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Marie Larsson

Publications and source records attributed to Marie Larsson.

At least 19 recordsLinked to original sources
PubMed2025

Altered DNA Methylation Pattern Contributes to Differential Epigenetic Immune Signaling in the Upper Respiratory Airway of Unvaccinated COVID-19 Patients.

SARS-CoV-2 infection remains a global health concern, with its impact on host immune responses not fully understood. In a case-control study, we examined how COVID-19 affects DNA methylation patterns in the upper respiratory airway of hospitalized individuals. DNA methylation arrays were performed on nasopharyngeal samples at inclusion/hospitalization and 6 weeks post-inclusion. We found a distinct DNA methylation pattern in COVID-19 patients compared to healthy controls, identifying 510,099 differentially methylated CpGs. Within the transcription start sites (TSSs) and gene body, COVID-19 patients displayed a higher number of genes/CpGs with elevated methylation levels. Enrichment analysis of TSS-methylated genes revealed effects of SARS-CoV-2 on genes associated with type I interferons, anti-viral and inflammatory responses, and immune functions. Some CpG methylations were transient, and normalized at group level by 6 weeks post-inclusion. Several IFN-regulated genes, including OAS1, OAS3, IFIT3, and MX1, were identified. Among the top regulators were IL17A and ERK1/2, both involved in inflammatory processes. Networks nodes included IGF1 and EGF, associated with processes including tissue repair and activation of immune responses. Overall, our data suggests that COVID-19 can impact the upper airway by modifying gene methylation patterns. This could have implications for conditioning of the airways, how individuals respond to future airway infections, and therapeutic interventions.

Humans↗
PubMed2006

Assessment of visceral pain-related pseudo-affective responses to colorectal distension in mice by intracolonic manometric recordings.

UNLABELLED: Recently, a new manometric method has been proposed to quantify visceromotor responses (VMR) to colorectal distension (CRD) in rats. This method is based on monitoring pressure changes within the distending balloon during CRD. This study assesses the applicability of such a technique to the quantification of VMRs to CRD in mice. Electrical activity of the abdominal muscles and pressure changes within the distending balloon (mechanical response) were simultaneously recorded in conscious mice during CRD (phasic ascending, 10-80 mm Hg, or repetitive, 55 mm Hg). There was a clear stimulus-response relationship with a strong correlation between electrical and mechanical responses during the ascending (r(2) = 0.899, n = 7) or repetitive phasic CRD (r(2) = 0.926, n = 8). Repetitive phasic distensions (55 mm Hg) increased the mechanical and electrical responses by 71 +/- 20% and 42 +/- 16%, respectively (pulses 10-12 vs. 1-3; n = 8, both P < .01). Atropine (0.5 or 1 mg/kg, subcutaneously) did not affect the mechanical response to CRD. The mu-opioid agonist, fentanyl (0.05 mg/kg, subcutaneously), completely prevented the sensitizing response associated to repetitive distensions. These results show that noninvasive, surgery-free manometry of intracolonic pressure is a reliable method to assess VMRs to CRD in mice. The analgesic effect of compounds could be determined, indicating that the method can be used in pharmacologic studies. PERSPECTIVE: The model presented to assess visceral pain in mice allows a broad use of this species in pharmacological studies and will be of use in the characterization of potential targets and new drugs for the treatment of human pathologies with visceral pain arising from the gut as a significant component.

Abdominal Muscles↗
PubMed2005

Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions.

HIV-1 directly activates human plasmacytoid DCs (pDCs) by upregulating the expression of costimulatory and MHC molecules and maturation markers, increasing T cell stimulatory activity, and inducing the production of type I interferons and TNF-alpha. A consequence of this activation is the bystander maturation of myeloid DCs and overall enhancement of antigen-presenting function. However, little is known about the mechanism(s) of pDC activation by HIV-1. Here we demonstrate by in vitro studies that IFN-alpha production by pDC in response to HIV-1 requires at least 2 interactions between the cell and virus. Initially, envelope-CD4 interactions mediate endocytosis of HIV-1, as demonstrated through the use of inhibitors of binding, fusion, endocytosis, and endosomal acidification. Subsequently, endosomally delivered viral nucleic acids, particularly RNA, stimulate pDCs through TLRs, as activation is reproduced with purified genomic RNA but not viral RNA packaging-deficient HIV-1 and blocked with different inhibitory TLR ligands. Finally, by using genetic complementation, we show that TLR7 is the likely primary target. Viral RNA rather than DNA in early retrotranscripts appears to be the active factor in HIV-1 that induces IFN-alpha secretion by pDCs. Since the decline in pDCs in chronic HIV-1 infection is associated with high viral loads and opportunistic infections, exploiting this natural adjuvant activity of HIV-1 RNA might be useful in the development of vaccines for the prevention of AIDS.

CD4 Antigens↗
PubMed2005

HIV-1 and the hijacking of dendritic cells: a tug of war.

Dendritic cells are critical for host immunity and are involved both in the innate and adaptive immune responses. They are among the first cells targeted by HIV-1 in vivo at mucosal sites. Dendritic cells can sequester HIV-1 in endosomal compartments for several days and transmit infectious HIV-1 to interacting T cells in the lymph node, which is the most important site for viral replication and spread. Initially, the cellular immune response developed against HIV-1 is strong, but eventually it fails to control and resolve the infection. The most dramatic effect seen on the immune system during untreated HIV-1 infection is the destruction of helper CD4(+) T cells, which leads to subsequent immune deficiency. However, the immunomodulatory effects of HIV-1 on different dendritic cell subpopulations may also play an important role in the pathogenesis of HIV-1. This review discusses the effects HIV-1 exerts on dendritic cells in vivo and in vitro, including the binding and uptake of HIV by dendritic cells, the formation of infectious synapses, infection, and the role of dendritic cells in HIV-1 pathogenesis.

Animals↗
PubMed2004

Ten years of international experience with liver transplantation for familial amyloidotic polyneuropathy: results from the Familial Amyloidotic Polyneuropathy World Transplant Registry.

BACKGROUND: Transthyretin (TTR) amyloidosis is a group of systemic amyloidoses disorders caused by an amyloidogenic TTR variant. Untreated, it slowly leads to severely disabling symptoms that relentlessly progress until the death of the patient. Because the mutant form of TTR is produced mainly in the liver, successful orthotopic liver transplantation (OLT) results in the elimination of the source of the variant TTR molecule and is presently the only known curative treatment. OLT in patients with familial amyloidotic polyneuropathy (FAP) was first performed in 1990 at the Karolinska Institute in Sweden, and because the results were promising other centers took up the procedure. METHODS: To gain as great an experience as possible regarding this treatment, the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR) was initiated in 1995, and this article presents the 10-year registry results. RESULTS: A total of 54 centers in 16 countries have performed OLT for FAP, and today approximately 60 OLTs are performed annually worldwide. During the last decade, a total of 539 patients have undergone 579 OLTs. Patient survival is excellent (overall 5-year patient survival 77%) and comparable to the survival with OLT performed for other chronic liver disorders, but longer follow-up is needed to compare the outcome after OLT with the natural course of the disease. The main cause of death was cardiac related (39%). CONCLUSIONS: We believe that the FAPWTR has become a valuable tool that will help to accurately evaluate the potential risks and benefits of OLT in patients with FAP and promote a fruitful collaboration between centers engaged in this field.

Adult↗
PubMed2004

DC-virus interplay: a double edged sword.

Myeloid and plasmacytoid dendritic cells, a family of professional antigen presenting cells, are crucial in generating and maintaining anti-viral immunity. Many viruses have evolved to avoid, subvert, and even counterattack them. In this article, we focus on the tuning of innate and adaptive responses induced by human dendritic cells, and on the inhibition of their functions by viruses of medical significance. A constant "tug of war" goes on between dendritic cells and viruses and a main dendritic cell countermeasure is cross-presentation/priming.

Dendritic Cells↗
PubMed2004

Human immunodeficiency virus type 1 activates plasmacytoid dendritic cells and concomitantly induces the bystander maturation of myeloid dendritic cells.

In this study, we analyzed the phenotypic and physiological consequences of the interaction of plasmacytoid dendritic cells (pDCs) with human immunodeficiency virus type 1 (HIV-1). pDCs are one cellular target of HIV-1 and respond to the virus by producing alpha/beta interferon (IFN-alpha/beta) and chemokines. The outcome of this interaction, notably on the function of bystander myeloid DC (CD11c+ DCs), remains unclear. We therefore evaluated the effects of HIV-1 exposure on these two DC subsets under various conditions. Blood-purified pDCs and CD11c+ DCs were exposed in vitro to HIV-1, after which maturation markers, cytokine production, migratory capacity, and CD4 T-cell stimulatory capacity were analyzed. pDCs exposed to different strains of infectious or even chemically inactivated, nonreplicating HIV-1 strongly upregulated the expression of maturation markers, such as CD83 and functional CCR7, analogous to exposure to R-848, a synthetic agonist of toll-like receptor-7 and -8. In addition, HIV-1-activated pDCs produced cytokines (IFN-alpha and tumor necrosis factor alpha), migrated in response to CCL19 and, in coculture, matured CD11c+ DCs, which are not directly activated by HIV. pDCs also acquired the ability to stimulate naïve CD4+ T cells, albeit less efficiently than CD11c+ DCs. This HIV-1-induced maturation of both DC subsets may explain their disappearance from the blood of patients with high viral loads and may have important consequences on HIV-1 cellular transmission and HIV-1-specific T-cell responses.

CD11c Antigen↗
PubMed2004

Lack of phenotypic and functional impairment in dendritic cells from chimpanzees chronically infected with hepatitis C virus.

Dendritic cells (DCs), which are potent antigen-presenting cells (APCs), are used as adjuvants for the treatment of cancer and infectious diseases in human and nonhuman primates, with documented clinical efficacy. The hepatitis C virus (HCV)-chimpanzee model is the best available model for testing the immunotherapeutic effects of DCs in the setting of a chronic infection, as chimpanzees develop a persistent infection resembling that seen in humans. However, several reports have suggested that DCs derived from chronically infected individuals or nonhuman primates are functionally compromised. As a prelude to clinical studies, we evaluated whether functionally mature DCs could be generated in chimpanzee plasma by good manufacturing practice using CD14(+) mononuclear precursors from chronically infected chimpanzees. DCs generated in a medium with HCV-negative plasma and treated with a defined cocktail of cytokines or a CD40 ligand trimer matured fully, as measured by the induction of CD83 expression and the upregulation of costimulatory molecules. Furthermore, the expression of CCR7 was induced, suggesting an acquisition of migration capacity. Mature DCs were capable of stimulating allogeneic T cells, antigen-specific memory CD4(+) T cells, and HCV-specific CD8(+)-T-cell clones. In all cases, there was no evidence of HCV infection in DCs. Furthermore, these DCs maintained their phenotype and APC function after cryopreservation. Finally, no discernible differences were noted between DCs derived from HCV-infected and uninfected chimpanzees. In summary, precursor cells from HCV-infected chimpanzees are fully capable of differentiating into functional, mature DCs, which can now be reproducibly prepared for investigations of their immunotherapeutic potential in the setting of chronic HCV infection.

Animals↗
PubMed2003

Characterization of the MHC class I cross-presentation pathway for cell-associated antigens by human dendritic cells.

Major histocompatibility complex (MHC) class I presentation of exogenous antigens is the mechanism enabling professional antigen-presenting cells (APCs) to induce CD8+ T-cell responses against viruses and tumors that do not have access to the classical MHC class I pathway. We have characterized the uptake, processing, and MHC class I cross-presentation by human dendritic cells (DCs) of cell-associated antigens derived from physiologically relevant sources, namely, vaccinia virus-infected apoptotic and necrotic cells. We show that cross-presentation is a rapid process, detectable within 2 to 4 hours after uptake of dead cells, and that proteolysis by cathepsin D in an acidic endosomal compartment is essential for cross-presentation. The presentation is abolished when the phagocytic or macropinocytic functions of the cells are inhibited and is dependent on transporter associated with antigen processing, sensitive to brefeldin A, and requires functional proteasomes. Altogether, these data suggest that antigens derived from apoptotic and necrotic cells require access to the cytosol to intersect with the conventional MHC class I pathway for presentation of cytosolic proteins.

ATP-Binding Cassette Transporters↗
PubMed2003

Activation of influenza virus-specific CD4+ and CD8+ T cells: a new role for plasmacytoid dendritic cells in adaptive immunity.

Plasmacytoid dendritic cells (pDCs) contribute to innate antiviral immune responses by producing type I interferons (IFNs) upon exposure to enveloped viruses. However, their role in adaptive immune responses, such as the initiation of antiviral T-cell responses, is not known. In this study, we examined interactions between blood pDCs and influenza virus with special attention to the capacity of pDCs to activate influenza-specific T cells. pDCs were compared with CD11c(+) DCs, the most potent antigen-presenting cells (APCs), for their capacity to activate T-cell responses. We found that like CD11c(+) DCs, pDCs mature following exposure to influenza virus, express CCR7, and produce proinflammatory chemokines, but differ in that they produce type I IFN and are resistant to the cytopathic effect of the infection. After influenza virus exposure, both DC types exhibited an equivalent efficiency to expand anti-influenza virus cytotoxic T lymphocytes (CTLs) and T helper 1 (TH1) CD4(+) T cells. Our results pinpoint a new role of pDCs in the induction of antiviral T-cell responses and suggest that these DCs play a prominent role in the adaptive immune response against viruses.

Antigen Presentation↗
PubMed2003

Report from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR) and the Domino Liver Transplant Registry (DLTR).

Familial amyloidotic polyneuropathy (FAP) is a fatal disease, belonging to a group of systemic disorders caused by an amyloidogenic transthyretin (TTR) variant. Orthotopic liver transplantation (OLT) eliminates the source of the variant TTR molecule, and is presently the only known curative treatment. A fascinating consequence of this treatment is the possibility of retransplanting the removed FAP liver into another non-FAP patient, which created the so-called domino liver transplantation (DLT) procedure. The Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR) was initiated in 1995, and in 1999 a Domino Liver Transplantation Registry (DLTR) was created. Herein data from these Registries are presented. A total number of 56 centers in 16 countries have performed OLT for FAP, and, today, approximately 65-70 OLTs are performed annually worldwide. During the last decade, a total of 623 patients have undergone 660 OLTs. Patient survival is excellent and comparable to the survival with OLT performed for other chronic liver disorders. Twenty-six centers in 12 countries have reported recipients of DLT grafts and presently 30-35 DLTs are performed annually. The FAPWTR and DLTR have become useful tools in evaluating the potential risks and benefits of these relatively new therapeutic options, in addition to encouraging a rewarding collaboration between centers involved in the management of these patients.

Amyloid Neuropathies, Familial↗
PubMed2002

A clinical grade cocktail of cytokines and PGE2 results in uniform maturation of human monocyte-derived dendritic cells: implications for immunotherapy.

Dendritic cells (DCs) can induce tumor- or pathogen-specific T cell responses in humans. We comprehensively compared the clinically available DC maturation stimuli for their ability to promote uniformly mature DCs that elicit higher levels of T cell responses. We compared the standard maturation stimulus, autologous monocyte-conditioned medium (MCM), with a synthetic double stranded RNA (poly I:C), soluble CD40 ligand trimer, and a defined cocktail of cytokines (TNF-alpha, IL-1 beta, IL-6) and PGE(2) to promote mature phenotype and function in human monocyte-derived DCs. The cocktail was the most efficient despite the lack of induction of IL-12p70. While these results support the use of the MCM-mimic cocktail in clinical DC immunotherapy trials, the roles of it's individual constituents remain to be completely defined.

Cell Division↗
PubMed2002

Dendritic cell amplification of HIV type 1-specific CD8+ T cell responses in exposed, seronegative heterosexual women.

In the Heterosexual AIDS Transmission Study (HATS), the frequency of high-risk sexual activity and viral load in the seropositive partner were shown to correlate with HIV-1 transmission. However, these parameters could not account for the status of some exposed, seronegative (ESN) individuals who remained uninfected despite years of exposure. To test the hypothesis that antiviral immune responses are a correlate of nontransmission in this cohort, we developed two sensitive methods for assessing HIV-1-specific humoral and cell-mediated responses. To quantify T cell responses, autologous mature dendritic cells (DCs) were used as antigen-presenting cells to elicit HIV-1-specific IFN-gamma production by ELISPOT. Antibody responses to HIV-1 gp120 were assessed by combination immunoprecipitation-Western blot (IP-WB). Previous studies of this cohort, using limiting dilution analysis, did not reveal HIV-1-specific cytotoxic T lymphocyte activity. However, when autologous DCs were used to present HIV-1 antigens, T cells from three of eight ESN women (38%) responded by producing IFN-gamma. T cells from three of four seropositive partners responded to HIV-1 antigens, whereas five negative controls did not. The use of DCs as antigen-presenting cells increased sensitivity by 2- to 30-fold relative to standard ELISPOT. Using IP-WB, low levels of gp120-reactive antibodies were detected in plasma from 1 of 14 ESN women. These results support the hypothesis that HIV-1-specific T cell responses play a role in immune surveillance in this cohort of North American serodiscordant couples. This report also demonstrates the ability of dendritic cells to reveal T cell responses that might be overlooked by other methods.

Blotting, Western↗
PubMed2002

Activation of HIV-1 specific CD4 and CD8 T cells by human dendritic cells: roles for cross-presentation and non-infectious HIV-1 virus.

BACKGROUND: The CD4 T cells in mucosal subepithelia are the first cells to become infected during sexual transmission of HIV-1. Dendritic cells (DC) are located in the same area and are known to play a central role in antiviral immune responses. However, extensive viral replication, syncytia formation and cell death follows the interaction between T cells and DC previously exposed to HIV-1. Despite this, anti-HIV responses are generated that control viremia following acute infection. OBJECTIVE: The anti-HIV-1 cellular immune responses observed may be activated by sources other than productively infected DC. HIV-1 induces apoptosis both in cells it infects and in bystander cells. Furthermore, retroviral replication typically generates a predominance of defective particles. We tested whether DC exposed to antigen from either of these sources could elicit anti-HIV specific immune responses. DESIGN AND METHODS: Apoptotic or necrotic monocytes infected with vaccinia virus vectors encoding HIV antigens, a cell line with integrated HIV-1 and apoptotic CD4 T cells pulsed with non-infectious or infectious HIV-1 virus were used as sources of antigens to assess cross presentation by DC. Furthermore, direct DC presentation of antigen from non-infectious and infectious HIV-1 was examined. RESULTS: We find that dead cells expressing HIV-1 antigens as well as non-infectious HIV-1 particles can be acquired and processed by DC, leading to the activation, differentiation and expansion of viral antigen-specific CD4 and CD8 T cells from seropositive individuals. CONCLUSIONS: These sources of antigens may be critical for the generation and maintenance of anti-HIV-1 immunity by DC.

Antigen Presentation↗
PubMed2002

Amplification of low-frequency antiviral CD8 T cell responses using autologous dendritic cells.

OBJECTIVE: To utilize the potent antigen-presenting capacity of mature dendritic cells (MDC) in order to develop a rapid, sensitive method for quantifying antigen-specific CD8 T cells present at low frequency in peripheral blood. DESIGN: Peripheral blood mononuclear cells (PBMC) were obtained from seven HIV-1-positive individuals with low to moderate CD8 T cell responses, including five on highly active antiretroviral therapy (HAART). IFN-gamma ELISPOT assays were performed using either monocytes or MDC to present antigens expressed by recombinant vaccinia viruses (r-VV). METHODS: Peripheral blood-derived monocytes were cultured for 5-6 days in the presence of IL-4 and granulocyte macrophage colony-stimulating factor, then matured in monocyte-conditioned medium. MDC were infected with r-VV and co-cultured in an ELISPOT assay with autologous monocyte-depleted PBMC. RESULTS: Relative to autologous monocytes, MDC amplified detection of antigen-specific CD8 T cells by 2-30-fold in response to antigens from HIV-1, Epstein-Barr virus and cytomegalovirus. Furthermore, antigenic specificities were revealed that had not been detected using standard ELISPOT of PBMC. CONCLUSION: This assay will prove useful for the detection of memory T cells present at low frequency, and may be of interest for identifying subdominant cytotoxic T lymphocyte epitopes. This method may have broad applications for the detection of antiviral CD8 T cell responses in patient populations in whom such responses have been difficult to detect, including HIV-1-seropositive individuals with advanced disease or undergoing HAART.

Adult↗
PubMed2002

Interactions between dead cells and dendritic cells in the induction of antiviral CTL responses.

Dendritic cells - professional antigen-presenting cells - are key players for activating adaptive immune responses against viruses. Apoptosis or lytic cell death often accompanies viral infection. Dendritic cells can acquire infected dead or dying cells as exogenous sources of antigens for presentation on MHC class I and II molecules to initiate T cell responses. This pathway of activating T cells may be critical for the development of effective antiviral immunity in vivo.

Antigen Presentation↗
PubMed2002

Residual viral replication during antiretroviral therapy boosts human immunodeficiency virus type 1-specific CD8+ T-cell responses in subjects treated early after infection.

Human immunodeficiency virus type 1 (HIV-1)-infected subjects treated early after infection have preserved HIV-1-specific CD4+ T-cell function. We studied the effect of highly active antiretroviral therapy (HAART) on the frequency of HIV-1-specific CD8+ T cells in patients treated during early (n = 31) or chronic (n = 23) infection. The degree of viral suppression and time of initiation of treatment influenced the magnitude of the CD8+ T-cell response. HIV-1-specific CD8+ T cells can increase in number after HAART in subjects treated early after infection who have episodes of transient viremia.

Acute Disease↗