| 1. |
- Bergenfelz, Caroline, et al.
(författare)
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Systemic Monocytic-MDSCs Are Generated from Monocytes and Correlate with Disease Progression in Breast Cancer Patients.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Myeloid-derived suppressor cells (MDSCs) are highly immunosuppressive myeloid cells, which increase in cancer patients. The molecular mechanism behind their generation and function is unclear. Whereas granulocytic-MDSCs correlate with poor overall survival in breast cancer, the presence and relevance of monocytic-MDSCs (Mo-MDSCs) is unknown. Here we report for the first time an enrichment of functional blood Mo-MDSCs in breast cancer patients before they acquire a typical Mo-MDSC surface phenotype. A clear population of Mo-MDSCs with the typical cell surface phenotype (CD14+HLA-DRlow/-CD86low/-CD80low/-CD163low/-) increased significantly first during disease progression and correlated to metastasis to lymph nodes and visceral organs. Furthermore, monocytes, comprising the Mo-MDSC population, from patients with metastatic breast cancer resemble the reprogrammed immunosuppressive monocytes in patients with severe infections, both by their surface and functional phenotype but also at their molecular gene expression profile. Our data suggest that monitoring the Mo-MDSC levels in breast cancer patients may represent a novel and simple biomarker for assessing disease progression.
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| 2. |
- Bergenfelz, Caroline, et al.
(författare)
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Wnt5a induces a tolerogenic phenotype of macrophages in sepsis and breast cancer patients.
- 2012
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Ingår i: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 188:11, s. 5448-5458
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Tidskriftsartikel (refereegranskat)abstract
- A well-orchestrated inflammatory reaction involves the induction of effector functions and, at a later stage, an active downregulation of this potentially harmful process. In this study we show that under proinflammatory conditions the noncanonical Wnt protein, Wnt5a, induces immunosuppressive macrophages. The suppressive phenotype induced by Wnt5a is associated with induction of IL-10 and inhibition of the classical TLR4-NF-κB signaling. Interestingly, this phenotype closely resembles that observed in reprogrammed monocytes in sepsis patients. The Wnt5a-induced feedback inhibition is active both during in vitro LPS stimulation of macrophages and in patients with sepsis caused by LPS-containing, Gram-negative bacteria. Furthermore, using breast cancer patient tissue microarrays, we find a strong correlation between the expression of Wnt5a in malignant epithelial cells and the frequency of CD163(+) anti-inflammatory tumor-associated macrophages. In conclusion, our data point out Wnt5a as a potential target for an efficient therapeutic modality in severe human diseases as diverse as sepsis and malignancy.
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| 3. |
- Bergenfelz, Caroline, et al.
(författare)
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Wnt5a inhibits human monocyte derived myeloid dendritic cell generation.
- 2013
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 78:2, s. 194-204
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Tidskriftsartikel (refereegranskat)abstract
- Wnt5a is a non-canonical Wnt protein that is expressed at elevated levels in inflammatory conditions. Its role in inflammation remains unclear, although it is known that Wnt5a is expressed at a higher level in monocyte-derived myeloid dendritic cells (Mo-mDCs) than in monocytes and macrophages. The function of Wnt5a in dendritic cells (DCs) remains relatively unexplored. Here, we found that under Mo-mDC culture conditions, Wnt5a inhibited the generation of CD14(+/low) Mo-mDCs while promoting the generation of CD14(+/++) CD16(+) monocytes. We could further show that stimulation of monocytes with rWnt5a induced a rapid IL-6 production and that the rWnt5a treated Mo-mDC differentiation was restored upon blocking of IL-6. Also conditioned media from Wnt5a stimulated human breast cancer cells producing IL-6, specifically inhibited Mo-mDC differentiation. These observations are strengthened by our finding that patients with sepsis, a disease involving elevated Wnt5a and IL-6 levels, also showed a significant increase in the CD14(+) CD16(++) /CD14(+/++) CD16(+) monocyte populations, which was accompanied by a significant decrease in circulating mDCs. We finally show that under typical Mo-mDC culture conditions, monocytes isolated from sepsis patients as compared to healthy controls, preferentially differentiated into CD14(+/++) HLA-DR(++) cells. We suggest that Wnt5a is a possible candidate mediator for the CD14(+/++) CD16(+) monocyte accumulation seen in infectious disease and cancer patients. This article is protected by copyright. All rights reserved.
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| 4. |
- Henriksson, Gunnel, et al.
(författare)
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Humoral response to Clostridium difficile in inflammatory bowel disease, including correlation with immunomodulatory treatment
- 2019
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Ingår i: JGH Open. - : Wiley. - 2397-9070. ; 3:2, s. 154-158
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aim: An abnormal immune response to intestinal bacteria has been observed in Crohn's disease (CD). Clostridium difficile infection incidence and severity are increased in CD, but reports on the humoral response have provided conflicting results. We aimed to shed light on the possible role of C. difficile in CD pathogenesis by paying attention to the influence of immunomodulatory treatment on the humoral response.Methods: A total of 71 consecutive outpatients with CD, 67 with ulcerative colitis (UC), and 121 healthy controls were analyzed for serum IgA and IgG to C. difficile toxins A and B.Results: IgA levels were similar in all study groups. IgG to toxin A was increased similarly in CD and UC (P = 0.02 for both). In contrast, IgG to toxin B was elevated only in CD patients not receiving disease-modifying anti-inflammatory bowel disease drugs (DMAID) (n = 16) (P = 0.0001), while the CD medication subgroup (n = 47) had a level similar to healthy controls. The UC results were not influenced by DMAID treatment.Conclusion: Our findings add support to the idea of a disturbed interaction between intestinal cells and the microbiota being part of the CD disease mechanism. An abnormal immune response to C. difficile toxin B may be a critical component of this interaction.
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| 5. |
- Holmdahl, Torsten, et al.
(författare)
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A Head-to-Head Comparison of Hydrogen Peroxide Vapor and Aerosol Room Decontamination Systems.
- 2011
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Ingår i: Infection Control & Hospital Epidemiology. - : Cambridge University Press (CUP). - 0899-823X .- 1559-6834. ; 32:9, s. 831-836
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Tidskriftsartikel (refereegranskat)abstract
- Objective. New technologies have emerged in recent years for the disinfection of hospital rooms and equipment that may not be disinfected adequately using conventional methods. There are several hydrogen peroxide-based area decontamination technologies on the market, but no head-to-head studies have been performed. Design. We conducted a head-to-head in vitro comparison of a hydrogen peroxide vapor (HPV) system (Bioquell) and an aerosolized hydrogen peroxide (aHP) system (Sterinis). Setting. The tests were conducted in a purpose-built 136-m(3) test room. Methods. One HPV generator and 2 aHP machines were used, following recommendations of the manufacturers. Three repeated tests were performed for each system. The microbiological efficacy of the 2 systems was tested using 6-log Tyvek-pouched Geobacillus stearothermophilus biological indicators (BIs). The indicators were placed at 20 locations in the first test and 14 locations in the subsequent 2 tests for each system. Results. All BIs were inactivated for the 3 HPV tests, compared with only 10% in the first aHP test and 79% in the other 2 aHP tests. The peak hydrogen peroxide concentration was 338 ppm for HPV and 160 ppm for aHP. The total cycle time (including aeration) was 3 and 3.5 hours for the 3 HPV tests and the 3 aHP tests, respectively. Monitoring around the perimeter of the enclosure with a handheld sensor during tests of both systems did not identify leakage. Conclusion. One HPV generator was more effective than 2 aHP machines for the inactivation of G. stearothermophilus BIs, and cycle times were faster for the HPV system.
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| 6. |
- Janols, Helena, et al.
(författare)
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A high frequency of MDSCs in sepsis patients, with the granulocytic subtype dominating in gram-positive cases.
- 2014
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Ingår i: Journal of Leukocyte Biology. - 1938-3673. ; 96:5, s. 685-693
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Tidskriftsartikel (refereegranskat)abstract
- The causative microorganisms dictate the type of MDSC generated in sepsis patients, and a large proportion of PMN-MDSCs in gram-positive sepsis includes immunosuppressive myeloid blasts. MDSCs constitute a heterogeneous population of immature myeloid cells that potently suppress immune responses. They were identified originally in cancer patients and have since been reported to occur also in chronic inflammation, autoimmunity, and even bacterial infections. Human MDSCs are commonly divided into Mo-MDSCs and granulocytic (PMN-MDSCs) subtypes. To what extent the bona fide cancer MDSCs are representative of the proposed MDSCs found in other diseases is not well known. PMN-MDSCs have been found previously to be enriched among LDGs in density gradient-centrifuged blood. In this study, we analyzed potential MDSCs in sepsis patients with different causative microorganisms, using total peripheral blood compared with density gradient-centrifuged blood. We found a high frequency of typical CD14(+)HLA-DR(low) Mo-MDSCs in all sepsis patients, whereas the typical PMN-MDSCs, as well as a prominent CD14(low) PMN-MDSC-like population, appeared preferentially in gram-positive cases. The CD14(low) PMN-MDSC variant was demonstrated to suppress T cell proliferation in vitro via a ROS-dependent mechanism, to display an increased IL-10:TNF-α ratio, and to present with signs of immaturity: blast morphology and low cytokine levels. We conclude that a spectrum of cells with MDSC features is enriched in sepsis and that the microbial origin of sepsis contributes to the substantial interindividual patient variation in the MDSC pattern.
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| 7. |
- Janols, Helena, et al.
(författare)
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Heterogeneity among septic shock patients in a set of immunoregulatory markers.
- 2014
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Ingår i: European Journal of Clinical Microbiology & Infectious Diseases. - : Springer Science and Business Media LLC. - 1435-4373 .- 0934-9723. ; 33:3, s. 313-324
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Tidskriftsartikel (refereegranskat)abstract
- Immune activation is a regular feature of sepsis, but the incidence and nature of the ensuing inflammation-resolving and immunosuppressive component is less well understood. In this study, we compared immunoregulatory markers on blood leukocytes from patients with Gram-negative or Gram-positive sepsis or septic shock, and compared this to blood from patients with severe virosis or healthy controls. To this end, blood from 32 patients with sepsis, including ten cases with shock, and 12 patients with severe virosis were analysed by flow cytometry for the expression levels of monocyte HLA-DR, CD11c, CD14 and CD40, and for frequencies of CD163(+)-suppressive monocytes, HLA-DR(+) or CD40(+)-activated T cells and Tregs. Plasma cytokine levels were analysed as a functional measurement. Signs of immunosuppression dominated in the septic shock and Gram-positive sepsis groups, whereas monocyte activation was common in Gram-negative sepsis patients without shock. However, the main finding was the large inter-individual variation of immune activation and immunosuppression, with no correlation to prognosis among the shock patients. The pronounced inter-individual variation in the analysed monocyte and lymphocyte markers forms a strong argument that, when immunomodulatory treatment is considered in a sepsis patient, it should be personalised and guided by a detailed immune status assessment.
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| 8. |
- Janols, Helena, et al.
(författare)
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Lymphocyte and monocyte flow cytometry immunophenotyping as a diagnostic tool in uncharacteristic inflammatory disorders.
- 2010
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Ingår i: BMC Infectious Diseases. - : Springer Science and Business Media LLC. - 1471-2334. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Patients with uncharacteristic inflammatory symptoms such as long-standing fatigue or pain, or a prolonged fever, constitute a diagnostic and therapeutic challenge. The aim of the present study was to determine if an extended immunophenotyping of lymphocytes and monocytes including activation markers can define disease-specific patterns, and thus provide valuable diagnostic information for these patients. METHODS: Whole blood from patients with gram-negative bacteraemia, neuroborreliosis, tuberculosis, acute mononucleosis, influenza or a mixed connective tissue disorders, as diagnosed by routine culture and serology techniques was analysed for lymphocyte and monocyte cell surface markers using a no-wash, no-lyse protocol for multi-colour flow cytometry method. The immunophenotyping included the activation markers HLA-DR and CD40. Plasma levels of soluble TNF alpha receptors were analysed by ELISA. RESULTS: An informative pattern was obtained by combining two of the analysed parameters: (i), the fractions of HLA-DR-expressing CD4+ T cells and CD8+ T cells, respectively, and (ii), the level of CD40 on CD14+ CD16- monocytes. Patients infected with gram-negative bacteria or EBV showed a marked increase in monocyte CD40, while this effect was less pronounced for tuberculosis, borrelia and influenza. The bacterial agents could be distinguished from the viral agents by the T cell result; CD4+ T cells reacting in bacterial infection, and the CD8+ T cells dominating for the viruses. Patients with mixed connective tissue disorders also showed increased activation, but with similar engagement of CD4+ and CD8+ T cells. Analysis of soluble TNF alpha receptors was less informative due to a large inter-individual variation. CONCLUSION: Immunophenotyping including the combination of the fractions of HLA-DR expressing T cell subpopulations with the level of CD40 on monocytes produces an informative pattern, differentiating between infections of bacterial and viral origin. Furthermore, a quantitative analysis of these parameters revealed the novel finding of characteristic patterns indicating a subacute bacterial infection, such as borreliosis or tuberculosis, or a mixed connective tissue disorder. The employed flow cytometric method is suitable for clinical diagnostic laboratories, and may help in the assessment of patients with uncharacteristic inflammatory symptoms.
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| 9. |
- Klarin, Bengt, et al.
(författare)
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Lactobacillus plantarum 299v reduces colonisation of Clostridium difficile in critically ill patients treated with antibiotics
- 2008
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 52:8, s. 1096-1102
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Tidskriftsartikel (refereegranskat)abstract
- Background: The incidence of Clostridium difficile-associated disease (CDAD) in hospitalised patients is increasing. Critically ill patients are often treated with antibiotics and are at high risk of developing CDAD. Lactobacillus plantarum 299v (Lp299v) has been found to reduce recurrence of CDAD. We investigated intensive care unit (ICU) patients regarding the impact of Lp299v on C. difficile colonisation and on gut permeability and parameters of inflammation and infection in that context. Methods: Twenty-two ICU patients were given a fermented oatmeal gruel containing Lp299v, and 22 received an equivalent product without the bacteria. Faecal samples for analyses of C. difficile and Lp299v were taken at inclusion and then twice a week during the ICU stay. Other cultures were performed on clinical indication. Infection and inflammation parameters were analysed daily. Gut permeability was assessed using a sugar probe technique. Main Results: Colonisation with C. difficile was detected in 19% (4/21) of controls but in none of the Lp299v-treated patients (p < 0.05). Conclusions: Enteral administration of the probiotic bacterium Lp299v to critically ill patients treated with antibiotics reduced colonisation with C. difficile. Trial registration: Current Controlled Trials ISRCTN85655545
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| 10. |
- Magnusson, Cecilia, et al.
(författare)
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Ribotyping of Clostridium difficile strains associated with nosocomial transmission and relapses in a Swedish County
- 2013
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Ingår i: APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. - : Wiley. - 1600-0463. ; 121:2, s. 153-157
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Tidskriftsartikel (refereegranskat)abstract
- Clostridium difficile is an emerging threat in hospital environments. To analyse possible transmission and to distinguish between relapse and reinfection a collection of C. difficile isolates, sampled from 162 consecutive episodes of C. difficile infection, were PCR ribotyped. Two ribotypes (001 and 012) were prone to cause nosocomial acquisition. Moreover, ribotype 001 had a tendency to cause relapses as almost one in two patients with this ribotype had one or more relapses. By using PCR ribotyping strains inclined to cause relapses and strains associated with hospital transmission might be detected. This enables optimized hygiene measures and may improve the choice of treatment regimen.
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