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      Multiplex Immunoassay of Lower Genital Tract Mucosal Fluid from Women Attending an Urban STD Clinic Shows Broadly Increased IL1ß and Lactoferrin

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          Abstract

          Background

          More than one million new cases of sexually transmitted diseases (STDs) occur each day. The immune responses and inflammation induced by STDs and other frequent non-STD microbial colonizations (i.e. Candida and bacterial vaginosis) can have serious pathologic consequences in women including adverse pregnancy outcomes, infertility and increased susceptibility to infection by other pathogens. Understanding the types of immune mediators that are elicited in the lower genital tract by these infections/colonizations can give important insights into the innate and adaptive immune pathways that are activated and lead to strategies for preventing pathologic effects.

          Methodology/Principal Findings

          32 immune mediators were measured by multiplexed immunoassays to assess the immune environment of the lower genital tract mucosa in 84 women attending an urban STD clinic. IL-3, IL-1ß, VEGF, angiogenin, IL-8, ß2Defensin and ß3Defensin were detected in all subjects, Interferon-α was detected in none, while the remaining mediators were detected in 40% to 93% of subjects. Angiogenin, VEGF, FGF, IL-9, IL-7, lymphotoxin-α and IL-3 had not been previously reported in genital mucosal fluid from women. Strong correlations were observed between levels of TNF-α, IL-1ß and IL-6, between chemokines IP-10 and MIG and between myeloperoxidase, IL-8 and G-CSF. Samples from women with any STD/colonization had significantly higher levels of IL-8, IL-3, IL-7, IL-1ß, lactoferrin and myeloperoxidase. IL-1ß and lactoferrin were significantly increased in gonorrhea, Chlamydia, cervicitis, bacterial vaginosis and trichomoniasis.

          Conclusions/Significance

          These studies show that mucosal fluid in general appears to be an environment that is rich in immune mediators. Importantly, IL-1ß and lactoferrin are biomarkers for STDs/colonizations providing insights into immune responses and pathogenesis at this mucosal site.

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          Most cited references30

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          The inflammasomes: guardians of the body.

          The innate immune system relies on its capacity to rapidly detect invading pathogenic microbes as foreign and to eliminate them. The discovery of Toll-like receptors (TLRs) provided a class of membrane receptors that sense extracellular microbes and trigger antipathogen signaling cascades. More recently, intracellular microbial sensors have been identified, including NOD-like receptors (NLRs). Some of the NLRs also sense nonmicrobial danger signals and form large cytoplasmic complexes called inflammasomes that link the sensing of microbial products and metabolic stress to the proteolytic activation of the proinflammatory cytokines IL-1beta and IL-18. The NALP3 inflammasome has been associated with several autoinflammatory conditions including gout. Likewise, the NALP3 inflammasome is a crucial element in the adjuvant effect of aluminum and can direct a humoral adaptive immune response. In this review, we discuss the role of NLRs, and in particular the inflammasomes, in the recognition of microbial and danger components and the role they play in health and disease.
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            Angiogenins: a new class of microbicidal proteins involved in innate immunity.

            Although angiogenins have been implicated in tumor-associated angiogenesis, their normal physiologic function remains unclear. We show that a previously uncharacterized angiogenin, Ang4, is produced by mouse Paneth cells, is secreted into the gut lumen and has bactericidal activity against intestinal microbes. Ang4 expression is induced by Bacteroides thetaiotaomicron, a predominant member of the gut microflora, revealing a mechanism whereby intestinal commensal bacteria influence gut microbial ecology and shape innate immunity. Furthermore, mouse Ang1 and human angiogenin, circulating proteins induced during inflammation, exhibit microbicidal activity against systemic bacterial and fungal pathogens, suggesting that they contribute to systemic responses to infection. These results establish angiogenins as a family of endogenous antimicrobial proteins.
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              The prevalence of bacterial vaginosis in the United States, 2001-2004; associations with symptoms, sexual behaviors, and reproductive health.

              Bacterial vaginosis (BV), a disturbance of vaginal microflora, is a common cause of vaginal symptoms and is associated with an increased risk of acquisition of sexually transmitted infections, HIV, and with adverse pregnancy outcomes. We determined prevalence and associations with BV among a representative sample of women of reproductive age in the United States. Women aged 14-49 years participating in the National Health and Nutrition Examination Survey 2001-2004 were asked to submit a self-collected vaginal swab for Gram staining. BV, determined using Nugent's score, was defined as a score of 7-10. The prevalence of BV was 29.2% (95% confidence interval 27.2%-31.3%) corresponding to 21 million women with BV; only 15.7% of the women with BV reported vaginal symptoms. Prevalence was 51.4% among non-Hispanic blacks, 31.9% among Mexican Americans, and 23.2% among non-Hispanic whites (P <0.01 for each comparison). Although BV was also associated with poverty (P <0.01), smoking (P <0.05), increasing body mass index (chi2 P <0.0001 for trend), and having had a female sex partner (P <0.005), in the multivariate model, BV only remained positively associated with race/ethnicity, increasing lifetime sex partners (chi2 P <0.001 for trend), increasing douching frequency (chi2 P for trend <0.001), low educational attainment (P <0.01), and inversely associated with current use of oral contraceptive pills (P <0.005). BV is a common condition; 84% of women with BV did not report symptoms. Because BV increases the risk of acquiring sexually transmitted infections, BV could contribute to racial disparities in these infections.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                10 May 2011
                : 6
                : 5
                : e19560
                Affiliations
                [1 ]Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois, United States of America
                [2 ]Department of Medicine, John Stroger Hospital of Cook County, Chicago, Illinois, United States of America
                [3 ]Ruth M. Rothstein CORE Center, Chicago, Illinois, United States of America
                [4 ]Division of Epidemiology and Biostatistics, University of Illinois, Chicago, Illinois, United States of America
                [5 ]BD Biosciences, San Diego, California, United States of America
                [6 ]Department of Biological Sciences, Case School of Dental Medicine, Cleveland, Ohio, United States of America
                University of California Merced, United States of America
                Author notes

                Conceived and designed the experiments: GTS SRK ALL RB. Performed the experiments: SG. Analyzed the data: HYC GTS. Contributed reagents/materials/analysis tools: AW. Wrote the paper: GTS. Statistical analysis and interpretation of results: HYC RB SRK AW GTS. Design and implementation of sample collection and data collection: SRK TTT MB.

                Article
                10-PONE-RA-19951
                10.1371/journal.pone.0019560
                3091877
                21572958
                f37d506f-196b-4dec-809b-59847f3fe6f4
                Spear et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 17 June 2010
                : 9 April 2011
                Page count
                Pages: 7
                Categories
                Research Article
                Medicine
                Infectious Diseases
                Obstetrics and Gynecology
                Women's Health

                Uncategorized
                Uncategorized

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