by
Geoffrey Hart;
Munir Akkaya;
Asiya Chida;
Chungwen Wei;
Scott Jenks;
Christopher Tipton;
Chenfeng He;
Ben S. Wendel;
Jeff Skinner;
Gunjan Arora;
Kassoum Kayentao;
Aissata Ongoiba;
Ogobara Doumbo;
Boubacar Traore;
David L. Narum;
Ning Jiang;
Peter D. Crompton;
Ignacio Sanz;
Susan K. Pierce
Plasmodium falciparum malaria is a deadly infectious disease in which Abs play a critical role in naturally acquired immunity. However, the specificity and nature of Abs elicited in response to malaria are only partially understood. Autoreactivity and polyreactivity are common features of Ab responses in several infections and were suggested to contribute to effective pathogen-specific Ab responses. In this article, we report on the regulation of B cells expressing the inherently autoreactive VH4-34 H chain (identified by the 9G4 mAb) and 9G4 + plasma IgG in adults and children living in a P. falciparum malaria-endemic area in West Africa. The frequency of 9G4 + peripheral blood CD19 + B cells was similar in United States adults and African adults and children; however, more 9G4 + B cells appeared in classical and atypical memory B cell compartments in African children and adults compared with United States adults. The levels of 9G4 + IgG increased following acute febrile malaria but did not increase with age as humoral immunity is acquired or correlate with protection from acute disease. This was the case, even though a portion of 9G4 + B cells acquired phenotypes of atypical and classical memory B cells and 9G4 + IgG contained equivalent numbers of somatic hypermutations compared with all other VHs, a characteristic of secondary Ab repertoire diversification in response to Ag stimulation. Determining the origin and function of 9G4 + B cells and 9G4 + IgG in malaria may contribute to a better understanding of the varied roles of autoreactivity in infectious diseases.
Interleukin-22 (IL-22) acts protectively and harmfully on intestinal tissue depending on the situation; therefore, IL-22 signaling needs to be tightly regulated. IL-22 binding protein (IL-22BP) binds IL-22 to inhibit IL-22 signaling. It is expressed in intestinal and lymphoid tissues, although its precise distribution and roles have remained unclear. In this study, we show that IL-22BP is highly expressed by CD11b + CD8α- dendritic cells in the subepithelial dome region of Peyer's patches (PPs). We found that IL-22BP blocks IL-22 signaling in the follicle-associated epithelium (FAE) covering PPs, indicating that IL-22BP plays a role in regulating the characteristics of the FAE. As expected, FAE of IL-22BP-deficient (Il22ra2 -/- ) mice exhibited altered properties such as the enhanced expression of mucus and antimicrobial proteins as well as prominent fucosylation, which are normally suppressed in FAE. Additionally, Il22ra2 -/- mice exhibited the decreased uptake of bacterial antigens into PPs without affecting M cell function. Our present study thus demonstrates that IL-22BP promotes bacterial uptake into PPs by influencing FAE gene expression and function.
Deoxynucleoside triphosphates (dNTPs) are the building blocks of DNA and their biosynthesis is tightly regulated in the cell. HPLC-MS and enzyme-based methods are currently employed to determine dNTP concentrations from cellular extracts. Here, we describe a highly efficient, HIV-1 reverse transcriptase (RT)-based assay to quantitate dNTP concentrations. The assay is based on the ability of HIV-1 RT to function at very low dNTP concentrations, thus providing for the high sensitivity of detection.
Upon recognition of specific molecular patterns on microbes, host cells trigger an innate immune response, which culminates in the production of type I interferons, proinflammatory cytokines and chemokines, and restricts pathogen replication and spread within the host. At each stage of this response, there are stimulatory and inhibitory signals that regulate the magnitude, quality, and character of the response. Positive regulation promotes an antiviral state to control and eventually clear infection, whereas negative regulation dampens inflammation and prevents immune-mediated tissue damage. An overexuberant innate response can lead to cell and tissue destruction, and the development of spontaneous autoimmunity. The retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), RIG-I and melanoma differentiation-associated gene 5 (MDA5), belong to a family of cytosolic host RNA helicases that recognize distinct nonself RNA signatures and trigger innate immune responses against several RNA viruses by signaling through the essential adaptor protein mitochondrial antiviral signaling (MAVS). The RLR signaling pathway is tightly regulated to maximize antiviral immunity and minimize immune-mediated pathology. This review highlights contemporary findings on negative regulators of the RLR signaling pathway, with specific focus on the proteins and biological processes that directly regulate RIG-I, MDA5 and MAVS signaling function.
by
Mark J. Sotir;
Douglas H. Esposito;
Elizabeth Barnett;
Karen Leder;
Phyllis E Kozarsky;
Poh L. Lim;
Effrossyni Gkrania-Klotsas;
Davidson H. Hamer;
Susan Kuhn;
Bradley A. Connor;
Rashila Pradhan;
Eric Caumes
This work is written by (a) US Government employee(s) and is in the public domain in the US. Measles remains a risk for travelers, with 94 measles diagnoses reported to the GeoSentinel network from 2000 to 2014, two-thirds since 2010. Asia was the most common exposure region, then Africa and Europe. Efforts to reduce travel-associated measles should target all vaccine-eligible travelers, including catch-up vaccination of susceptible adults.
Ebola virus disease (EVD) is associated with elevated cytokine levels, and hypercytokinemia is more pronounced in fatal cases. This type of hyperinflammatory state is reminiscent of 2 rheumatologic disorders known as macrophage activation syndrome and hemophagocytic lymphohistiocytosis, which are characterized by macrophage and T-cell activation. An evaluation of 2 cohorts of patients with EVD revealed that a marker of macrophage activation (sCD163) but not T-cell activation (sCD25) was associated with severe and fatal EVD. Furthermore, substantial immunoreac-tivity of host tissues to a CD163-specific antibody, predominantly in areas of extensive immunostaining for Ebola virus antigens, was observed in fatal cases. These data suggest that host macrophage activation contributes to EVD pathogenesis and that directed antiinflammatory therapies could be beneficial in the treatment of EVD.
Background: Case definitions for asthma incidence in early life vary between studies using medical records to define disease. This study assessed the impact of different approaches to using medical records on estimates of asthma incidence by age 3 and determined the validity of early-life asthma case definitions in predicting school-age asthma. Methods: Asthma diagnoses and medications by age 3 were used to classify 7103 children enrolled in Kaiser Permanente Georgia according to 14 definitions of asthma. School-age asthma was defined as an asthma diagnosis between ages 5 and 8. Sensitivity (probability of asthma by age 3 given school-age asthma), specificity (probability of no asthma by age 3 given no school-age asthma), positive and negative predictive values (probability of (no) school-age asthma given (no) asthma by age 3), and likelihood ratios (combining sensitivity and specificity) were used to determine predictive ability. Results: 9.0–35.2% of children were classified as asthmatic by age 3 depending on asthma case definition. Early-life asthma classifications were more specific than sensitive and were better at identifying children who would not have school-age asthma (negative predictive values: 80.7–86.6%) than at predicting children who would have school-age asthma (positive predictive values: 43.5–71.5%). Conclusions: Choice of case definition had a large impact on the estimate of asthma incidence. While ability to predict school-age asthma was limited, several case definitions performed similarly to clinical asthma prediction tools used in previous asthma research (e.g., the Asthma Predictive Index).
by
An V. Nguyen;
Nicole J. Cohen;
Harvey Lipman;
Clive M. Brown;
Noelle-Angelique Molinari;
William L. Jackson;
Hannah Kirking;
Paige Szymanowski;
Todd W. Wilson;
Bisan Salhi;
Rebecca R. Roberts;
David W. Stryker;
Daniel B. Fishbein
Despite limited evidence regarding their utility, infrared thermal detection systems (ITDS) are increasingly being used for mass fever detection. We compared temperature measurements for 3 ITDS (FLIR ThermoVision A20M [FLIR Systems Inc., Boston, MA, USA], OptoTherm Thermoscreen [OptoTherm Thermal Imaging Systems and Infrared Cameras Inc., Sewickley, PA, USA], and Wahl Fever Alert Imager HSI2000S [Wahl Instruments Inc., Asheville, NC, USA]) with oral temperatures (≥100°F = confirmed fever) and self-reported fever. Of 2,873 patients enrolled, 476 (16.6%) reported a fever, and 64 (2.2%) had a confirmed fever. Self-reported fever had a sensitivity of 75.0%, specificity 84.7%, and positive predictive value 10.1%. At optimal cutoff values for detecting fever, temperature measurements by OptoTherm and FLIR had greater sensitivity (91.0% and 90.0%, respectively) and specificity (86.0% and 80.0%, respectively) than did self-reports. Correlations between ITDS and oral temperatures were similar for Opto-Therm (ρ = 0.43) and FLIR (ρ = 0.42) but significantly lower for Wahl (ρ = 0.14; p<0.001). When compared with oral temperatures, 2 systems (OptoTherm and FLIR) were reasonably accurate for detecting fever and predicted fever better than self-reports.
by
Christine L. Mattson;
Mark Freedman;
Jennifer L. Fagan;
Emma L. Frazier;
Linda Beer;
Ping Huang;
Eduardo E. Valverde;
Christopher Johnson;
Catherine Sanders;
A.D. McNaghten;
Patrick Sullivan;
Amy Lansky;
Jonathan Mermin;
James Heffelfinger;
Jacek Skarbinski
Objective: To describe the prevalence and association of sexual risk behaviours and viral suppression among HIV-infected adults in the United States. Design: Cross-sectional analysis of weighted data from a probability sample of HIVinfected adults receiving outpatient medical care. The facility and patient response rates were 76 and 51%, respectively.
Methods: We analysed 2009 interview and medical record data. Sexual behaviours were self-reported in the past 12 months. Viral suppression was defined as all viral load measurements in the medical record during the past 12 months less than 200 copies/ml.
Results: An estimated 98 022 (24%) HIV-infected adults engaged in unprotected vaginal or anal sex; 50 953 (12%) engaged in unprotected vaginal or anal sex with at least one partner of negative or unknown HIV status; 23 933 (6%) did so while not virally suppressed. Persons who were virally suppressed were less likely than persons who were not suppressed to engage in vaginal or anal sex [prevalence ratio, 0.88; 95% confidence interval (CI), 0.82-0.93]; unprotected vaginal or anal sex (prevalence ratio, 0.85; 95% CI, 0.73-0.98); and unprotected vaginal or anal sex with a partner of negative or unknown HIV status (prevalence ratio, 0.79; 95% CI, 0.64-0.99).
Conclusion: The majority of HIV-infected adults receiving medical care in the U.S. did not engage in sexual risk behaviours that have the potential to transmit HIV, and of the 12% who did, approximately half were not virally suppressed. Persons who were virally suppressed were less likely than persons who were not suppressed to engage in sexual risk behaviours.
by
Yi-Bin Chen;
Tao Wang;
Michael T. Hemmer;
Colleen Brady;
Daniel R. Couriel;
Amin Alousi;
Joseph Pidala;
Alvaro Urbano-Ispizua;
Sung Won Choi;
Taiga Nishihori;
Takanori Teshima;
Yoshishiro Inamoto;
Baldeep Wirk;
David I Marks;
Hisham Abdel-Azim;
Leslie Lehmann;
Lolie Yu;
Menachem Bitan;
Mitchell S. Cairo;
Muna Qayed;
Rachel Salit
Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (<18 years)=810, double (≥18 years)=594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22-29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.