Biomedical subjects

Jan Andersson

Publications and source records attributed to Jan Andersson.

At least 19 recordsLinked to original sources

PubMed2006

Upregulation of interferon-alpha and RANTES in the cervix of HIV-1-seronegative women with high-risk behavior.

OBJECTIVE: The expression of innate immune molecules associated with potential blocking activity of HIV-1 propagation was analyzed in the cervical tissue of a group of African HIV-1 IgG-negative commercial sex workers (CSWs) with an HIV-1-encountering risk behavior. METHODS: Cervical biopsies from the superior portion of the ectocervix were assessed for innate immune molecules and evaluated in situ by computerized image analysis at the single-cell level. RESULTS: A higher expression of interferon-alpha (IFNalpha) and RANTES was detected in CSWs and HIV-1-infected individuals as compared to low-risk HIV-1-uninfected controls (Neg Ctrls). Most (>90%) of RANTES-expressing cells were CD8 cells as determined by confocal microscopy. In contrast, the expression of leukemia inhibitory factor (LIF) and secretory leukocyte protease inhibitor (SLPI) was comparable between the groups. The expression of beta-defensin 2 was highest in HIV-1-infected individuals. CONCLUSIONS: Induction of IFNalpha and RANTES expression in cervical mucosa may contribute to protection of sexual HIV-1 transmission in subjects with a higher risk behavior.

Adolescent↗

PubMed2006

HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS.

Regulatory T (Treg) cells accumulate in the lymphoid tissues of human immunodeficiency virus (HIV)-infected individuals, contributing to the inability of the immune system to control virus replication. We investigate here Treg-cell numbers and functional markers (FOXP3, CTLA-4, IDO, and TGF-beta1) in lymphoid tissues from untreated infected hosts with progressive or nonprogressive disease (HIV-infected humans and simian immunodeficiency virus [SIV]-infected macaques). We found that increased numbers of FOXP3(+) T cells as well as increased expression of Treg-cell-associated functional markers were detected only during progressive disease. Such increases were not correlated with immune activation. Of importance, a high-perforin/FOXP3 ratio was associated with nonprogressive disease, suggesting that the immune control of virus replication represents a balance between cell-mediated immune responses and Treg-cell-mediated counter regulation of such responses. Furthermore, using an in vitro model of Treg-cell-HIV interactions, we showed that exposure of Treg cells to HIV selectively promoted their survival via a CD4-gp120-dependent pathway, thus providing an underlying mechanism for the accumulation of Treg cells in infected hosts with active viral replication. Considered together, our findings imply that therapeutic manipulation of Treg-cell number and/or function could improve immune control of HIV infection.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Enhanced susceptibility of multidrug resistant strains of Mycobacterium tuberculosis to granulysin peptides correlates with a reduced fitness phenotype.

Previously it was shown that the antimicrobial protein granulysin possesses potent membranolytic activity against Mycobacterium tuberculosis. Here we demonstrate that granF2 and G13, which are two short synthetic peptides derived from granulysin, inhibited the in vitro growth of clinical isolates of both multidrug resistant and drug susceptible strains of M. tuberculosis. Importantly, a particularly high activity against multidrug resistant M. tuberculosis correlated with a reduced growth rate compared to drug susceptible strains. A synergistic antibacterial effect of granF2 was further observed in combination with ethambutol, a compound with a documented effect on cell wall permeability. This finding suggests that granF2 and ethambutol exert their functions at different levels of the mycobacterial surface. Upon infection of macrophages in vitro, granF2 but not G13 efficiently reduced the intracellular growth of multidrug resistant M. tuberculosis in the presence of the pore-forming protein streptolysin O. The apoptotic function of granF2 apparently promoted destruction of host cells whereby the peptide gained access to and killed intracellular bacteria. Thus, a cost of resistance and a subsequent reduced fitness, measured as decreased growth among multidrug resistant strains of M. tuberculosis, could be associated with increased susceptibility to natural immune defense mechanisms, such as antimicrobial peptides of granulysin. However, a robust cell wall and the membrane of cells still provide physical shelter for the bacteria that may spare sensitive M. tuberculosis stains from being killed.

Antigens, Differentiation, T-Lymphocyte↗

PubMed2006

Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic.

Shigella is a major cause of morbidity, mortality, and growth retardation for children in developing countries. Emergence of antibiotic resistance among Shigellae demands the development of effective medicines. Previous studies found that the endogenous antimicrobial peptide LL-37 is down-regulated in the rectal epithelium of patients during shigellosis and that butyrate up-regulates the expression of LL-37 in colonic epithelial cells in vitro and decreases severity of inflammation in experimental shigellosis. In this study, Shigella-infected dysenteric rabbits were treated with butyrate (0.14 mmol/kg of body weight) twice daily for 3 days, and the expression levels of the rabbit homologue to LL-37, CAP-18, were monitored in the colon. Butyrate treatment resulted in (i) reduced clinical illness, severity of inflammation in the colon, and bacterial load in the stool, (ii) significant up-regulation of CAP-18 in the surface epithelium, and (iii) disappearance of CAP-18-positive cells in lamina propria. The active CAP-18 peptide was released in stool from its proform by butyrate treatment. In healthy controls, CAP-18 expression was localized predominantly to the epithelial surface of the colon. In infected rabbits, CAP-18 expression was localized to immune and inflammatory cells in the colon, whereas the ulcerated epithelium was devoid of CAP-18 expression. The combination of CAP-18 and butyrate was more efficient in killing Shigella in vitro than CAP-18 alone. Our findings indicate that oral butyrate treatment in shigellosis may be of clinical value because of induction of the endogenous cathelicidin CAP-18 in the colonic epithelium, stimulation of the release of the active peptide CAP-18, and promoting elimination of Shigella.

Administration, Oral↗

PubMed2006

HMGB1 activates replication of latent HIV-1 in a monocytic cell-line, but inhibits HIV-1 replication in primary macrophages.

High mobility group box protein 1 (HMGB1) is an abundant component of mammalian cells that can be released into extracellular milieu actively or by cells that undergo necrosis. Exposure of inflammatory and endothelial cells to HMGB1 leads to the release of cytokines, including TNF-alpha and IL-6. To evaluate the impact of exogenous HMGB1 on viral replication in HIV-1 infected cells, we studied models of latent and acute infection. Extracellular HMGB1 dose dependently increased HIV-1 replication in the monocytic cells, U1, which is an established model for studying latent HIV-1 infection. Dexamethasone, a known inhibitor of NF-kappaB signaling in U1 cells, inhibited HMGB1-induced stimulation of the viral production. Addition of HMGB1 to primary monocytic cells with active HIV-1 infection elicited the opposite effect, due to suppression of the viral replication. The mechanism of this unexpected finding was explained by an HMGB1-mediated increased release of chemokines (RANTES, MIP-1alpha, and MIP-1beta) that are known to inhibit HIV-1 replication. The stimulatory effect of the HMGB1 was not present when latently infected T-cells (ACH-2) were used as target cells. Our data suggest that extracellular HMGB1 has a dichotomic effect on the HIV-1 infection in monocytes but not in lymphocytes. Both activation of latent HIV-1 infection and inhibition of active replication can thus be seen in vitro.

Cell Survival↗

PubMed2006

Differential expression of IFN-alpha and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1-infected patients.

Loss of CD4+ T cells, the hallmark of HIV pathogenesis, was suggested to be partly due to apoptosis. We recently reported that IFN-alpha produced by HIV-1-activated plasmacytoid dendritic cells (pDCs) contributes to CD4+ T cell apoptosis by the TNF-related apoptosis-inducing ligand (TRAIL)/death receptor (DR)5 pathway. Here, we show that HIV-1-induced intracellular expression of IFN-alpha in pDCs is coupled to increased expression of IFN regulatory factor 7 and MyD88 by pDCs in vivo and in vitro. Expression of IFN-alpha was increased in lymphoid tonsillar tissue (LT) of patients with progressive (HIV(prog)) compared with nonprogressive (HIV(NP)) HIV-1 disease and to uninfected controls. LT from HIV(prog) exhibited higher TRAIL and DR5 mRNA levels than LT from HIV(NP) or controls. TRAIL mRNA levels in LT correlated with plasma viral load. We show that HIV-1 induces IFN-alpha and the TRAIL/DR5 apoptotic pathway in LT, suggesting a role for these cytokines in HIV-1 immunopathogenesis.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Early induction of leukemia inhibitor factor (LIF) in acute HIV-1 infection.

BACKGROUND: Leukemia inhibitor factor (LIF) is thought to play a substantial role in protecting CD4 T cells in lymphoid tissues (LT) from infection by HIV-1. OBJECTIVE: To investigate whether primary HIV-1 infected subjects with sustained virological control (< 1000 HIV-1 RNA copies/ml plasma) post-cessation antiretroviral therapy (ART) had a higher initial LIF response during primary HIV-1 infection (PHI) as compared with those individuals who did not achieve a similar control (> 9000 HIV-1 RNA copies/ml plasma) of HIV-1 replication. MATERIAL AND METHODS: Consecutively obtained HIV plasma samples were collected from primary HIV-1 infected subjects. A group of acutely Epstein-Barr virus-infected subjects and a group of HIV-1-seronegative healthy individuals served as controls. All samples were tested by ELISA for LIF and sgp130, the soluble form of LIF's signalling receptor. RESULTS: LIF and sgp130 plasma levels were significantly increased in primary HIV-1-infected subjects as compared with HIV-1-seronegative controls. Peak plasma levels of LIF occurred during the first week of PHI whereas sgp130 peaked between 2 and 4 weeks after the onset of PHI. Furthermore a positive correlation was found between viral load and plasma levels of LIF during PHI. Both LIF and sgp130 plasma concentrations were significantly lower during the viral rebound phase after treatment interruption as compared with the PHI phase. CONCLUSIONS: LIF induction occurred in the initial stages of viral dissemination during PHI. It may be a part of the virally induced generalized pro-inflammatory response. LIF levels at PHI did not predict low levels of HIV viraemia after discontinuation of ART. LIF was not increased following ART interruption in this early treated population.

Acute Disease↗

PubMed2006

Studies of HIV-associated immune responses in lymphoid compartments.

Acute HIV-1 infection results in profound depletion of CD4+ memory T cells in lymphoid tissue (LT) and subsequent persistent replication in activated CD4+ T cells despite induction of an HIV-specific cell-mediated immune response. Interferon-alpha, proinflammatory cytokines, and beta-chemokine production is present in LT. However, impaired expression of co-stimulatory molecules including CD80, CD86, and CD40L may contribute to low polyfunctional CD4+ T cell as well CD8+ T-cell activity. Accumulation of regulatory CD4+ T cells in LT may add to the lack of HIV-specific CD4+ T-cell proliferation and dysfunctional cytotoxic CD8+ T-cell response in LT.

CD4 Antigens↗

PubMed2006

Effects of the timing and identity of retrieval cues in individual recall: an attempt to mimic cross-cueing in collaborative recall.

Inhibitory effects in collaborative recall have been attributed to cross-cueing among partners, in the same way that part-set cues are known to impair recall in individuals. However, studies of part-set cueing in individuals typically involve presenting cues visually at the start of recall, whereas cross-cueing in collaboration is likely to be spoken and distributed over time. In an attempt to bridge this gap, three experiments investigated effects of presenting spoken part-set or extra-list cues at different times during individual recall. Cues had an inhibitory effect on recollection in the early part of the recall period, especially when presented in immediate succession at the start of recall. There was no difference between the effects of part-set and extra-list cues under these presentation conditions. However, more inhibition was generated by part-set than extra-list cues when cue presentation was distributed throughout recall. These results are interpreted as suggesting that cues presented during recall disrupt memory in two ways, corresponding to either blocking or modifying retrieval processes. Implications for explaining and possibly ameliorating inhibitory effects in collaborative recall are discussed.

Adult↗

PubMed2006

What people believe about memory.

Two representative samples of adult Norwegians (n=2000) were asked a set of general and specific questions regarding their beliefs and opinions about human memory. The results indicate that on many questions, such as time of the earliest memories, inhibiting effects of collaboration, and memory for dramatic versus ordinary events, the views of the general public concurred with current research findings, and people in general had realistic views about their own memory performance. On other questions, such as the reliability of olfactory as compared with visual and auditory memory, the memory of small children in comparison with that of adults, the likelihood of repression of adult traumatic memories, and on more general questions such as the possibility of training memory and the capacity limitations of long-term memory, a large proportion of the participants expressed views that are less supported by scientific evidence. Implications of these findings are briefly discussed.

Adult↗

PubMed2006

The face you recognize may not be the one you saw: memory conjunction errors in individuals with or without learning disability.

Memory conjunction errors, that is, when a combination of two previously presented stimuli is erroneously recognized as previously having been seen, were investigated in a face recognition task with drawings and photographs in 23 individuals with learning disability, and 18 chronologically age-matched controls without learning disability. Compared to the controls, individuals with learning disability committed significantly more conjunction errors, feature errors (one old and one new component), but had lower correct recognition, when the results were adjusted for different guessing levels. A dual-processing approach gained more support than a binding approach. However, neither of the approaches could explain all of the results. The results of the learning disability group were only partly related to non-verbal intelligence.

Adult↗

PubMed2006

Epstein-Barr virus and Hodgkin's lymphoma.

Hodgkin's lymphoma (HL) is a lymphoproliferative disorder of B-lymphocytes. Epstein-Barr virus (EBV) antigens can be detected in tumours in up to 40% of all HL cases. Patients with EBV-associated HL also show increased levels of EBV-infected B-lymphocytes in blood compared with normal individuals and non-EBV-associated HL cases. A peculiar pattern of restricted EBV-antigen expression, dominated by latent membrane protein-1 (LMP-1), LMP-2 and EBV nuclear antigen-1, is the characteristic feature of tumour-specific Hodgkin/Reed-Sternberg cells. This knowledge has generated studies examining adoptive immunotherapy of autologous or allogeneic cytotoxic T-cells for the treatment of refractory EBV-positive HL cases. Whether aborted EBV or another infectious aetiology is involved in non-EBV-associated HL cases remains an open question.

Epstein-Barr Virus Infections↗

PubMed2005

Developmental disorders in larvae of eelpout (Zoarces viviparus) from German and Swedish Baltic coastal waters.

Pregnant eelpout were collected for several years at German and Swedish Baltic coastal stations with different impact of pollutants and the prevalence of fry abnormalities compared between sites. Mortality of apparently normal developed larvae was observed with high variability in both German and Swedish sites. Malformation of larvae was a prominent disorder at all German stations with a prevalence ranging from about 50% up to a maximum of 90% in almost all analysed samples. At the Swedish stations malformation rates were significantly lower (range: 0-6%). Growth retardation of fry was clearly more prominent in eelpout from German coastal waters as well. Taken together the field data suggests that impaired larval development was associated with the state of environmental pollution at the sampling locations.

Animals↗

PubMed2005

Homeostatic and functional analysis of mature B cells in lambda5-deficient mice.

The peripheral B-cell pool is in dynamic equilibrium and is controlled by a variety of factors. The rate of generation of B cells can influence both the composition and size of the peripheral B-cell compartment. Mice deficient for lambda5 gene expression have a block in early B-cell development leading to a markedly reduced number of peripheral B cells. To address the question of how this early developmental block influences the composition of the B-cell pool, we have analyzed mature B-cell subpopulations in lambda5-deficient mice. In analogy with other situations of B lymphopenia, the proportion was increased but not the absolute number of marginal-zone B cells, whereas those of follicular B cells were decreased. Immunohistology revealed that B-cell follicles were smaller in overall size and contained a prominent B-cell replete marginal zone. BrdU labelling kinetics showed slower turnover of follicular as well as of marginal-zone B cells. Functionally, lambda5(-/-) mice were able to mount not only primary but also secondary thymus-dependent as well as thymus-independent responses, albeit mostly at reduced levels.

Animals↗

PubMed2005

Impact of therapeutic immunization on HIV-1 viremia after discontinuation of antiretroviral therapy initiated during acute infection.

BACKGROUND: Treatment strategies that would induce durable virological control of human immunodeficiency virus (HIV)-1 in the absence of continued antiretroviral therapy (ART) are highly desirable.METHODS. We assessed, in a randomized, double-blind, placebo-controlled trial, whether the addition of therapeutic vaccines (ALVAC-HIV [vCP1452] or ALVAC-HIV and Remune) to ART initiated during acute infection could increase the probability of having a plasma viral load </=1000 HIV-1 RNA copies/mL 24 weeks after planned discontinuation of ART.RESULTS. All 79 randomized subjects completed the immunization schedule, and 78 discontinued ART with no major safety concerns. After immunization, subjects in the vaccine study arms had significantly increased HIV-1-specific CD4(+) and CD8(+) T cell responses, by interferon- gamma enzyme-linked immunospot assay, compared with those in the placebo study arm. Overall, 17.7% of subjects had </=1000 HIV-1 RNA copies/mL 24 weeks after discontinuation of ART, with no significant difference between the vaccine study arms and the placebo study arm (15.4% vs. 22.2%; difference, -6.8% [95% confidence interval, -26.8% to 10.0%]; P=.54).CONCLUSION. Therapeutic immunization and ART, compared with ART alone, generated HIV-1-specific cellular immunity but did not lead to better virological control of HIV-1 24 weeks after discontinuation of ART. Our trial design appears to be feasible and safe for testing future immune-boosting strategies.

AIDS Vaccines↗

PubMed2005

The prevalence of regulatory T cells in lymphoid tissue is correlated with viral load in HIV-infected patients.

Inadequate local cell-mediated immunity appears crucial for the establishment of chronic HIV infection. Accumulation of regulatory T cells (Treg) at the site of HIV replication, the lymphoid organs, may influence the outcome of HIV infection. Our data provide the first evidence that chronic HIV infection changes Treg tissue distribution. Several molecules characteristics of Treg (FoxP3, CTLA-4, glucocorticoid-induced TNFR family-related receptor, and CD25) were expressed more in tonsils of untreated patients compared with antiretroviral-treated patients. Importantly, most FoxP3+ cells expressed CTLA-4, but not CD69. Furthermore, a direct correlation between FoxP3 levels and viral load was evident. In contrast, FoxP3 expression was decreased in circulating T cells from untreated patients, but normalized after initiation of treatment. Functional markers of Treg activity (indoleamine 2,3-dioxygenase, TGF-beta, and CD80) were markedly increased in the tonsils of untreated patients. Our data could provide a new basis for immune-based therapies that counteract in vivo Treg and thereby reinforce appropriate antiviral immunity.

Adult↗

PubMed2005

Origin of the prolactin-releasing hormone (PRLH) receptors: evidence of coevolution between PRLH and a redundant neuropeptide Y receptor during vertebrate evolution.

We present seven new vertebrate homologs of the prolactin-releasing hormone receptor (PRLHR) and show that these are found as two separate subtypes, PRLHR1 and PRLHR2. Analysis of a number of vertebrate sequences using phylogeny, pharmacology, and paralogon analysis indicates that the PRLHRs are likely to share a common ancestry with the neuropeptide Y (NPY) receptors. Moreover, a micromolar level of NPY was able to bind and inhibit completely the PRLH-evoked response in PRLHR1-expressing cells. We suggest that an ancestral PRLH peptide started coevolving with a redundant NPY binding receptor, which then became PRLHR, approximately 500 million years ago. The PRLHR1 subtype was shown to have a relatively high evolutionary rate compared to receptors with fixed peptide preference, which could indicate a drastic change in binding preference, thus supporting this hypothesis. This report suggests how gene duplication events can lead to novel peptide ligand/receptor interactions and hence spur the evolution of new physiological functions.

Animals↗

PubMed2005

Determination of in vivo protein synthesis in human palatine tonsil.

The palatine tonsils are constantly exposed to ingested or inhaled antigens which, in turn, lead to a permanent activation of tonsillar immune cells, even in a basic physiological state. The aim of the present study was to investigate if the immunological activation of the human palatine tonsil is reflected by a high metabolic activity, as determined by in vivo measurement of protein synthesis. The protein synthesis rate of the tonsil was also compared with that of the circulating T-lymphocytes, the total blood mononuclear cells and the whole population of blood leucocytes. Phenotypic characterization of immune-competent cells in tonsil tissue and blood was performed by flow cytometry. Pinch tonsil biopsies were taken after induction of anaesthesia in healthy adult patients (n=12) scheduled for ear surgery, uvulopalatopharyngoplasty or nose surgery. Protein synthesis was quantitatively determined during a 90-min period by a flooding-dose technique. The in vivo protein synthesis rate in the palatine tonsils was 22.8+/-5.7%/24 h (mean+/-S.D.), whereas protein synthesis in the circulating T-lymphocytes was 10.7+/-3.4%/24 h, in mononuclear cells was 10.8+/-2.8%/24 h and in leucocytes was 3.2+/-1.2%/24 h. CD3+ lymphocytes were the most abundant cell population in the tonsil. The in vivo protein synthesis rate in human tonsils was higher compared with the circulating immune cells. This high metabolic rate may reflect the permanent immunological activity present in human tonsils, although cell phenotypes and activity markers do not explain the differences.

Adult↗