolvers" (n = 18 C1; n = 24 C2), "normothermic" (n = 54 C1; n = 31 C2), and "hypothermic" (n = 29 C1; n = 20 C2). Both "hyperthermic, slow resolvers" and "hyperthermic, fast resolvers" had high levels of G-CSF, CCL2, and interleukin-10 compared with the "hypothermic" group when controlling for cohort and timing of cytokine measurement (p < 0.05). In contrast to the "hyperthermic, slow resolvers," the "hyperthermic, fast resolvers" showed significant decreases in the levels of several cytokines over a 24-hour period, including interleukin-1RA, interleukin-6, interleukin-8, G-CSF, and M-CSF (p < 0.001). CONCLUSIONS: Temperature trajectory subphenotypes are associated with consistent cytokine profiles in two distinct cohorts of infected patients. These subphenotypes could play a role in the bedside identification of cytokine profiles in patients with sepsis.

Febrile Temperature Critically Controls the Differentiation and Pathogenicity of T Helper 17 Cells.

Fever, an evolutionarily conserved physiological response to infection, is also commonly associated with many autoimmune diseases, but its role in T cell differentiation and autoimmunity remains largely unclear. T helper 17 (Th17) cells are critical in host defense and autoinflammatory diseases, with distinct phenotypes and pathogenicity. Here, we show that febrile temperature selectively regulated Th17 cell differentiation in vitro in enhancing interleukin-17 (IL-17), IL-17F, and IL-22 expression. Th17 cells generated under febrile temperature (38.5°C-39.5°C), compared with those under 37°C, showed enhanced pathogenic gene expression with increased pro-inflammatory activities in vivo. Mechanistically, febrile temperature promoted SUMOylation of SMAD4 transcription factor to facilitate its nuclear localization; SMAD4 deficiency selectively abrogated the effects of febrile temperature on Th17 cell differentiation both in vitro and ameliorated an autoimmune disease model. Our results thus demonstrate a critical role of fever in shaping adaptive immune responses with implications in autoimmune diseases.

Impact of immunological state on eco-physiological variables in one of the southernmost lizards in the world.

The immune state is an essential component of survival as it directly influences physiological performance and health status. Variation in the leukocyte profile, a significantly increase in body temperature, and a detriment of the eco-physiological performance are among the possible consequences of an unhealthy state. In this study we analyse and discuss how field body temperature, preferred body temperature, the speed for sprint and long runs, locomotor stamina, and body condition can be affected by the immunological state (i.e. leukocyte profile) in a wild population of Liolaemus sarmentoi. Juveniles and adult males with a high percentage of eosinophils, basophils, and a low percentage of monocytes preferred higher body temperatures in a thermal gradient, while pregnant females maintained thermal preferences independently of leukocyte profile. Although juveniles with a high percentage of heterophils showed less locomotor stamina, adult males and pregnant females showed no differences in locomotor performance in relation to leukocyte profile. This study represents a starting point in eco-immunology of a wild lizard population of Liolaemus in cold and temperate environments of Patagonia where the southward shift in the geographic ranges of pathogen populations due to global warming represents a threat to resident host populations.

Perinatal Immune Activation Produces Persistent Sleep Alterations and Epileptiform Activity in Male Mice.

Increasing evidence suggests a role for inflammation in neuropsychiatric conditions, including autism spectrum disorder (ASD). Previous work in rodents has established that immune activation during critical developmental periods can cause phenotypes that reproduce core features of ASD, including decreased social interaction, aberrant communication, and increased repetitive behavior. In humans, ASD is frequently associated with comorbid medical conditions including sleep disorders, motor hyperactivity, and seizures. Here we use a 'two-hit' immune-activation paradigm to determine whether perinatal immune activation can also produce these comorbid features in mice. In this paradigm, we treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C), which simulates a viral infection, on gestational day 12.5 according to an established maternal immune activation regimen. A subset of the offspring also received a second 'hit' of lipopolysaccharide (LPS), which simulates a bacterial infection, on postnatal day 9. At 6 weeks of age, mice were implanted with wireless telemetry transmitters that enabled continuous measurements of electroencephalography (EEG), electromyography (EMG), locomotor activity, and subcutaneous temperature. Effects at 7 and 12 weeks of age were compared. Both prenatal Poly I:C and postnatal LPS produced changes in locomotor activity and temperature patterns, increases in slow-wave sleep, and shifts in EEG spectral power, several of which persisted at 12 weeks of age. Postnatal LPS also produced persistent increases in spontaneous bursts of epileptiform activity (spike-wave discharges) that occurred predominantly during sleep. Our findings demonstrate that early-life immune activation can lead to long-lasting physiologic perturbations that resemble medical comorbidities often seen in ASD and other neuropsychiatric conditions.

The Frequency of White Blood Cell and Temperature Events During Mechanical Ventilation and Their Association With Ventilator-Associated Events.

BACKGROUND: Changes in white blood cell (WBC) counts and/or temperature could have important implications in patients on ventilators, but the frequency of these events is uncertain. METHODS: We reviewed the medical records from 281 ventilation episodes in our medical intensive care unit to determine patient characteristics and the indications for ventilation. We determined the number of days during each ventilation episode in which the temperature (<96.8°F, >100.4°F) or WBC count (<4000/µL, >12 000/µL) was out of the normal range. RESULTS: This study included 257 patients with a mean Acute Physiology and Chronic Health Evaluation 2 score of 13.5 ± 5.9 and a mean initial Pao2/Fio2 of 210 ± 110. The median number of ventilator days was 4 (interquartile range, 3-9). One hundred ninety-six of 275 eligible ventilator episodes (71.3%) had 1 or more temperature events, and 194 of 253 eligible ventilator episodes (76.7%) had 1 or more WBC events. Nineteen patients met the Center for Disease Control criteria for a ventilator-associated event (VAE). Twelve patients had an increased WBC count during the VAE period, and 11 had an increased temperature during this period. CONCLUSIONS: White blood cell counts and temperature events occur frequently in patients on ventilators and need evaluation but do not reliably identify patients with ventilator-associated complications.

Risk factors, host response and outcome of hypothermic sepsis.

BACKGROUND: Hypothermia is associated with adverse outcome in patients with sepsis. The objective of this study was to characterize the host immune response in patients with hypothermic sepsis in order to determine if an excessive anti-inflammatory response could explain immunosuppression and adverse outcome. Markers of endothelial activation and integrity were also measured to explore potential alternative mechanisms of hypothermia. Finally we studied risk factors for hypothermia in an attempt to find new clues to the etiology of hypothermia in sepsis. METHODS: Consecutive patients diagnosed with sepsis within 24 hours after admission to ICUs in two tertiary hospitals in the Netherlands were included in the study (n = 525). Hypothermia was defined as body temperature below 36 °C in the first 24 h of ICU admission. RESULTS: Hypothermia was identified in 186 patients and was independently associated with mortality. Levels of proinflammatory and anti-inflammatory cytokines were not different between groups. Hypothermia was also not associated with an altered response to ex vivo stimulation with lipopolysaccharide in a subset of 15 patients. Risk factors for hypothermia included low body mass index, hypertension and chronic cardiovascular insufficiency. Levels of the endothelial activation marker fractalkine were increased during the first 4 days of ICU stay. CONCLUSIONS: Hypothermia during sepsis is independently associated with mortality, which cannot be attributed to alterations in the host immune responses that were measured in this study. Given that risk factors for hypothermic sepsis are mainly cardiovascular and that the endothelial activation marker fractalkine increased in hypothermia, these findings may suggest that vascular dysfunction plays a role in hypothermic sepsis.

No fever and leucocytosis in response to a lipopolysaccharide challenge in an insectivorous bat.

Bat immune systems may allow them to respond to zoonotic agents more efficiently than other mammals. As the first line of defence, the taxonomically conserved acute phase immune reaction of leucocytosis and fever is crucial for coping with infections, but it is unknown if this response is a key constituent to bat immunological success. We investigated the acute phase reaction to a standard lipopolysaccharide (LPS) challenge in Pallas's mastiff bats (Molossus molossus). Challenged bats lost mass, but in contrast to other mammals showed no leucocytosis or fever. There also was no influence on body temperature reduction during torpor. When compared to recent genome-wide assays for constituent immune genes, this lack of a conserved fever response to LPS contributes to a clearer understanding of the innate immune system in bat species and of the coevolution of bats with a wide diversity of pathogens.

IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ.

IL-15 is currently undergoing clinical trials to assess its efficacy for treatment of advanced cancers. The combination of IL-15 with soluble IL-15Rα generates a complex termed IL-15 superagonist (IL-15 SA) that possesses greater biological activity than IL-15 alone. IL-15 SA is considered an attractive antitumor and antiviral agent because of its ability to selectively expand NK and memory CD8(+) T (mCD8(+) T) lymphocytes. However, the adverse consequences of IL-15 SA treatment have not been defined. In this study, the effect of IL-15 SA on physiologic and immunologic functions of mice was evaluated. IL-15 SA caused dose- and time-dependent hypothermia, weight loss, liver injury, and mortality. NK (especially the proinflammatory NK subset), NKT, and mCD8(+) T cells were preferentially expanded in spleen and liver upon IL-15 SA treatment. IL-15 SA caused NK cell activation as indicated by increased CD69 expression and IFN-γ, perforin, and granzyme B production, whereas NKT and mCD8(+) T cells showed minimal, if any, activation. Cell depletion and adoptive transfer studies showed that the systemic toxicity of IL-15 SA was mediated by hyperproliferation of activated NK cells. Production of the proinflammatory cytokine IFN-γ, but not TNF-α or perforin, was essential to IL-15 SA-induced immunotoxicity. The toxicity and immunological alterations shown in this study are comparable to those reported in recent clinical trials of IL-15 in patients with refractory cancers and advance current knowledge by providing mechanistic insights into IL-15 SA-mediated immunotoxicity.

Immune and inflammatory responses of Australian firefighters after repeated exposures to the heat.

When firefighters work in hot conditions, altered immune and inflammatory responses may increase the risk of a cardiac event. The present study aimed to establish the time course of such responses. Forty-two urban firefighters completed a repeat work protocol in a heat chamber (100 ± 5°C). Changes to leukocytes, platelets, TNFα, IL-6, IL-10, LPS and CRP were evaluated immediately post-work and also after 1 and 24 h of rest. Increases in core temperatures were associated with significant increases in leukocytes, platelets and TNFα directly following work. Further, platelets continued to increase at 1 h (+31.2 ± 31.3 × 10(9) l, p < 0.01) and remained elevated at 24 h (+15.9 ± 19.6 × 10(9) l, p < 0.01). Sustained increases in leukocytes and platelets may increase the risk of cardiac events in firefighters when performing repeat work tasks in the heat. This is particularly relevant during multi-day deployments following natural disasters. Practitioner Summary: Firefighters regularly re-enter fire affected buildings or are redeployed to further operational tasks. Should work in the heat lead to sustained immune and inflammatory changes following extended rest periods, incident controllers should plan appropriate work/rest cycles to minimise these changes and any subsequent risks of cardiac events.

Accurate Prediction of the Stage of Histological Chorioamnionitis before Delivery by Amniotic Fluid IL-8 Level.

OBJECTIVE: To estimate the stage of histological chorioamnionitis (h-CAM) antenatally using clinical data. MATERIALS AND METHODS: Four hundred and twenty-eight singleton mothers were recruited. Clinical data including the levels of white blood cell count (WBC), C-reactive protein (CRP), amniotic fluid interleukin-8 (AF-IL-8) at Cesarean section, and maternal body temperature (MBT) were collected. RESULTS: Histological chorioamnionitis was present in 45.3% of the cases. Poor neonatal prognosis was highest (59.1%) in cases with h-CAM stage III. AF-IL-8 (odds ratio: 8.5, 95% CI: 5.1-14.8, P < 0.0001) and MBT (odds ratio: 2.3, 95% CI: 1.13-4.1, P = 0.0192) were independent risk factors for h-CAM. The cutoff value of AF-IL-8 for predicting each stage of h-CAM (stage I or higher, stage II or higher, and stage III) were ≥9.9 ng/mL, ≥17.3 ng/mL, and ≥55.9 ng/mL, respectively. CONCLUSION: The stage of h-CAM was able to be predicted accurately by the level of AF-IL-8 before delivery.

The neuron-specific interleukin-1 receptor accessory protein is required for homeostatic sleep and sleep responses to influenza viral challenge in mice.

Interleukin-1ß (IL1) is involved in sleep regulation and sleep responses induced by influenza virus. The IL1 receptor accessory protein (AcP) and an alternatively spliced isoform of AcP found primarily in neurons, AcPb, form part of the IL1 signaling complex. IL1-induced sleep responses depend on injection time. In rat cortex, both IL1 mRNA and AcPb mRNA peak at Zeitgeber Time (ZT) 0 then decline over the daylight hours. Sleep deprivation enhances cortical IL1 mRNA and AcPb mRNA levels, but not AcP mRNA. We used wild type (WT) and AcPb knockout (KO) mice and performed sleep deprivation between ZT10 and 20 or between ZT22 and 8 based on the time of day expression profiles of AcPb and IL1. We hypothesized that the magnitude of the responses to sleep loss would be strain- and time of day-dependent. In WT mice, NREMS and REMS rebounds occurred regardless of when they were deprived of sleep. In contrast, when AcPbKO mice were sleep deprived from ZT10 to 20 NREMS and REMS rebounds were absent. The AcPbKO mice expressed sleep rebound if sleep loss occurred from ZT22 to 8 although the NREMS responses were not as robust as those that occurred in WT mice. We also challenged mice with intranasal H1N1 influenza virus. WT mice exhibited the expected enhanced sleep responses. In contrast, the AcPbKO mice had less sleep after influenza challenge compared to their own baseline values and compared to WT mice. Body temperature and locomotor activity responses after viral challenge were lower and mortality was higher in AcPbKO than in WT mice. We conclude that neuron-specific AcPb plays a critical role in host defenses and sleep homeostasis.

TNF-alpha in bulls experimentally infected with Trypanosoma vivax: a pilot study.

There are few studies about the immune response during trypanosomosis in cattle. The objective of this research was to evaluate the effect of experimental infection with Trypanosoma vivax (T. vivax) on serum levels of TNF-alpha in bulls and its relationship to hematocrit, body temperature and parasitemia. Two adult crossbred bulls were infected experimentally with T. vivax and two were used as controls. The bulls were evaluated during a 64 day period in terms of temperature, hematocrit, and parasitemia. Serum TNF-alpha levels were determined by ELISA, using an antibody specific for bovine. TNF-alpha in serum began rising on the seventh day after infection and reached a peak on day 40 of post-infection, then dropped. The lowest hematocrit levels corresponded to the upper levels of TNF-alpha, for each animal. In conclusion, the experimental infection of cattle with T. vivax promotes the release of TNF-alpha, demonstrating a pro-inflammatory immune response to this hemotropic parasite. Moreover, the lowest hematocrit levels coincide with high concentrations of TNF-alpha, suggesting that this cytokine can be linked to the observed anemia during the course of infection by T. vivax in cattle.

Cardiac arrest patients have an impaired immune response, which is not influenced by induced hypothermia.

INTRODUCTION: Induced hypothermia is increasingly applied as a therapeutic intervention in ICUs. One of the underlying mechanisms of the beneficial effects of hypothermia is proposed to be reduction of the inflammatory response. However, a fear of reducing the inflammatory response is an increased infection risk. Therefore, we studied the effect of induced hypothermia on immune response after cardiac arrest. METHODS: A prospective observational cohort study in a mixed surgical-medical ICU. Patients admitted at the ICU after surviving cardiac arrest were included and during 24 hours body temperature was strictly regulated at 33°C or 36°C. Blood was drawn at three time points: after reaching target temperature, at the end of the target temperature protocol and after rewarming to 37°C. Plasma cytokine levels and response of blood leucocytes to stimulation with toll-like receptor (TLR) ligands lipopolysaccharide (LPS) from Gram-negative bacteria and lipoteicoic acid (LTA) from Gram-positive bacteria were measured. Also, monocyte HLA-DR expression was determined. RESULTS: In total, 20 patients were enrolled in the study. Compared to healthy controls, cardiac arrest patients kept at 36°C (n = 9) had increased plasma cytokines levels, which was not apparent in patients kept at 33°C (n = 11). Immune response to TLR ligands in patients after cardiac arrest was generally reduced and associated with lower HLA-DR expression. Patients kept at 33°C had preserved ability of immune cells to respond to LPS and LTA compared to patients kept at 36°C. These differences disappeared over time. HLA-DR expression did not differ between 33°C and 36°C. CONCLUSIONS: Patients after cardiac arrest have a modest systemic inflammatory response compared to healthy controls, associated with lower HLA-DR expression and attenuated immune response to Gram-negative and Gram-positive antigens, the latter indicative of an impaired immune response to bacteria. Patients with a body temperature of 33°C did not differ from patients with a body temperature of 36°C, suggesting induced hypothermia does not affect immune response in patients with cardiac arrest. TRIAL REGISTRATION: ClinicalTrials.gov NCT01020916, registered 25 November 2009.

A new tetravalent canine leptospirosis vaccine provides at least 12 months immunity against infection.

A key success factor in the vaccination of dogs against leptospirosis is long term protection against establishment of the renal carrier state, in order to protect other dogs, as well as humans, against this re-emerging zoonotic disease. In this paper, we describe the ability of a new European tetravalent vaccine containing antigen from Leptospira interrogans (sensu lato) serogroups Icterohaemorrhagiae, Canicola, Grippotyphosa and Australis to control infection and renal excretion in dogs at 12 months after vaccination. In order to demonstrate the efficacy of all four vaccine components, four separate challenge studies were performed. For each study two groups of dogs were used (a group receiving the leptospirosis vaccine and a control group). Twelve months after the second vaccination all dogs in the vaccine and control groups were challenged, both intraperitoneally and conjunctivally, using a pathogenic challenge strain from one of four serogroups. Parameters recorded post-challenge were: clinical signs of disease, change in body temperature, total leucocyte count, thrombocyte count, presence of challenge organisms in blood, urine and kidney tissue, and evidence of interstitial nephritis at necropsy four weeks after challenge. The vaccine was able to either prevent or significantly reduce infection following challenge with the strains of all four serogroups. The vaccine was also able to prevent or significantly reduce renal infection following Canicola and Icterohaemorrhagiae challenge, and there was a trend of reduction of renal infection with Australis (serovar Bratislava). In the case of the Grippotyphosa study, challenge led to no detectable renal infection in any dog of the control group. In conclusion, in this study significant protective immunity was achieved in dogs 12 months after a basic vaccination schedule of two doses against strains of serogroups Canicola, Icterohaemorrhagiae, Grippotyphosa and Australis.

Rapid desensitization of mice with anti-FcγRIIb/FcγRIII mAb safely prevents IgG-mediated anaphylaxis.

BACKGROUND: Stimulatory IgG receptors (FcγRs) on bone marrow-derived cells contribute to the pathogenesis of several autoimmune and inflammatory disorders. Monoclonal antibodies that block FcγRs might suppress these diseases, but they can induce anaphylaxis. OBJECTIVE: We wanted to determine whether a rapid desensitization approach can safely suppress IgG/FcγR-mediated anaphylaxis. METHODS: Mice were injected with serially increasing doses of 2.4G2, a rat mAb that blocks the inhibitory FcγR, FcγRIIb, and the stimulatory receptor, FcγRIII. Rectal temperature was used to detect the development of anaphylaxis. Passive and active IgG-mediated anaphylaxis were evaluated in mice that had been rapidly desensitized with 2.4G2 or mock-desensitized in mice in which monocyte/macrophages, basophils, or neutrophils had been depleted or desensitized and in mice in which FcγRI, FcγRIII, and/or FcγRIV had been deleted or blocked. RESULTS: Rapid desensitization with 2.4G2 prevented 2.4G2-induced shock and completely suppressed IgG-mediated anaphylaxis. Rapid desensitization of ovalbumin-sensitized mice with 2.4G2 was safer and more effective than rapid desensitization with ovalbumin. 2.4G2 treatment completely blocked FcγRIII and removed most FcγRI and FcγRIV from nucleated peripheral blood cells. Because IgG(2a)-mediated anaphylaxis was partially FcγRI and FcγRIV dependent, the effects of 2.4G2 on FcγRI and FcγRIV were probably crucial for its complete inhibition of IgG(2a)-mediated anaphylaxis. IgG(2a)-mediated anaphylaxis was partially inhibited by depletion or desensitization of monocyte/macrophages, basophils, or neutrophils. CONCLUSION: IgG-mediated anaphylaxis can be induced by ligation of FcγRI, FcγRIII, or FcγRIV on monocycte/macrophages, basophils, or neutrophils and can be safely suppressed by rapid desensitization with anti-FcγRII/RIII mAb. A similar approach may safely suppress other FcγR-dependent immunopathology.

Wasp venom allergy: effect of anti-IgE antibody on wasp venom anaphylaxis in a mouse model.

BACKGROUND: Although anti-IgE antibody (Ab) therapy was recently shown to be effective in patients with bronchial asthma, no study has reported the effect of IgE therapy in the prevention of wasp venom anaphylaxis. In this study, we used a mouse model of wasp venom allergy to investigate the effect of anti-IgE Ab on wasp venom anaphylaxis. METHODS: We developed a mouse model of wasp venom allergy by intraperitoneally (i.p.) injecting wasp venom into BALB/c mice twice on experimental day (day) 0 and 7. On day 20, a group of mice received an i.p. injection of mouse anti-IgE Ab as a pretreatment, and another group received rat anti-IgG1 Ab. On day 21, the animals were challenged by i.p. injection of wasp venom, and 30 min later, body temperature was measured and serum levels of leukotriene (LT) B4 and LTC4 were determined using enzyme immunoassay. RESULTS: The body temperature of mice treated with anti-IgE Ab and controls before and after wasp venom challenge was 37.8±0.2 vs 37.7± 0.3°C before challenge and 37.8±0.2 vs 37.1± 0.3°C after challenge, respectively, showing that anti-IgE Ab treatment significantly prevented body temperature from falling (p <0.05). Furthermore, anti-IgE Ab treatment reduced total serum IgE levels in the treated mice (42.2±15.9 pg/ml), compared with controls (105.9±23.1 pg/ml, p <0.05), and inhibited the secretion of LTC4 in the treated mice (32.0±18.8 pg/ml), but not in the controls (162.4±12.4 pg/ml, p <0.05), following challenge with wasp venom. CONCLUSION: The results of the present study indicate that anti-IgE Ab treatment is an effective preventive measure against wasp venom-induced anaphylaxis.

Perspective on fever: the basic science and conventional medicine.

This review describes how fever is generated as a regulated increase in body temperature. It results from an upward shift in the thermoregulatory set point, mediated by pyrogenic cytokines released from monocytes/macrophages in response to infection or trauma. Evidence will be presented that fever is part of an integrated host defense system, and that failure to generate a fever in response to infection is generally associated with a poorer prognosis.

Epicutaneous sensitization results in IgE-dependent intestinal mast cell expansion and food-induced anaphylaxis.

BACKGROUND: Sensitization to food antigen can occur through cutaneous exposure. OBJECTIVE: We sought to test the hypothesis that epicutaneous sensitization with food antigen predisposes to IgE-mediated anaphylaxis on oral allergen challenge. METHODS: BALB/c mice were epicutaneously sensitized by repeated application of ovalbumin (OVA) to tape-stripped skin over 7 weeks or orally immunized with OVA and cholera toxin (CT) weekly for 8 weeks and then orally challenged with OVA. Body temperature was monitored, and serum mouse mast cell protease 1 levels were determined after challenge. Tissue mast cell (MC) counts were examined by using chloroacetate esterase staining. Levels of serum OVA-specific IgE and IgG(1) antibodies and cytokines in supernatants of OVA-stimulated splenocytes were measured by means of ELISA. Serum IL-4 levels were measured by using an in vivo cytokine capture assay. RESULTS: Epicutaneously sensitized mice exhibited expansion of connective tissue MCs in the jejunum, increased serum IL-4 levels, and systemic anaphylaxis after oral challenge, as evidenced by decreased body temperature and increased serum mouse mast cell protease 1 levels. Intestinal MC expansion and anaphylaxis were IgE dependent because they did not occur in epicutaneously sensitized IgE(-/-) mice. Mice orally immunized with OVA plus CT did not have increased serum IL-4 levels, expanded intestinal MCs, or anaphylaxis after oral challenge, despite OVA-specific IgE levels and splenocyte cytokine production in response to OVA stimulation, which were comparable with those of epicutaneously sensitized mice. CONCLUSION: Epicutaneously sensitized mice, but not mice orally immunized with antigen plus CT, have expansion of intestinal MCs and IgE-mediated anaphylaxis after single oral antigen challenge. IgE is necessary but not sufficient for food anaphylaxis, and MC expansion in the gut can play an important role in the development of anaphylaxis.

Sensitizing capacity and allergenicity of enzymatically cross-linked sodium caseinate in comparison to sodium caseinate in a mouse model for cow's milk allergy.

A transglutaminase cross-linked caseinate was designed for use in dairy products to increase the viscosity of food matrices. The difference in structure of cross-linked caseinate might have implications for the risk of developing cow's milk allergy. The sensitizing capacity and the allergenicity (the potency to induce an allergic effector response) of cross-linked sodium caseinate was investigated using a mouse model for cow's milk allergy. Mice were orally sensitized with cross-linked caseinate or caseinate using cholera toxin as adjuvant. Anaphylactic shock reactions, change in body temperature, acute allergic skin response, caseinate-, cross-linked caseinate-IgE and mMCP-1 concentrations were determined after challenge with cross-linked caseinate or caseinate. Sensitization with cross-linked caseinate did not result in anaphylactic shock symptoms, drop in body temperature or release of serum mMCP-1. A tendency toward decreased casein-specific IgE levels was observed. The allergenicity did not differ between both products. These results indicate that in already caseinate-sensitized mice, cross-linked caseinate did not provoke more pronounced allergenic reactions compared to sodium caseinate. On top of that, reduced sensitization to cross-linked caseinate was observed. Cross-linked caseinate might therefore be an interesting new dietary concept for humans at risk for food allergy although more mechanistic studies and clinical trials are needed for validation.