Search

Short palate, lung, and nasal epithelium clone 1 (SPLUNC1) is a kind of secretory protein, and gets expressed abundantly in normal respiratory epithelium of humans. As a natural immune molecule, SPLUNC1 is proved to be involved in inflammatory response and airway host defense. This review focuses on summarizing and discussing the role of SPLUNC1 in regulating airway surface liquid (ASL) and participating in airway host defense. PubMed and MEDLINE were used for searching and identifying the data in this review. The domain of bactericidal/permeability-increasing protein in SPLUNC1 and the α-helix, α4, are essential for SPLUNC1 to exert biological activities. As a natural innate immune molecule, SPLUNC1 plays a significant role in inflammatory response and airway host defense. Its special expression patterns are not only observed in physiological conditions, but also in some respiratory diseases. The mechanisms of SPLUNC1 in airway host defense include modulating ASL volume, acting as a surfactant protein, inhibiting biofilm formation, as well as regulating ASL compositions, such as LL-37, mucins, Neutrophil elastase, and inflammatory cytokines. Besides, potential correlations are found among these different mechanisms, especially among different ASL compositions, which should be further explored in more systematical frameworks. In this review, we summarize the structural characteristics and expression patterns of SPLUNC1 briefly, and mainly discuss the mechanisms of SPLUNC1 exerted in host defense, aiming to provide a theoretical basis and a novel target for future studies and clinical treatments.

Background: Food antigens are clearly implicated in the induction and persistence of eosinophilic oesophagitis. Dietary elimination to identify triggers is tedious and expensive. Alternatives that can mitigate cost and improve patient quality of life during this process are needed., Aims: To test the hypothesis that antibodies against foods that trigger eosinophilic oesophagitis are secreted into the oesophageal lumen where they can be collected by oesophageal brushings., Methods: We evaluated food-specific immune responses within brushings in 68 patients undergoing endoscopy (12 controls, 13 resolved eosinophilic oesophagitis and 43 active eosinophilic oesophagitis). Seventeen participants identified their trigger foods via food elimination diets. Immunoglobulin A and immunoglobulin G4 antibodies against the four most common eosinophilic oesophagitis food triggers were measured using the ImmunoCAP assay in the oesophageal brushings. Food-specific antibody values were compared between active eosinophilic oesophagitis, resolved eosinophilic oesophagitis and controls., Results: Patients with active eosinophilic oesophagitis (>15 eosinophils/hpf) demonstrated increased immunoglobulin A and immunoglobulin G4 levels to common eosinophilic oesophagitis triggers compared to controls (327 ± 380 vs 150 ± 130 for immunoglobulin A, and 1534 ± 3346 vs 178 ± 123 for immunoglobulin G4, P < 0.003). Specific trigger foods were associated with elevated immunoglobulin A and immunoglobulin G4 responses compared to foods that did not trigger oesophageal eosinophilia (733 ± 469 vs 142 ± 64, P < 0.001 immunoglobulin A and 2620 ± 3228 vs 526 ± 1050, P < 0.001 immunoglobulin G4)., Conclusions: Food-specific antibodies are easily collected along the oesophageal lumen of eosinophilic oesophagitis patients. Further studies are needed to validate our preliminary findings to determine whether these antibodies can be used to guide elimination diet therapy., (© 2020 John Wiley & Sons Ltd.)

Oral administration of pathogen-specific recombinant antibodies may help to prevent infant gastrointestinal (GI) pathogen infection; however, to neutralize an infectious agent, these antibodies must resist degradation in the GI tract. Palivizumab, a recombinant antibody specific for the respiratory syncytial virus (RSV), was used as a model for pathogen-specific IgG in human milk. The aim was to compare the remaining binding capacity of palivizumab in milk between three mothers after exposure to an in vitro model of infant gastrointestinal digestion (gastric and duodenal fluids) using ELISA. The neutralizing capacity of palivizumab in pooled human milk, gastric contents, and stools from preterm infants was also evaluated for blocking RSV with green fluorescent protein (RSV-GFP) infection in Hep-2 cells using confocal and inverted microscopy and flow cytometry. The reduction of palivizumab binding capacity in human milk and digested samples was slightly different between mothers. Overall, palivizumab decreased 50% after simulated gastric digestion with pepsin and 62% after simulated intestinal digestion with pancreatin. Palivizumab (2-8 μg/mL) in human milk or stool samples blocked RSV (3.4 × 10 4 FFU/mL) infection (no syncytia formation on Hep-2 cells) by microscopy. Syncytia formation was detected on Hep-2 cells when RSV was incubated in gastric contents or virus medium with 2-4 μg/mL of palivizumab, but no infection was observed at 8 μg/mL. No fluorescence (absence of infected cells) was detected when palivizumab (100 μg/mL) was incubated in human milk or medium with RSV-GFP (1.1 × 10 5 FFU/mL), whereas fluorescence increased with the reduced concentration of palivizumab using flow cytometry. These results suggest that undigested and digested matrices could change the binding and neutralizing capacity of viral pathogen-specific antibodies.

Background: There is growing interest both in testing IgE in nasal secretions (NS) and in molecular diagnosis of seasonal allergic rhinitis (SAR). Yet, the reliability of nasal IgE detection with the newest molecular assays has never been assessed in a large cohort of pollen allergic patients., Objective: To investigate with microarray technology and compare the repertoires of specific IgE (sIgE) antibodies in NS and sera of a large population of children and adults with SAR., Methods: Nasal secretions were collected with an absorbent device (Merocel 2000 ® , Medtronic) and a minimal dilution procedure from 90 children and 71 adults with SAR. Total IgE (tIgE) (ImmunoCAP, Thermo Fisher Scientific (TFS)) and sIgE antibodies against 112 allergen molecules (ISAC-112, TFS) were measured in NS and serum., Results: Nasal sIgE was detectable in 68.3% of the patients. The detected nasal sIgE antibodies recognized airborne (88%), vegetable (10%), and animal food or other (<1%) allergen molecules. The prevalence and average levels of sIgE in NS and serum were highly interrelated at population level. A positive nasal sIgE antibody to a given molecule predicted the detection of the same antibody in the patient's serum with a specificity of 99.7% and a sensitivity of 40%., Conclusions: The concentration of sIgE is much lower in nasal secretions than in the serum. sIgE assays with very high analytical sensitivity and sampling methods with minimal dilution will be therefore needed to validate nasal secretions as alternative to serum in testing the sIgE repertoire., (© 2019 The Authors. Pediatric Allergy and Immunology published by John Wiley & Sons Ltd.)

A previous study revealed that fucoidan inhibited mast cell degranulation through the upregulation of galectin-9 in blood. The purpose of this study is to elucidate its mechanism using ovalbumin (OVA) induced anaphylaxis model mice (BALB/c, Female, 5-week-old) and mast cell line (RBL-2H3 cells). Oral administration of fucoidan after sensitization with OVA/Al(OH) 3 inhibited reduction of rectal temperature induced by activation of mast cells. Fucoidan increased galectin-9 mRNA expression only in colonic epithelial cells. These results suggested that fucoidan could suppress the allergic symptoms in sensitized mice by inducing galectin-9 production from colonic epithelial cells. In addition, to check the influence of galectin 9 on the degranulation of mast cells, RBL-2H3 cell lines were treated directly with recombinant galectin-9. As expected, galectin-9 inhibited degranulation of RBL-2H3 cells pre-bound with IgE. Moreover, the residual amounts of IgE on RBL-2H3 cells were decreased by an addition of galectin-9. It was demonstrated that galectin-9 could remove IgE even if IgE was already bound to mast cells and suppress the mast cells degranulation induced by antigen. This study shows that fucoidan might become an effective therapeutic agent for patients already developed type I allergic diseases., Competing Interests: The authors declare no conflict of interest.

Purpose: Aspirin-exacerbated respiratory disease (AERD) is a severe form of chronic rhinosinusitis with nasal polyps (CRSwNP) accompanied by asthma and an aspirin intolerance. The underlying pathomechanism of AERD still remains unclear, recent data suggest a complex inflammatory imbalance. In the present study, we investigated the cytokine patterns in AERD, CRSwNP and healthy control patients. Furthermore, we describe the change in cytokine level in the course of aspirin desensitization (AD) with continuous intake of aspirin., Methods: The study included a total of 104 participants, 48 healthy controls, 45 patients with nasal polyps and 11 patients with AERD undergoing AD. Nasal secretions were analyzed for IL-1β, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17, THF-α, IFN-γ, eotaxin and ECP using Bio-Plex Human Cytokine Assay and Uni-CAP FEIA. Baseline measurements of cytokine levels were performed in all 104 patients; in patients with AERD, follow-up was performed 1-6 and 6-24 months after the initiation of AD., Results: Our preliminary results show a T H 2 dominated, eosinophilic milieu in AERD patients, which decreased in the first weeks of AD. However, after 6 months of AD, proinflammatory cytokines show a tendency to increase again. Also, T H 1 as well as T reg associated cytokine seem to increase over time., Conclusions: For the first time, the present work shows the cytokine pattern in nasal secretions of AERD patients before and during AD. Further investigation of the complex interaction of inflammatory cytokines during AD might reveal important insights into the disease entity of AERD and open up new horizons for a targeted therapy.

Purpose of Review: IgE is a key player in multiple inflammatory airway diseases. Ample literature demonstrates its presence in mucosa of patients with allergic rhinitis (AR), local allergic rhinitis (LAR), asthma, or chronic rhinosinusitis with nasal polyposis (CRSwNP)., Recent Findings: Current evidence shows that high-affinity IgE in blood stream of allergic individuals derives mainly from the mucosae. Also, mucosal synthesis of IgE can occur in the absence of systemic atopy, and may be relevant in atopic and non-atopic phenotypes of rhinitis as demonstrated in LAR. Specific IgE (sIgE) detection varies depending on technique used for sample collection and its measurement. sIgE detection is highly specific for diagnosis of LAR. Moreover, measurement of sIgE in secretions could be useful in monitoring response to allergen-specific immunotherapy in both AR and LAR phenotypes. This review will focus on recent developments in the role of IgE in respiratory diseases, and the clinical implications of its measurement in secretions.

Protein secretion upon TLR, TNFR1, and IFNGR ligation in the human airways is considered to be central for the orchestration of pulmonary inflammatory and immune responses. In this study, we compared the gene expression and protein secretion profiles in response to specific stimulation of all expressed TLRs and in further comparison to TNFR1 and IFNGR in primary human airway epithelial cells. In addition to 22 cytokines, we observed the receptor-induced regulation of 571 genes and 1,012 secreted proteins. Further analysis revealed high similarities between the transcriptional TLR sensor and TNFR1 effector responses. However, secretome to transcriptome comparisons showed a broad receptor stimulation-dependent release of proteins that were not transcriptionally regulated. Many of these proteins are annotated to exosomes with associations to, for example, antigen presentation and wound-healing, or were identified as secretable proteins related to immune responses. Thus, we show a hitherto unrecognized scope of receptor-induced responses in airway epithelium, involving several additional functions for the immune response, exosomal communication and tissue homeostasis.

Women remain at risk of human papillomavirus (HPV) infection for most of their lives. The duration of protection against HPV-16/18 from prophylactic vaccination remains unknown. We investigated the 10-year immune response and long-term safety profile of the HPV-16/18 AS04-adjuvanted vaccine (AS04-HPV-16/18 vaccine) in females aged between 15 and 55 years at first vaccination. Females who received primary vaccination with three doses of AS04-HPV-16/18 vaccine in the primary phase-III study (NCT00196937) were invited to attend annual evaluations for long-term immunogenicity and safety. Anti-HPV-16/18 antibodies in serum and cervico-vaginal secretions (CVS) were measured using enzyme-linked immunosorbent assay (ELISA). Serious adverse events (SAEs) were recorded throughout the follow-up period. Seropositivity rates for anti-HPV-16 remained high (≥96.3%) in all age groups 10 years after first vaccination. It was found that 99.2% of 15-25-year olds remained seropositive for anti-HPV-18 compared to 93.7% and 83.8% of 26-45-year olds and 45-55-year olds, respectively. Geometric mean titers (GMT) remained above natural infection levels in all age groups. Anti-HPV-16 and anti-HPV-18 titers were at least 5.3-fold and 3.1-fold higher than titers observed after natural infection, respectively, and were predicted to persist above natural infection levels for ≥30 years in all age groups. At Year 10, anti-HPV-16/18 antibody titers in subjects aged 15-25 years remained above plateau levels observed in previous studies. Correlation coefficients for antibody titers in serum and CVS were 0.64 (anti-HPV-16) and 0.38 (anti-HPV-18). This study concluded that vaccinated females aged 15-55 years elicited sustained immunogenicity with an acceptable safety profile up to 10 years after primary vaccination, suggesting long-term protection against HPV., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

We investigated the mucosal distribution and neutralization potency of rhesus recombinant versions of the HIV-specific, broadly neutralizing antibody b12 (RhB12) following intravenous administration to lactating rhesus monkeys. IgG and dimeric IgA (dIgA) administration resulted in high plasma concentrations of broadly neutralizing antibody (bnAb), but the monomeric IgA (mIgA) was rapidly cleared from the systemic compartment. Interestingly, differences in the distribution of the RhB12 isoform were observed between the mucosal compartments. The peak concentration of RhB12 IgG was higher than dIgA in saliva, rectal, and vaginal secretions, but the bnAb concentration in milk was one to two logs higher after dIgA administration than with IgG or mIgA infusion. Neutralization was observed in plasma of all animals, but only those infused with RhB12 dIgA showed moderate levels of virus neutralization in milk. Remarkably, virus-specific secretory IgA was detected in mucosal compartments following dIgA administration. The high milk RhB12 dIgA concentration suggests that passive immunization with dIgA could be more effective than IgG to inhibit virus in breast milk.

Semenogelins are proteins originating in the seminal vesicle and are useful markers for the presumptive identification of human semen. Detection of semenogelin can be done with a commercially available membrane test. In this study, a commercially available membrane test for human semenogelin proteins was used to assess for cross-reactivity in dog bodily fluids to allow for the potential utilization for detection of human semen in dog bodily fluids. The authors analyzed canine semen and other bodily fluids, including urine, saliva, vaginal secretions, fecal material, and blood. They also examined the distribution of human semenogelin I transcripts in the canine testis, prostate, and several bodily fluids by reverse transcription polymerase chain reaction. No cross-reactivity was observed in the canine bodily fluids tested except for a single rectal swab, which was negative on a second test. Further testing should be done to validate the use of this kit for screening samples from dogs suspected to have been victims of sexual abuse., (© The Author(s) 2015.)

Greater inhibitory activity against Escherichia coli and levels of human β defensin (HBD)-2 in genital tract secretions predicted HIV acquisition in women in the HPTN 035 trial. We investigated whether higher levels of E. coli inhibitory activity and antimicrobial peptides in cervicovaginal lavage (CVL) samples predicted HIV acquisition in women in the CAPRISA 002 Acute Infection Study. E. coli inhibitory activity and antimicrobial peptides were quantified in CVL from a subset of CAPRISA 002 participants who did not seroconvert (n=39) and from seroconverting women prior to infection (n=17) and during acute infection (n=11). Women who acquired HIV had significantly greater preinfection CVL E. coli inhibitory activity (p=0.01) and HBD-1 levels (p=0.02) compared to women who remained uninfected. Preinfection E. coli inhibitory activity remained significantly associated with seroconversion following adjustment for the presence of bacterial vaginosis (OR 1.45; 95% CI 1.07, 1.97). Partial least squares discriminant analysis confirmed that preinfection CVL E. coli inhibitory activity, together with higher CVL concentrations of HBD-1 and secretory leukocyte protease inhibitor, distinguished seroconverters from nonseroconverters with 67% calibration accuracy. CVL concentrations of human neutrophil peptides (HNP) 1-3 increased significantly with acute infection (p=0.001) and correlated with plasma viral set point (r=0.66, p=0.03). E. coli inhibitory activity in genital tract secretions could provide a biomarker of HIV risk. The correlation between HNP 1-3 and viral set point merits further investigation of the relationship between mucosal inflammation during early HIV infection and disease progression.

Objective: Cationic proteins found in cervicovaginal secretions (CVS) are known to contribute to the early antiviral immune response against HIV-infection in vitro. We here aimed to define additional antiviral factors that are over-expressed in CVS from female sex workers at high risk of infection., Methods: CVS were collected from Kenyan HIV-seronegative (n = 34) and HIV-seropositive (n = 12) female sex workers, and were compared with those from HIV-seronegative low-risk women (n = 12). The highly exposed seronegative (HESN) sex workers were further divided into those with less (n = 22) or more (n = 12) than three years of documented sex work. Cationic protein-depleted CVS were assessed for HIV-neutralizing activity by a PBMC-based HIV-neutralizing assay, and then characterized by proteomics., Results: HIV neutralizing activity was detected in all unprocessed CVS, however only CVS from the female sex worker groups maintained its HIV neutralizing activity after cationic protein-depletion. Differentially abundant proteins were identified in the cationic protein-depleted secretions including 26, 42, and 11 in the HESN>3 yr, HESN<3 yr, and HIV-positive groups, respectively. Gene ontology placed these proteins into functional categories including proteolysis, oxidation-reduction, and epidermal development. The proteins identified in this study include proteins previously associated with the HESN phenotype in other cohorts as well as novel proteins not yet associated with anti-HIV activities., Conclusion: While cationic proteins appear to contribute to the majority of the intrinsic HIV neutralizing activity in the CVS of low-risk women, a broader range of non-cationic proteins were associated with HIV neutralizing activity in HESN and HIV-positive female sex workers. These results indicate that novel protein factors found in CVS of women with high-risk sexual practices may have inherent antiviral activity, or are involved in other aspects of anti-HIV host defense, and warrant further exploration into their mode of action.

Rationale: Nasal allergen provocations may be useful in investigating the pathophysiology of allergic rhinitis and effects of treatments., Objective: To use grass pollen nasal allergen challenge (NAC) to investigate the effects of allergen immunotherapy in a cross-sectional study., Methods: We studied nasal and cutaneous responses in untreated subjects with seasonal grass-pollen allergic rhinitis (n = 14) compared with immunotherapy-treated allergics (n = 14), plus a nonatopic control group (n = 14). Volunteers underwent a standardized NAC with 2000 biological units of timothy grass allergen (equivalent to 1.3 μg major allergen, Phl p5). Nasal fluid was collected and analysed by ImmunoCAP and multiplex assays. Clinical response was assessed by symptom scores and peak nasal inspiratory flow (PNIF). Cutaneous response was measured by intradermal allergen injection. Retrospective seasonal symptom questionnaires were also completed., Results: Immunotherapy-treated patients had lower symptom scores (P = 0.04) and higher PNIF (P = 0.02) after challenge than untreated allergics. They had reduced early (P = 0.0007) and late (P < 0.0001) skin responses, and lower retrospective seasonal symptom scores (P < 0.0001). Compared to untreated allergics, immunotherapy-treated patients had reduced nasal fluid concentrations of IL-4, IL-9 and eotaxin (all P < 0.05, 8 h level and/or area under the curve comparison), and trends for reduced IL-13 (P = 0.07, area under the curve) and early-phase tryptase levels (P = 0.06)., Conclusions: Nasal allergen challenge is sensitive in the detection of clinical and biological effects of allergen immunotherapy and may be a useful surrogate marker of treatment efficacy in future studies., (© 2015 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Characterization of the immune correlates of protection against HIV infection is crucial for the development of preventive strategies. This study examined HIV-1 envelope (Env) glycoproteins, specifically immunoglobulin G (IgG), in systemic and mucosal compartments of female Beninese commercial sex workers (CSWs). Samples of 23 HIV-1-positive and 20 highly exposed HIV-1-seronegative (HESN) CSWs were studied. HIV-1 Env-specific IgG detection in sera and cervicovaginal lavages (CVLs) from the study population was done by cell-based ELISA. The HIV neutralizing activity was evaluated with a neutralization assay. The HIV-1-specific antibody-dependent cellular cytotoxicity (ADCC) response of the cohort was measured with a FACS-based assay evaluating the ADCC-mediated elimination of gp120-coated target cells. No anti-HIV-1 Env-specific IgG neutralizing or ADCC activities were detected in samples from HESN CSWs. Samples from HIV-1-infected CSWs presented ADCC activity in both sera and CVLs. Anti-Env IgG from sera and CVLs from HIV-1-infected CSWs preferentially recognized Env in its CD4-bound conformation. HIV-1-infected CSWs have ADCC-mediating IgG that preferentially recognizes Env in its CD4-bound conformation at the mucosal site.

Background: Many participants in microbicide trials remain uninfected despite ongoing exposure to HIV-1. Determining the emergence and nature of mucosal HIV-specific immune responses in such women is important, since these responses may contribute to protection and could provide insight for the rational design of HIV-1 vaccines., Methods and Findings: We first conducted a pilot study to compare three sampling devices (Dacron swabs, flocked nylon swabs and Merocel sponges) for detection of HIV-1-specific IgG and IgA antibodies in vaginal secretions. IgG antibodies from HIV-1-positive women reacted broadly across the full panel of eight HIV-1 envelope (Env) antigens tested, whereas IgA antibodies only reacted to the gp41 subunit. No Env-reactive antibodies were detected in the HIV-negative women. The three sampling devices yielded equal HIV-1-specific antibody titers, as well as total IgG and IgA concentrations. We then tested vaginal Dacron swabs archived from 57 HIV seronegative women who participated in a microbicide efficacy trial in Southern Africa (HPTN 035). We detected vaginal IgA antibodies directed at HIV-1 Env gp120/gp140 in six of these women, and at gp41 in another three women, but did not detect Env-specific IgG antibodies in any women., Conclusion: Vaginal secretions of HIV-1 infected women contained IgG reactivity to a broad range of Env antigens and IgA reactivity to gp41. In contrast, Env-binding antibodies in the vaginal secretions of HIV-1 uninfected women participating in the microbicide trial were restricted to the IgA subtype and were mostly directed at HIV-1 gp120/gp140.

Problem: Whether the concentrations of antiviral proteins, and anti-HIV activity, within human vaginal secretions change across the menstrual cycle is unknown., Method of Study: Using a menstrual cup, vaginal secretions from pre-menopausal women were recovered at the proliferative (d6-8), mid-cycle (d13-15), and secretory (d21-23) stages of the menstrual cycle. Antiviral protein concentration was determined by ELISA, and anti-HIV activity assessed using the TZM-bl reporter cell line., Results: CCL20, RANTES, elafin, HBD2, SDF-1α, and IL-8 levels were detectable in the secretions. Vaginal secretions had anti-HIV activity against specific clade B strains of HIV, with significant inhibition of IIIB and increased infectivity of transmitted/founder CH077.t. No significant differences in either antiviral protein concentration or anti-HIV activity with respect to menstrual cycle stage were measured, but marked differences were observed in both parameters over the course of the cycle between different women and in consecutive cycles from the same woman., Conclusion: The vagina contains a complement of antiviral proteins. The variation in anti-HIV activity demonstrates that immune protection in the vagina is not constant. Intra- and interindividual variations suggest that factors in addition to sex hormones influence antiviral protection. Lastly, the menstrual cup is a new model for recovering undiluted vaginal secretions from women throughout their reproductive life., (© 2014 John Wiley & Sons Ltd.)

Human epididymis protein 4 (HE4) is a protease inhibitor and a recently identified serum biomarker for ovarian cancer. Properties of HE4 in the genital tract of healthy women have not been evaluated. We evaluated associations between HE4 and a second vaginal protease inhibitor, secretory leukocyte protease inhibitor (SLPI), with vaginal concentrations of innate immune mediators or proteases and with the types of vaginal bacterial communities. Vaginal secretions were collected from 18 healthy reproductive age women and assayed by enzyme-linked immunosorbent assay for concentrations of HE4, SLPI, kallikrein 5, cathepsin B, interleukin 1β (IL-1), IL-1 receptor antagonist (IL-1 ra), mannose-binding lectin (MBL), the inducible 70-kDa heat shock protein, and matrix metalloproteinase (MMP)-8. The species composition of vaginal bacterial communities in 16 women was characterized by sequencing amplicons derived from 16S bacterial ribosomal RNA genes. Correlations between any 2 assays were analyzed by the Spearman rank correlation tests. Differences in the concentrations of HE4 and SLPI, and between soluble components and vaginal community types, were analyzed by the Mann-Whitney U tests. Vaginal HE4 concentrations, but not SLPI levels, were positively correlated with levels of IL-1β (P = .0152), IL-1ra (P = .0061), MBL (P = .0100), and MMP-8 (P = .0315). The median vaginal HE4 level, as well as concentrations of MBL, IL-1β, IL-1ra, and MMP-8, was highest when Gardnerella vaginalis dominated a vaginal community. The association between HE4, elevated levels of proteases, immune mediators and high proportions of G vaginalis strongly suggests that HE4 is a component of the proinflammatory immune response in the female genital tract.

A comparative evaluation of the immunity stimulated with a vaccine regimen that includes simian immunodeficiency virus (SIV), interleukin 2 (IL-2), and IL-15 DNAs, recombinant modified vaccinia virus Ankara (rMVA), and inactivated SIVmac239 particles administered into the oral and nasal cavities, small intestine, and vagina was carried out in female rhesus macaques to determine the best route to induce diverse anti-SIV immunity that may be critical to protection from SIV infection and disease. All four immunizations generated mucosal SIV-specific IgA. Oral immunization was as effective as vaginal immunization in inducing SIV-specific IgA in vaginal secretions and generated greater IgA responses in rectal secretions and saliva samples compared to the other immunization routes. All four immunizations stimulated systemic T-cell responses against Gag and Env, albeit to a different extent, with oral immunization providing greater magnitude and nasal immunization providing wider functional heterogeneity. SIV-specific T cells producing gamma interferon (IFN-γ) dominated these responses. Limited levels of SIV-specific IgG antibodies were detected in plasma samples, and no SIV-specific IgG antibodies were detected in secretions. Vaccination also induced CD4(+) and CD8(+) T-cell responses in the rectal and vaginal mucosa with greater functional heterogeneity than in blood samples. Rectal T-cell responses were significantly greater in the orally vaccinated animals than in the other animals. The most balanced, diverse, and higher-magnitude vaginal T-cell responses were observed after intestinal vaccination. Significantly higher CD8(+) granzyme B-positive T-cell responses were observed systemically after intestinal vaccination and in rectal cells after oral immunization. The majority of SIV-specific T cells that produced granzyme B did not produce cytokines. Of the immunization routes tested, oral vaccination provided the most diverse and significant response to the vaccine.

The bivalent HPV16/18 vaccine induces high antibody concentrations in serum while data about antibody responses in the cervix are limited. In this study, we investigated pre- and post-vaccination antibody responses against seven high-risk HPV types by detection of IgG and IgA HPV-specific antibodies in cervical secretion samples (CVS) and serum. From an HPV vaccine monitoring study CVS and serum samples were available (pre-vaccination (n = 297), one year (n = 211) and two years (n = 141) post-dose-one vaccination) from girls aged 14-16 y. The girls were vaccinated with the bivalent HPV vaccine at months 0, 1 and 6. CVS was self-sampled using a tampon. Samples were tested for HPV-specific antibodies (HPV16/18/31/33/45/52/58) by a VLP-based multiplex immunoassay. Post-vaccination, IgG and IgA antibody levels for HPV16/18 were detectable in CVS and amounted to 2% and 1% of the IgG and IgA antibody levels observed in serum, respectively. The antibody levels remained constant between one and two years after vaccination. The correlation between CVS and serum was similar for IgG and IgA vaccine-derived antibody levels for HPV16 (rs = 0.58, rs = 0.54) and HPV18 (rs = 0.50, rs = 0.55). Vaccine-derived IgG antibody levels against cross-reactive HPV types in CVS and in serum were highest for HPV45. No IgA cross-reactive antibody responses could be detected in CVS. Post-vaccination, HPV16/18 IgG and IgA antibodies are not only detectable in serum but also in CVS. The correlation of HPV16/18 IgG antibody levels between serum and CVS suggests that vaccine induced HPV antibodies transudate and/or exudate from the systemic circulation to the cervical mucosa to provide protection against HPV infections.

The mucosal environment may impact the risk for human immunodeficiency virus type 1 (HIV-1) acquisition. Immune mediators were measured in vaginal fluid collected from HPTN 035 participants who acquired HIV-1 and from those who remained HIV-1 negative (controls). Mediator concentrations were similar in samples obtained before as compared to after HIV-1 acquisition in the 8 seroconverters. Compared with controls, seroconverters were more likely to have detectable levels of HβD-2 (odds ratio [OR], 2.39; P = .005) and greater Escherichia coli bactericidal activity (OR, 1.22; P = .01) prior to seroconversion. E. coli bactericidal activity remained significant in a multivariable analysis (P = .02) and may be a biomarker for HIV-1 acquisition.

Objective: To test the immunoglobulin free light chain (FLC) from nasal secretion(s) and serum of patients with allergic rhinitis and non-allergic rhinitis for the purpose of exploring the possible immunological mechanism., Methods: Sixty consecutive patients were selected between September and December in 2009, involving 30 patients with allergic rhinitis and 30 patients with non-allergic rhinitis, diagnosed by symptoms, signs, SPT and sIgE. Thirty volunteers was chosen as health control (HC). ELISA was used to detect the total IgE, eosinophil cationic protein (ECP), mast cell tryptase (MCT), κFLC, λFLC in nasal secretion and serum. The data was statistically analyzed by SPSS 17.0 software., Results: According to the VAS scores, the nasal symptoms of AR and NAR, including sneeze, nasal discharge, nasal obstruction and nasal itching were compared. There was no statistical difference (t value was 1.189, 0.741, 0.758, 0.797, respectively, P < 0.5); In serum, κFLC, λFLC, IgE, ECP & MCT were increased in NAR compared to HC (P < 0.05); λFLC was increased in NAR compared to AR group (P < 0.05), κFLC and ECP were increased in AR. There was no significant difference between AR and NAR (P < 0.05); In nasal secretion, κFLC, λFLC, IgE, ECP and MCT were increased in AR and NAR compared to HC, and the ECP and IgE were significantly increased in AR compared to NAR (P < 0.05). ; In nasal secretion, the FLCs revealed a significantly higher correlation with MCT (r value was 0.518 and 0.484, P < 0.01), and in serum revealed a significant correlation with ECP (r value was 0.343 and 0.342, P < 0.01)., Conclusions: Immunoglobulin free light chain takes part in the path of physiological process of allergic rhinitis and non-allergic rhinitis with the immunological mechanism.

Unlabelled: Sublingual (SL) and intranasal (IN) administration of a Bacillus subtilis-based tetanus vaccine was tested in piglets, which more closely mimic the human immune system than mice. Piglets were immunized by the SL, IN or oral routes with vaccine expressing tetanus toxin fragment C, or commercial tetanus vaccine given by intramuscular injection as a control. Tetanus toxoid specific ELISA and passive neutralization tests were used to measure IgG and IgA levels in serum and mucosal secretions, and assess protective serum antibodies, respectively. The nature of the immune response was explored by MHC Class II, TGF-β1 expression, and ELISA assays for multiple cytokines. SL or IN immunization of piglets induced neutralizing tetanus toxoid specific serum antibody and local salivary and vaginal IgA responses. Standard tetanus vaccine resulted in systemic antibodies, whereas oral administration of the Bacillus-based vaccine was ineffective. Further analyses indicated a balanced Th1/Th2 response to SL or IN immunization., Conclusion: This study demonstrates for the first time that SL or IN administration is effective for inducing both systemic and mucosal responses in a piglet model, indicating that SL or IN delivery of a B. subtilis-based tetanus vaccine can be a simple, non-invasive, low cost strategy to induce immunity to tetanus., (Copyright © 2011. Published by Elsevier Masson SAS.)

Vitamin A deficiency (VAD) alters the phenotype of airway epithelium and attenuates the epithelial defense system, and many studies have reported the association of VAD with respiratory disease. In this study, we investigated changes in submucosal glands (SMG) in a mouse model of VAD. C57BL/6 mice were fed a vitamin A-devoid diet and the others were fed a control diet (1.2 mg retinol/kg). The areas of serous and mucous cells of SMG were measured in 4-, 8-, and 20-wk-old male mice. The volume and lysozyme concentration of glandular secretions were also measured. The 2 groups did not differ in body weight or general morbidity at 3-10 wk of age, although serum retinol concentrations were greater in the control mice than in the VAD mice after 4 wk. Upon histological evaluation, we found that the areal ratio of serous cells:total SMG cells was significantly lower after 8 wk in the VAD mice compared with the control mice, although the total area of SMG did not differ between groups throughout the 20-wk experiment. The number of secretory bubbles did not differ between the groups, but total secretion volume was reduced by 35% in 8-wk-old VAD mice compared with controls. Furthermore, the concentration of lysozyme in secretions from 8-wk-old VAD mice was also less than in controls, compounding the effect of diminished secretion volume. In this study, we found serous cell hypotrophy/hypoplasia and dysfunction in VAD mice, which may contribute to the susceptibility to airway infection linked to VAD.

Unlabelled: The immune response to Neisseria gonorrhoeae is poorly understood, but its extensive antigenic variability and resistance to complement are thought to allow it to evade destruction by the host's immune defenses. We propose that N. gonorrhoeae also avoids inducing protective immune responses in the first place. We previously found that N. gonorrhoeae induces interleukin-17 (IL-17)-dependent innate responses in mice and suppresses Th1/Th2-dependent adaptive responses in murine cells in vitro through the induction of transforming growth factor β (TGF-β). In this study using a murine model of vaginal gonococcal infection, mice treated with anti-TGF-β antibody during primary infection showed accelerated clearance of N. gonorrhoeae, with incipient development of Th1 and Th2 responses and diminished Th17 responses in genital tract tissue. Upon secondary reinfection, mice that had been treated with anti-TGF-β during primary infection showed anamnestic recall of both Th1 and Th2 responses, with the development of antigonococcal antibodies in sera and secretions, and enhanced resistance to reinfection. In mouse knockout strains defective in Th1 or Th2 responses, accelerated clearance of primary infection due to anti-TGF-β treatment was dependent on Th1 activity but not Th2 activity, whereas resistance to secondary infection resulting from anti-TGF-β treatment during primary infection was due to both Th1- and Th2-dependent memory responses. We propose that N. gonorrhoeae proactively elicits Th17-driven innate responses that it can resist and concomitantly suppresses Th1/Th2-driven specific adaptive immunity that would protect the host. Blockade of TGF-β reverses this pattern of host immune responsiveness and facilitates the emergence of protective antigonococcal immunity., Importance: Pathogen-host interactions during infectious disease are conventionally thought of as two-way reactions, that of the host against the pathogen and vice versa, with the outcome dependent on which one ultimately prevails. We propose that Neisseria gonorrhoeae, a pathogen that has become extremely well adapted to its exclusive human host, proactively directs the manner in which the host responds in ways that are beneficial to its own survival but detrimental to the host. Gonorrhea is a widely prevalent sexually transmitted infection, and naturally occurring gonococcal strains are becoming resistant to most available antibiotics, yet no effective vaccine has been developed. These new insights into the immune response to N. gonorrhoeae should lead to novel therapeutic strategies and facilitate new approaches to vaccine development.

Female reproductive tract (FRT) epithelial cells protect against potential pathogens and sexually transmitted infections. The purpose of this study was to determine if epithelial cells from the upper FRT secrete antimicrobials that inhibit reproductive tract pathogens that threaten women's health. Apical secretions from primary cultures of Fallopian tube, uterine, cervical, and ectocervical epithelial cells were incubated with Neisseria gonorrhoeae, Candida albicans (yeast and hyphal forms), human immunodeficiency virus 1 (HIV-1), and Lactobacillus crispatus before being tested for their ability to grow and/or infect target cells. Epithelial cell secretions from the upper FRT inhibit N. gonorrhoeae and both forms of Candida, as well as reduce HIV-1 (R5) infection of target cells. In contrast, none had an inhibitory effect on L. crispatus. An analysis of cytokines and chemokines in uterine secretions revealed several molecules that could account for pathogen inhibition. These findings provide definitive evidence for the critical role of epithelial cells in protecting the FRT from infections, without comprising the beneficial presence of L. crispatus, which is part of the normal vaginal microflora of humans.

The nasopharynx-associated lymphoid tissue (NALT) of humans and other mammals is associated with immunity against airborne infections, though it is generally considered to be a secondary component of the mucosa-associated lymphoid system. We found that protective immunity to a virulence factor of nasal mucosa-colonizing Staphylococcus aureus, staphylococcal enterotoxin B (SEB), requires a functional NALT. We examined the role of NALT using intranasal (IN) vaccination with a recombinant SEB vaccine (rSEBv) combined with an adjuvant in a mouse model of SEB-induced toxic shock. The rSEBv was rapidly internalized by NALT cells at the mucosal barrier, and transport into NALT was accelerated by inclusion of a Toll-like receptor 4 (TLR4) agonist. Vaccine-induced germinal centers of B cells formed within NALT, accompanied by elevated levels of IgA(+) and IgG(+) cells, and these were further increased by TLR4 activation. The NALT was the site of specific anti-rSEBv IgA and IgG production but was also influenced by intraperitoneal (IP) inoculation and perhaps other isolated lymphoid follicles observed within the nasal cavity. Vaccination by the IN route generated robust levels of anti-rSEBv IgA in saliva, nasal secretions, and blood compared to much lower levels after IP vaccination. IN vaccination also induced secretion of anti-rSEBv IgG in the blood and nasal secretions. Significantly, the efficacy of IN vaccination was dependent on NALT, as surgical removal resulted in greater sensitivity to IN challenge with wild-type SEB. Thus, protective immunity to SEB within the nasal sinuses was elicited by responses originating in NALT.

Objective: The most important millipede species causing accidents in Brazil is Rhinocricus padbergi (order Spirobolida, family Rhinocricidae), a vegetarian scavenger distributed from Central to South America. Eleven clinical cases of dermal and oral accidental exposures to secretions from Rhinocricus spp. milipedes are described., Case Series: Eleven cases of skin and oral involvement after accidental contact with the secretions of Rhinocricus spp. in patients from 1to 46 years are detailed. Ten of the 11 accidents involved the feet and in 1 child the mouth. Mild pain was reported in two of the cases, and a transient local burning sensation was described by most of the patients. Three reported no pain or any sensation at all. What was observed in all patients was a dark reddish or blackish staining of the skin simulating inflammatory or even necrotic lesions, which resolved naturally after some weeks., Conclusion: Despite the necrotic appearance of Rhinocricus spp. skin lesions, only a very mild inflammation and no necrosis occur. Analysis of the content of 50 glands of these animals captured in the southeast region of Brazil identified 2-methil-1,4-benzoquinone and 3,3a,4,5-tetrahydro-1H-pyrrolo-[2,3-b] pyridine-2,6-dione as the substances responsible for the lesions. Benzoquinones are strongly irritant and persistent compounds, working very well as insect repellents and are toxic to a great variety of other parasites and pathogens. They also have tanning properties. No systemic toxic effects have been described so far after skin contact with benzoquinones or Rhinocricus species.

We previously developed a respiratory tract vaccine candidate against Ebola virus (EBOV) based on human parainfluenza virus type 3 (HPIV3), a respiratory paramyxovirus, expressing the EBOV GP envelope protein (HPIV3/GP) from an added gene. Two doses of this vaccine candidate delivered by the intranasal and intratracheal route protected monkeys against intraperitoneal challenge with EBOV; however, concerns exist that the vaccine candidate may have reduced immunogenicity in the adult human population due to pre-existing immunity against HPIV3. Here we developed a new vaccine candidate (NDV/GP) based on Newcastle disease virus (NDV), an avian paramyxovirus that is antigenically distinct from human viral pathogens and is highly attenuated in monkeys. Following one intranasal and intratracheal inoculation of Rhesus monkeys with NDV/GP, titers of EBOV-specific antibodies in respiratory tract secretions and serum samples determined by ELISA, as well as serum EBOV-neutralizing antibodies, were undetectable or low compared to those induced by HPIV3/GP. A second immunization resulted in a substantial boost in serum IgG ELISA titers, yet the titers remained lower than those induced by a second dose of HPIV3/GP. In contrast, the ELISA IgA titers in respiratory tract secretions and, more importantly, the serum EBOV-neutralizing antibody titers were equal to those induced after the second dose of HPIV3/GP. These data suggest that NDV/GP can be effective for immunization against EBOV alone, or in combination with either HPIV3/GP or another vaccine platform in a heterologous prime-boost regimen., (Published by Elsevier Ltd.)

This pooled analysis of data from four Phase III clinical trials was undertaken to assess the correlation between levels of anti-human papillomavirus (HPV)-16/18 antibodies in serum and cervicovaginal secretions (CVS) in girls and women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine. Serum and CVS samples were collected from a subset of women aged 10-65 years (N=350) at pre-specified time-points from 7 to 36 months post-vaccination. Anti-HPV-16/18 antibody levels in serum and CVS were measured by enzyme-linked immunosorbent assay. Pearson correlation coefficients between serum and CVS antibody levels, standardized for total immunoglobulin G, were calculated at each time-point in women with detectable antibodies in both serum and CVS. All subjects had seroconverted at Month 7 and remained seropositive through Month 36 for both antigens. Geometric mean titers of anti-HPV-16/18 antibodies in serum were substantially higher at all time-points than those in a control group of women who had cleared a natural HPV infection in another trial. In women with detectable antibodies in both serum and CVS, good correlation was seen between HPV-16/18 antibody levels at all time-points (Pearson correlation coefficient: 0.84-0.92 for HPV-16 and 0.90-0.91 for HPV-18). The strong correlation between levels of HPV-16/18 antibodies in serum and CVS up to 36 months post-vaccination in girls and women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine supports transudation of serum antibodies as the mechanism by which antibodies are introduced into CVS. These CVS antibodies may play a role in the protective efficacy of this vaccine.

Little is known about the prevalence of mucosal antibodies induced by infection with human coronaviruses (HCoV), including HCoV-229E and -OC43 and recently described strains (HCoV-NL63 and -HKU1). By enzyme-linked immunosorbent assay, we measured anti-HCoV IgG antibodies in serum and IgA antibodies in nasal wash specimens collected at seven U.S. sites from 105 adults aged 50 years and older (mean age, 67 ± 9 years) with chronic obstructive pulmonary disease. Most patients (95 [90%]) had at least one more chronic disease. More patients had serum antibody to each HCoV strain (104 [99%] had antibody to HCoV-229E, 105 [100%] had antibody to HCoV-OC43, 103 [98%] had antibody to HCoV-NL63, and 96 [91%] had antibody to HCoV-HKU1) than had antibody to each HCoV strain in nasal wash specimens (12 [11%] had antibody to HCoV-229E, 22 [22%] had antibody to HCoV-OC43, 8 [8%] had antibody to HCoV-NL63, and 31 [31%] had antibody to HCoV-HKU1), respectively (P < 0.0001). The proportions of subjects with IgA antibodies in nasal wash specimens and the geometric mean IgA antibody titers were statistically higher for HCoV-OC43 and -HKU1 than for HCoV-229E and -NL63. A higher proportion of patients with heart disease than not had IgA antibodies to HCoV-NL63 (6 [16%] versus 2 [3%]; P = 0.014). Correlations were highest for serum antibody titers between group I strains (HCoV-229E and -NL63 [r = 0.443; P < 0.0001]) and between group II strains (HCoV-OC43 and -HKU1 [r = 0.603; P < 0.0001]) and not statistically significant between HCoV-NL63 and -OC43 and between HCoV-NL63 and -HKU1. Patients likely had experienced infections with more than one HCoV strain, and IgG antibodies to these HCoV strains in serum were more likely to be detected than IgA antibodies to these HCoV strains in nasal wash specimens.

Outbreaks of highly pathogenic H5N1 influenza viruses have been reported in many countries worldwide. The possibility of pandemics caused by H5N1 influenza viruses is high since human infections by H5N1 viruses continually occur. In this study we determined the immune response and efficacy of inactivated H5N1 vaccine developed by reverse genetics in ferrets. Ferrets intramuscularly inoculated with two doses of H5N1 vaccine survived the lethal challenge with homologous or heterologous H5N1 influenza viruses, while 75% and 25% of ferrets immunized with one dose of H5N1 vaccine survived the lethal challenge with homologous and heterologous H5N1 influenza viruses, respectively. When we determined antibody subtypes specific for H5N1 influenza viruses in tissues and sera of vaccinated ferrets, IgG antibodies were detected mainly in the trachea, nostril, lung, heart, liver, kidney, intestine, spleen, and serum. Our results suggest that IgG antibodies may play a major role in protecting ferrets immunized with the inactivated H5N1 vaccine from lethal challenge with H5N1 influenza viruses.

Introduction: Natural killer (NK) cells have an inherent ability to recognize and destroy a wide array of cells rendered abnormal by stress or disease. NK cells can kill a targeted cell by forming a tight interface-the lytic immunological synapse. This represents a dynamic molecular arrangement that over time progresses through a series of steps to ultimately deliver the contents of specialized organelles known as lytic granules., Discussion: In order to mediate cytotoxicity, the NK cell faces the challenge of mobilizing the lytic granules, polarizing them to the targeted cell, facilitating their approximation to the NK cell membrane, and releasing their contents., Conclusion: This review is focused upon the final steps in accessing function through the lytic immunological synapse.

Non-protease inhibitor-based antiretroviral therapy (ART) is widely accepted as first-line ART in developing countries. Although reverse transcriptase inhibitor-based regimens have been studied in the peripheral blood, no studies have analyzed alterations in cytokine and chemokine levels, together in peripheral blood and genital secretions. Forty HIV-infected women with CD4 cell counts <200 cells/mm(3), asymptomatic, with no genital tract infection, willing to participate in the study, and adhere to ART were enrolled. Cervicovaginal lavage (CVL) was collected in the mid-cycle phase of menstrual cycle. Patients were initiated with reverse transcriptase-based antiretrovirals. Repeat sampling was performed at 24 weeks. Cytokines and chemokines were measured using ultrasensitive ELISA kits. Viral load declined to undetectable levels in 29 patients in the blood and in 33 cases in the CVL. Proinflammatory cytokines (tumor necrosis factor-alpha [TNF-alpha, interleukin-6 [IL-6], IL-1beta) in the serum and CVL showed a significant decrease in mean levels after therapy. IL-2 levels increased significantly whereas IL-12 and (IFN-gamma decreased in both compartments. Mean levels of IL-4 and IL-10 decreased significantly in the serum. There was direct correlation between serum and CVL levels of IL-2 and IL-10. IL-10 had a negative correlation with CD4% at baseline and 6 months of therapy. Mean levels of all alpha- and beta-chemokines decreased in serum after therapy. In CVL, mean levels of MIP-1alpha, RANTES, and IL-8 reduced and SDF-1alpha increased significantly (P value <0.001). Serum levels of all the cytokines, except IL-2, and all chemokines prior to therapy, were significantly higher than healthy controls. In CVL, mean levels of TNF-alpha, IL-6, IL-1beta, IL-12, IFN-gamma, IL-10, RANTES, and IL-8 were significantly higher, whereas IL-2, MIP-1alpha, and MIP-1beta were significantly lower than healthy controls. The mean levels of proinflammatory cytokines and chemokines significantly decreased in serum and CVL after therapy, possibly due to reduced viral load.

The CLCA proteins were first shown to exist in bovine trachea and named as chloride channels calcium activated (CLCA) due to the calcium-dependent chloride conductance that appeared to be activated on expression of these proteins in trachea and other secretory epithelial cells. Since their initial discovery the CLCA gene family has grown extensively and family members have been identified in bovine, human, murine, equine and porcine tissues. The CLCA proteins appear to have a role to play in chloride conductance across epithelial cells and hence epithelial fluid secretion; cell-cell adhesion, apoptosis, cell cycle control and tumorgenesis and metastasis; mucous production and cell signalling in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). There are four human homologues; hCLCA1, hCLCA2, hCLCA3 and hCLCA4. Interest in these proteins has gathered pace with the description of hCLCA1's involvement in several human respiratory diseases. This review will describe the CLCA gene family and then move on to look at the growing body of evidence that suggests that at least hCLCA1 has an important role in the pathogenesis of respiratory disease such as asthma, COPD and cystic fibrosis (CF).

A one-step modification ofimmunoenzyme assay (dot variant) is proposed for the detection of ABH-Lewis antigens in human discharges (saliva, sperm, vaginal discharge). Sensitivity and specificity of the new method is higher than those of other methods currently used in forensic medicine for the detection of antigens in human body discharges; its other advantages over routine techniques include procedural simplicity, high performance, and the possibility of conducting series measurements with minimal labour inputs. Moreover, it provides information not only about group characteristic but also about category of discharge. The analysis is carried out in supernatant fractions which permits to reserve cellular material for molecular-genetic studies.

Background: In young children with wheezing or bronchiolitis, especially with respiratory syncitial virus, blood eosinophilia and a high eosinophil cationic protein level in nasal secretions predicts subsequent wheezing in later childhood. However, whether eosinophil activation results from virus-induced inflammation or local eosinophilia per se precedes the onset of wheezing remains unknown. In the present study, we examined the association between the presence of nasal eosinophils during respiratory tract infection (RTI) and subsequent wheezing in young children., Methods: A total of 35 young children less than 3 years of age who visited our outpatient clinic with rhinorrhea between April and July 2004 were enrolled in this prospective cohort study. Subjects who were given diagnoses of allergic rhinitis were excluded. In all the subjects, the presence of eosinophils in nasal secretions was determined. The subjects were followed, and the cumulative incidences of wheezing during the subsequent 2- and 12-month periods were examined., Results: According to a logistic regression analysis adjusted for age, sex, family history, allergies, and wheezing at entry, young children with nasal eosinophil infiltration during acute RTI had a significantly higher risk of wheezing during the subsequent 2 months, compared with those without nasal eosinophil infiltration (adjusted odds ratio, 27.618, p = 0.016)., Conclusions: Our findings not only suggest that nasal eosinophil testing may serve as a convenient clinical marker for identifying young children at risk for subsequent wheezing, but also shed new light on the role of eosinophils in the onset of wheezing in young children.

The fucosylated ABH antigens, which constitute the molecular basis for the ABO blood group system, are also expressed in salivary secretions and gastrointestinal epithelia in individuals of positive secretor status; however, the biological function of the ABO blood group system is unknown. Gastric mucosa biopsies of 41 Rhesus monkeys originating from Southern Asia were analyzed by immunohistochemistry. A majority of these animals were found to be of blood group B and weak-secretor phenotype (i.e., expressing both Lewis a and Lewis b antigens), which are also common in South Asian human populations. A selected group of ten monkeys was inoculated with Helicobacter pylori and studied for changes in gastric mucosal glycosylation during a 10-month period. We observed a loss in mucosal fucosylation and concurrent induction and time-dependent dynamics in gastric mucosal sialylation (carbohydrate marker of inflammation), which affect H. pylori adhesion targets and thus modulate host-bacterial interactions. Of particular relevance, gastric mucosal density of H. pylori, gastritis, and sialylation were all higher in secretor individuals compared to weak-secretors, the latter being apparently "protected." These results demonstrate that the secretor status plays an intrinsic role in resistance to H. pylori infection and suggest that the fucosylated secretor ABH antigens constitute interactive members of the human and primate mucosal innate immune system.

A pathogenic role for Streptococcus (S) pyogenes infections in chronic plaque psoriasis is suspected but poorly defined. We separated cellular and supernatant proteins from S. pyogenes cultures by high-resolution two-dimensional gel electrophoresis, and used immunoblotting to demonstrate the diversity of serum or plasma IgGs that react with elements of the proteome of this bacterium. We have shown that a substantial proportion of IgG-reactive proteins from cultured S. pyogenes are secreted. The total secreted protein fraction, including diverse IgG-binding elements, was subsequently used in an ELISA to measure blood titers of reactive IgG. This ELISA showed that blood samples from patients with chronic plaque psoriasis contained significantly higher titers of reactive IgG than samples from age- and sex-matched healthy controls (P=0.0009). In contrast, neither a standard assay measuring antistreptolysin O titers nor ELISAs measuring titers of IgG reactive with protein fractions from Staphylococcus aureus and Staphylococcus epidermidis, were able to distinguish between blood samples from the two groups. These findings justify the hypothesis that S. pyogenes infections are more important in the pathogenesis of chronic plaque psoriasis than has previously been recognized, and indicate the need for further controlled therapeutic trials of antibacterial measures in this common skin disease.

This study examined the effect of an HIV vaccine on mucosal innate factor expression. Serum, gingival fluid, and genital mucosal secretions were collected from high-risk women and men enrolled in an HIV-1 efficacy vaccine trial and from low-risk women and men. Samples were tested by standard ELISA for lactoferrin, myeloid-related protein-8/14, and secretory leukocyte protease inhibitor. No consistent significant changes in innate factor levels were found in serum or secretions from vaccinees compared to placebo recipients or from high-risk compared to low-risk individuals. Because of the importance of innate immunity in host defense, evaluation of the mucosal innate immune system should be included in future HIV prevention trials.

Background: Respiratory syncytial virus (RSV) and influenza virus are common causes of infantile lower respiratory tract infection (LRTI). It is widely believed that both viral replication and inappropriately enhanced immune responses contribute to disease severity. In infants, RSV LRTI is known to be more severe than influenza virus LRTI., Methods: We compared cytokines and chemokines in secretions of infants surviving various forms of respiratory illness caused by RSV or influenza viruses, to determine which mediators were associated with more-severe illness. We analyzed lung tissue from infants with fatal cases of RSV and influenza virus LRTI to determine the types of inflammatory cells present. Autopsy tissues were studied for the lymphotoxin granzyme and the apoptosis marker caspase 3., Results: Quantities of lymphocyte-derived cytokines were minimal in secretions from infants with RSV infection. Concentrations of most cytokines were greater in influenza virus, rather than RSV, infection. Lung tissues from infants with fatal RSV and influenza virus LRTI demonstrated an extensive presence of viral antigen and a near absence of CD8-positive lymphocytes and natural killer cells, with marked expression of markers of apoptosis., Conclusions: Severe infantile RSV and influenza virus LRTI is characterized by inadequate (rather than excessive) adaptive immune responses, robust viral replication, and apoptotic crisis.

Phyllomedusa hypochondrialis skin secretion can cause both systemic and local effects. In this study, we describe the pattern of local acute inflammatory response after P. hypochondrialis skin secretion injection. The inflammatory reaction in the mice footpad was analysed, including the leukocyte recruitment into local tissue from the peripheral blood, in a mouse model of tissue injury. We also investigated the release of the cytokines IL-1, IL-6 and TNF-alpha, chemokines KC and MCP-1 and the eicosanoids LTB 4 and PGE(2) in mice. The present findings support the ability of P. hypochondrialis skin secretion to induce local inflammation. In addition, these skin secretion components play a role in the initial rolling and slowing of recruited leukocytes and the transition from rolling to adhesion. Levels of the proinflammatory cytokine IL-6, chemokines KC and MCP-1 as well as the eicosanoid PGE(2) were significantly increased after injection of a skin secretion of P. hypochondrialis (0.6 microg/30 microl intraplantar), whereas no changes in other parameters were observed. Finally, the mechanisms involved in the local inflammatory process induced by P. hypochondrialis skin secretion is one of the questions of relevance related to the complex pathophysiology induced by this particular secretion and other toxins.

Objective: Chronic respiratory tract infections are a common problem in patients with severe humoral immunodeficiency despite intravenous immunoglobulin therapy (IVIG), often presenting as rhinosinusitis., Methods: Because it is unclear whether IVIG is a good substitute at the mucosal surface, we analyzed immunoglobulin levels and inflammatory cytokines (ECP, IL-8, and TNF-alpha) in nasal secretions of 13 patients with common variable immunodeficiency (CVID) and in 10 patients with IgA deficiency., Results: In patients with CVID, median IgG and IgM levels did not differ significantly from controls, whereas inflammatory cytokines were markedly elevated, reflecting persistent inflammation at the mucosal site. In contrast, patients with IgA deficiency showed significantly raised IgG and IgM levels, whereas ECP and TNF-alpha were only slightly increased., Conclusion: Low levels of SIgA might be compensated locally at the mucosal site by high levels of IgM and IgG. Our findings implicate that adequate IVIG is not sufficient to prevent chronic inflammation of the sinuses in patients with severe humoral immunodeficiency.

The mucosal surface area of gastrointestinal, respiratory and urogenital tracts of an adult individuals is about 400 m2 and is the main route of infection and potential harmful agents penetration. It emphasize the essential role of the mucosal immune system (MALT). The beginnings of mucosal immunology, based on the people's observations and believes, descent from ancient times, when the attempt of immunization of human organism against distressed illness have been undertaken. Discovery of a MALT system elements and mechanisms of the mucosal immunity working occured in the 20th century. At that time, the base of beneficial properties of human and other animals' secretions have been recognized, starting from milk, through saliva, ending to feces. Nowadays, it is known, that in all secretions, beside innate defence, the main part of mucosal immunity perform antibodies synthetized locally, with the predominance of the class A (IgA). In this paper the greatest discoveries, leading to the understanding of mucosal immunization resulting in systemic resistance, have been approached.

Antigen presentation and immune activation are essential to the effective control of infectious diseases. In 485 North American adolescents at high risk for genital Chlamydia trachomatis infection, we found 2 human leukocyte antigen variants (DRB1*03-DQB1*04 and DQB1*06) to be associated with recurrent Chlamydia infection (adjusted relative odds [RO], >2.0; P<.01, for both variants). A G-C-C haplotype corresponding to variants at IL10 (encoding interleukin-10 [IL-10]) promoter positions -1082, -819, and -592 was underrepresented in individuals with recurrent infection (RO, 0.59; P=.046). These genetic associations were independent of nongenetic factors, including number of sex partners, race, sex, duration of follow-up, and human immunodeficiency virus type 1 seropositivity. Consistent with the observed IL10 association, cervical secretions in female adolescents without the IL10 G-C-C haplotype had elevated IL-10 concentrations after Chlamydia infection, which may reflect involvement of a Chlamydia-specific mechanism for genetically mediated, differential IL-10 expression in the genital tract.

Background: Interleukin 10 (IL-10) and IL-11 are known to have anti-inflammatory activities, and they have been implicated in the pathogenesis of respiratory syncytial virus (RSV) infection., Objectives: To determine IL-10, IL-11, and myeloperoxidase levels in nasal secretions of infants with acute RSV bronchiolitis and to investigate whether there are any differences in these levels in patients with vs without atopy., Methods: We measured IL-10, IL-11, and myeloperoxidase levels in nasal secretions of 44 infants (20 were atopic) with acute RSV bronchiolitis. The nasal secretion samples were obtained from patients at hospital admission and were stored immediately at -70 degrees C until analysis. Atopy was defined as having at least 1 positive skin prick test reaction to common allergens, a history of atopic dermatitis, or a high serum IgE level compared with age-matched controls., Results: Levels of IL-10, IL-11, and myeloperoxidase increased significantly in samples from infants with acute RSV bronchiolitis. Levels of IL-10 and IL-11 were significantly lower in patients with vs without atopy (P < .05). Myeloperoxidase levels showed no significant difference in patients with vs without atopy (P = .18). Patients with severe symptoms tended to have lower IL-10 levels (P = .09), but no relationship was shown between symptom severity and IL-11 levels. Nasal myeloperoxidase levels were significantly higher in patients with severe symptoms (P < .05)., Conclusions: Production of IL-10 and IL-11 was significantly lower in patients with vs without atopy during acute RSV bronchiolitis. The airway inflammation induced by RSV infection may be different in patients with vs without atopy, and this is associated with lower induction of these immunoregulatory cytokines in children with atopy.

Sexually transmitted diseases are a major health problem worldwide, but there is still a lack of knowledge about how to induce an optimal immune response in the genital tract of humans. In this study we vaccinated 21 volunteers nasally or vaginally with the model mucosal antigen cholera toxin B subunit and determined the level of specific immunoglobulin A (IgA) and IgG antibodies in vaginal and cervical secretions as well as in serum. To assess the hormonal influence on the induction of antibody responses after vaginal vaccination, we administered the vaccine either independently of the stage in the menstrual cycle or on days 10 and 24 in the cycle in different groups of subjects. Vaginal and nasal vaccinations both resulted in significant IgA and IgG anti-cholera toxin B subunit responses in serum in the majority of the volunteers in the various vaccination groups. Only vaginal vaccination given on days 10 and 24 in the cycle induced strong specific antibody responses in the cervix with 58-fold IgA and 16-fold IgG increases. In contrast, modest responses were seen after nasal vaccination and in the other vaginally vaccinated group. Nasal vaccination was superior in inducing a specific IgA response in vaginal secretions, giving a 35-fold increase, while vaginal vaccination induced only a 5-fold IgA increase. We conclude that a combination of nasal and vaginal vaccination might be the best vaccination strategy for inducing protective antibody responses in both cervical and vaginal secretions, provided that the vaginal vaccination is given on optimal time points in the cycle.