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1.
Mult Scler J Exp Transl Clin ; 6(1): 2055217319899695, 2020.
Article in English | MEDLINE | ID: mdl-32064115

ABSTRACT

BACKGROUND: The nature and extent of inflammation seen in multiple sclerosis (MS) varies throughout the course of the disease. Changes seen in CD4+ T-helper cells in relapsing-remitting (RR) MS and secondary progressive (SP) MS might differ qualitatively and/or quantitatively. OBJECTIVE: The objective of this paper is to study the frequencies of all major CD4+ T-helper subtypes - Th17, Th22 and Th1 lineage cells - in relapse, remission and secondary progression alongside CCR6 status, a chemokine receptor involved in migration of these cells into the central nervous system. METHODS: We compared 100 patients (50 RRMS and 50 SPMS) and 50 healthy volunteers and performed flow cytometric analysis of lymphocytes in blood samples. RESULTS: We demonstrated raised frequencies of various cell types along the Th17 axis; Th17, Th17.1 (IL-17+ interferon gamma+) and dual IL-17+ IL-22+ cells in RRMS. Th22 and CCR6+ Th1 cells (nonclassical Th1) were also increased in RRMS. All these cells were CCR6+. Only Th17 frequencies were elevated in SPMS. CONCLUSIONS: Increased frequencies of Th17 cells are implicated both in RRMS and SPMS. The CCR6 pathway includes Th17, Th22 and Th1 nonclassical cells, of which Th22 and Th1 cells represent the greatest subsets in MS.

2.
Brain Behav Immun ; 64: 71-79, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28336414

ABSTRACT

Considerable attention has been given to CCR6+ IL-17-secreting CD4+ T cells (Th17) in the pathology of a number of autoimmune diseases including multiple sclerosis (MS). However, other Th subsets also play important pathogenic roles, including those that secrete IFNγ and GM-CSF. CCR6 expression by Th17 cells allows their migration across the choroid plexus into the cerebrospinal fluid (CSF), where they are involved in the early phase of experimental autoimmune encephalomyelitis (EAE), and in MS these cells are elevated in the CSF during relapses and contain high frequencies of autoreactive cells. However, the relatively low frequency of Th17 cells suggests they cannot by themselves account for the high percentage of CCR6+ cells in MS CSF. Here we identify the dominant CCR6+ T cell subsets in both the blood and CSF as non-classic Th1 cells, including many that secrete GM-CSF, a key encephalitogenic cytokine. In addition, we show that Th cells secreting GM-CSF but not IFNγ or IL-17, a subset termed GM-CSF-only-secreting Th cells, also accumulate in the CSF. Importantly, in MS the proportion of IFNγ- and GM-CSF-secreting T cells expressing CCR6 was significantly enriched in the CSF, and was elevated in MS, suggesting these cells play a pathogenic role in this disease.


Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Multiple Sclerosis/cerebrospinal fluid , Receptors, CCR6/metabolism , Th1 Cells/metabolism , Adult , Aged , CD4 Antigens/metabolism , Female , Humans , Interferon-gamma/metabolism , Male , Middle Aged , Multiple Sclerosis/blood , Multiple Sclerosis/immunology , Receptors, CCR6/blood , Th17 Cells/metabolism
3.
J Neuroimmunol ; 276(1-2): 175-9, 2014 Nov 15.
Article in English | MEDLINE | ID: mdl-25146968

ABSTRACT

Cerebrospinal fluid (CSF) analysis is routinely used in the diagnostic work-up of multiple sclerosis (MS), by detecting CSF-specific oligoclonal bands (OCB). More recently, several studies have reported CSF free light chains (FLC) as an alternative. We show that absolute CSF κFLC concentrations were highly sensitive - more than OCB testing - and specific for clinically isolated syndrome, relapsing remitting and primary progressive MS. Measurement of κFLC alone was sufficient. Our results suggest that CSF κFLC levels measured by nephelometry, if validated in a larger series, are a preferred test to OCB analysis in the diagnostic work-up of patients suspected of having MS.


Subject(s)
Immunoglobulin kappa-Chains/cerebrospinal fluid , Multiple Sclerosis/cerebrospinal fluid , Oligoclonal Bands/cerebrospinal fluid , Adult , Aged , Female , Humans , Male , Middle Aged , Nephelometry and Turbidimetry , Sensitivity and Specificity , Young Adult
4.
Mucosal Immunol ; 5(2): 161-72, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22236998

ABSTRACT

The inflammatory response to lung infections must be tightly regulated, enabling pathogen elimination while maintaining crucial gas exchange. Using recently described "depletion of regulatory T cell" (DEREG) mice, we found that selective depletion of regulatory T cells (Tregs) during acute respiratory syncytial virus (RSV) infection enhanced viral clearance but increased weight loss, local cytokine and chemokine release, and T-cell activation and cellular influx into the lungs. Conversely, inflammation was decreased when Treg numbers and activity were boosted using interleukin-2 immune complexes. Unexpectedly, lung (but not draining lymph node) Tregs from RSV-infected mice expressed granzyme B (GzmB), and bone marrow chimeric mice with selective loss of GzmB in the Treg compartment displayed markedly enhanced cellular infiltration into the lung after infection. A crucial role for GzmB-expressing Tregs has not hitherto been described in the lung or during acute infections, but may explain the inability of children with perforin/GzmB defects to regulate immune responses to infection. The effects of RSV infection in mice with defective immune regulation closely parallel the observed effects of RSV in children with bronchiolitis, suggesting that the pathogenesis of bronchiolitis may involve an inability to regulate virus-induced inflammation.


Subject(s)
Bronchiolitis, Viral/immunology , Granzymes/metabolism , Pneumonia, Viral/immunology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Viruses/immunology , T-Lymphocytes, Regulatory/metabolism , Acute Disease , Animals , Antibodies/metabolism , Antigen-Antibody Complex/administration & dosage , Bronchiolitis, Viral/etiology , Bronchiolitis, Viral/prevention & control , Cell Movement/drug effects , Cells, Cultured , Child , Disease Models, Animal , Disease Progression , Granzymes/genetics , Granzymes/immunology , Humans , Interleukin-2/immunology , Interleukin-2/metabolism , Lung/immunology , Lung/pathology , Lung/virology , Lymphocyte Depletion , Mice , Respiratory Syncytial Virus Infections/complications , Respiratory Syncytial Virus Infections/therapy , Respiratory Syncytial Viruses/pathogenicity , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathology , T-Lymphocytes, Regulatory/virology , Viral Load/drug effects , Viral Load/immunology
5.
Antimicrob Agents Chemother ; 55(10): 4692-7, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21825292

ABSTRACT

MUT056399 is a highly potent new inhibitor of the FabI enzyme of both Staphylococcus aureus and Escherichia coli. In vitro, MUT056399 was very active against S. aureus strains, including methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), linezolid-resistant, and multidrug-resistant strains, with MIC(90)s between 0.03 and 0.12 µg/ml. MUT056399 was also active against coagulase-negative staphylococci, with MIC(90)s between 0.12 and 4 µg/ml. The antibacterial spectrum is consistent with specific FabI inhibition with no activity against bacteria using FabK but activity against FabI-containing Gram-negative bacilli. In vitro, resistant clones of S. aureus were obtained at a low frequency. All of the resistant clones analyzed were found to contain mutations in the fabI gene. In vivo, MUT056399, administered subcutaneously, protected mice from a lethal systemic infection induced by MSSA, MRSA, and vancomycin-intermediate S. aureus strains (50% effective doses ranging from 19.3 mg/kg/day to 49.6 mg/kg/day). In the nonneutropenic murine thigh infection model, the same treatment with MUT056399 reduced the bacterial multiplication of MSSA and MRSA in the thighs of immunocompetent mice. These properties support MUT056399 as a very promising candidate for a novel drug to treat severe staphylococcal infections.


Subject(s)
Anti-Bacterial Agents/pharmacology , Benzamides/pharmacology , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/antagonists & inhibitors , Escherichia coli Proteins/antagonists & inhibitors , Escherichia coli/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Phenyl Ethers/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Acetamides/pharmacology , Animals , Anti-Bacterial Agents/therapeutic use , Benzamides/therapeutic use , Drug Resistance, Multiple, Bacterial , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/genetics , Escherichia coli Proteins/genetics , Fatty Acid Synthase, Type II/antagonists & inhibitors , Fatty Acid Synthase, Type II/genetics , Female , Linezolid , Mice , Microbial Sensitivity Tests , Mutation , Oxazolidinones/pharmacology , Phenyl Ethers/therapeutic use , Staphylococcal Infections/microbiology , Vancomycin/pharmacology
6.
Gut ; 59(1): 79-87, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19828466

ABSTRACT

OBJECTIVE: Evidence suggests haematopoietic stem cells (HSCs) can migrate to injured liver and influence tissue repair. However, mechanisms governing HSC recruitment to injured hepatic microcirculation are poorly understood. These were investigated in vivo following hepatic ischaemia-reperfusion (IR) injury and in vitro using flow-based adhesion assays. DESIGN: Partial IR was induced in anaesthetised WT or PECAM-1(-/-) mice for 90 min. Recruitment of systemically administered HSCs was monitored and effects of function blocking antibodies against alpha(4)beta(1) integrin, CD18, CD44, PECAM-1 or VCAM-1 investigated. The kinetics and molecular events governing adhesion to murine cardiac endothelial cells in vitro were also determined. Effects of conditioned media from IR injured liver on HSC adhesion molecule expression was determined by FACS. RESULTS: Administered HSCs homed predominantly to lungs rather than liver, highlighting a potential therapeutic hurdle. Hepatic HSC recruitment following IR injury was inhibited by anti-alpha(4)beta(1) and anti-VCAM-1 antibodies. A role for alpha(4)beta(1) was also confirmed using flow-based adhesion assays. Incubating HSCs with conditioned media from IR injured liver increased alpha(4)beta(1) expression. CD18, CD44 and PECAM-1 were not involved in recruitment. CONCLUSIONS: This novel study demonstrates that the alpha(4)beta(1)/VCAM-1 pathway mediates HSC recruitment to injured liver. Manipulating this pathway may enhance delivery of HSCs to the liver.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Hematopoietic Stem Cells/physiology , Integrin alpha4beta1/metabolism , Reperfusion Injury/therapy , Vascular Cell Adhesion Molecule-1/metabolism , Alanine Transaminase/metabolism , Animals , Cell Adhesion/physiology , Cells, Cultured , Culture Media, Conditioned , Integrin alpha4beta1/physiology , Liver Circulation/physiology , Male , Mice , Mice, Inbred C57BL , Microcirculation/physiology , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Vascular Cell Adhesion Molecule-1/physiology
7.
Science ; 294(5543): 849-52, 2001 Oct 26.
Article in English | MEDLINE | ID: mdl-11679669

ABSTRACT

Listeria monocytogenes is a food-borne pathogen with a high mortality rate that has also emerged as a paradigm for intracellular parasitism. We present and compare the genome sequences of L. monocytogenes (2,944,528 base pairs) and a nonpathogenic species, L. innocua (3,011,209 base pairs). We found a large number of predicted genes encoding surface and secreted proteins, transporters, and transcriptional regulators, consistent with the ability of both species to adapt to diverse environments. The presence of 270 L. monocytogenes and 149 L. innocua strain-specific genes (clustered in 100 and 63 islets, respectively) suggests that virulence in Listeria results from multiple gene acquisition and deletion events.


Subject(s)
Bacterial Proteins/genetics , Genome, Bacterial , Listeria monocytogenes/genetics , Listeria/genetics , Adaptation, Physiological , Amino Acid Motifs , Bacillus subtilis/genetics , Bacterial Proteins/chemistry , Bacterial Proteins/physiology , Base Composition , Carrier Proteins/chemistry , Carrier Proteins/genetics , Chromosomes, Bacterial/genetics , DNA, Bacterial/chemistry , DNA, Bacterial/genetics , Gene Transfer, Horizontal , Genes, Bacterial , Genomics , Listeria/chemistry , Listeria/physiology , Listeria monocytogenes/chemistry , Listeria monocytogenes/pathogenicity , Listeria monocytogenes/physiology , Membrane Proteins/chemistry , Membrane Proteins/genetics , Sequence Analysis, DNA , Staphylococcus aureus/genetics , Transcription Factors/chemistry , Transcription Factors/genetics , Virulence/genetics
8.
J Bacteriol ; 182(20): 5931-4, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11004200

ABSTRACT

We identified in Listeria monocytogenes a gene encoding a protein homologous to MecA, a regulatory protein acting with ClpC and ComK in the competence pathway of Bacillus subtilis. In L. monocytogenes, MecA is involved, along with ClpC and ClpP, in the downregulation of a 64-kDa secreted protein. In B. subtilis, the MecA protein of L. monocytogenes behaves as a regulatory protein, controlling the transcription of comK and comG. Complete or disrupted ComK homologues were also found in L. monocytogenes. However, we failed to detect competence in various strains of L. monocytogenes, including those with intact ComK. Our results suggest that the functions of MecA in the saprophytes L. monocytogenes and B. subtilis have presumably diverged in response to their respective ecological niches.


Subject(s)
Bacillus subtilis/genetics , Bacterial Proteins/genetics , Listeria monocytogenes/genetics , Bacillus subtilis/metabolism , Bacterial Proteins/metabolism , Gene Expression Regulation, Bacterial , Kinetics , Listeria monocytogenes/growth & development , Listeria monocytogenes/metabolism , Mutagenesis , Phenotype , Restriction Mapping , Sequence Deletion , Transcription, Genetic
9.
Arch Sex Behav ; 29(4): 309-22, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10948721

ABSTRACT

Effects of mode of assessment, person, and situational variables on the accuracy of self-reports of sexual behavior remain uncertain. To evaluate these influences, 190 young women completed measures of erotophilia and social desirability and then monitored their health-related behaviors with a diary for 8 weeks. They returned on two occasions to complete either a face-to-face interview (FTFI) or a self-administered questionnaire (SAQ) regarding their behavior over the same interval. To check the apparent accuracy of participants' retrospective self-reports, a difference score was calculated by subtracting responses obtained on the FTFI or SAQ from the diary card. Results indicated that both modes of assessment were reliable; reliability did not differ as a function of mode of assessment. However, SAQs elicited less discrepant responses for protected vaginal sex; SAQ and FTFI reports for unprotected sexual behaviors were equivalent. Situational and person variables did not predict accuracy scores, which were impaired at higher frequencies of behavior. Results suggest that both modes of assessment were reliable and SAQs may be more accurate for some sexual behaviors.


Subject(s)
Interview, Psychological , Self Disclosure , Sexual Behavior/psychology , Surveys and Questionnaires , Adult , Female , Health Behavior , Humans , Random Allocation , Reproducibility of Results , Social Desirability
10.
Health Psychol ; 19(1): 3-11, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10711582

ABSTRACT

This randomized clinical trial evaluated an HIV-risk reduction (HIV-RR) intervention based on the information-motivation-behavioral skills model. At baseline, 102 women (M age = 29 years; 88% African American) completed a survey regarding HIV-related knowledge, risk perceptions, behavioral intentions, and risk behavior. Participants were then assigned to either the HIV-RR intervention or a health-promotion control group. Postintervention and follow-up data indicated that women in the HIV-RR program enhanced their knowledge and strengthened their risk reduction intentions relative to controls. Moreover, HIV-RR women who expressed "imperfect" intentions also increased their condom use, talked more with partners about condom use and HIV testing, and were more likely to have refused unprotected sex.


Subject(s)
Counseling , HIV Infections/prevention & control , Health Knowledge, Attitudes, Practice , Motivation , Women's Health , AIDS Serodiagnosis , Adolescent , Adult , Condoms , Female , Humans , Middle Aged , Poverty , Risk-Taking , Urban Population
11.
J Interferon Cytokine Res ; 19(9): 1059-66, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10505750

ABSTRACT

The activation antigen CD38, which has NAD+ glycohydrolase activity in its extracellular domain, is expressed by a large variety of cell types. Few investigations into the regulation of CD38 expression by physiologic stimuli have been reported. As the CD38 promoter contains potential binding sites for interferon (IFN) regulatory factor-1 (IRF-1), we investigated the influence of IFN type I (alpha and beta) and type II (gamma) on CD38 gene expression of leukemic B cells. Using the IFN-responsive B cell line Eskol, we found by RT-PCR analysis a rapid time-dependent induction in CD38 mRNA (starting at 6 h) with each type of IFN. This induction was independent of protein synthesis, suggesting that CD38 gene activation does not require IRF-1 but is merely under direct transcriptional regulation by latent IFN-inducible factors. mRNA stimulation was followed within 24 h by induction of membrane CD38, which coincided with rises of CD38-specific ectoenzymatic activities, that is, NAD+ glycohydrolase, (A/G)DP-ribosyl cyclase, and cyclic ADP ribose hydrolase activities. IFN failed to induce or upregulate the other CD38-related ectoenzymes analyzed, that is, CD39, CD73, CD157, and PC-1. Similarly, treatment of leukemic cells of patients with B chronic lymphocytic leukemia (B-CLL) with IFN resulted in an increase in CD38 mRNA mirrored by plasma membrane upregulation of CD38 and NAD+ glycohydrolase activity. Further investigation in relation to CD38 gene activation and B-CLL behavior remains to be defined.


Subject(s)
Antigens, CD , Antigens, Differentiation/genetics , Antineoplastic Agents/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Interferon Type I/pharmacology , Interferon-gamma/pharmacology , Leukemia, Hairy Cell/metabolism , NAD+ Nucleosidase/genetics , ADP-ribosyl Cyclase , ADP-ribosyl Cyclase 1 , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , DNA-Binding Proteins/metabolism , Drug Screening Assays, Antitumor , HL-60 Cells , Humans , Interferon Regulatory Factor-1 , Interferon-gamma/metabolism , Leukemia, Hairy Cell/immunology , Membrane Glycoproteins , Phosphoproteins/metabolism , Promoter Regions, Genetic , Signal Transduction/physiology , Transcriptional Activation , Tumor Cells, Cultured , Up-Regulation
12.
J Womens Health Gend Based Med ; 8(5): 657-61, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10839652

ABSTRACT

Our objective was to determine the priorities of low-income women regarding health, relationship, and social concerns. Street-intercept surveys were conducted with 161 low-income urban women (mean = 27 years, 85% African American, 80% single mothers) regarding their perceptions of the threat associated with 48 health and social problems. Women rated acquired immune deficiency syndrome (AIDS) as their most important health, social, or relationship concern. Nearly one half of all women indicated that they would attend risk reduction programs to learn how to avoid infection with human immunodeficiency virus (HIV). AIDS is perceived as a serious threat to women's health, and interventions to reduce risk are welcomed.


Subject(s)
Acquired Immunodeficiency Syndrome , Attitude to Health , HIV Infections , Poverty , Acquired Immunodeficiency Syndrome/prevention & control , Acquired Immunodeficiency Syndrome/psychology , Adult , Female , HIV Infections/prevention & control , HIV Infections/psychology , Health Surveys , Humans , Urban Population , Women's Health
13.
Arch Sex Behav ; 27(2): 155-80, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9562899

ABSTRACT

The trustworthiness of self-reported sexual behavior data has been questioned since Kinsey's pioneering surveys of sexuality in the United States (Kinsey et al., 1948, 1953). In the era of HIV and AIDS, researchers and practitioners have employed a diversity of assessment techniques but they have not escaped the fundamental problem of measurement error. We review the empirical literature produced since Catania et al.'s (1990) review regarding reliability and validity of self-administered and automated questionnaires, face-to-face interviews, telephone interviews, and self-monitoring approaches. We also provide specific recommendations for improving sexual behavior assessment. It is imperative that standardized self-report instruments be developed and used for sexual risk-behavior assessment.


Subject(s)
HIV Seropositivity/psychology , Health Planning Guidelines , Sexual Behavior/psychology , Surveys and Questionnaires , Adolescent , Adult , Female , Humans , Male , Middle Aged , Reproducibility of Results , Research , Risk-Taking
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