21 results on '"Hjelm F"'
Search Results
2. Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease
- Author
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Kalla, R., Adams, A. T., Bergemalm, D., Vatn, S., Kennedy, N. A., Ricanek, P., Lindstrom, J., Ocklind, A., Hjelm, F., Ventham, N. T., Ho, G. T., Petren, C., Repsilber, D., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Jahnsen, J., Vatn, M. H., Halfvarson, J., Satsangi, J., Kalla, R., Adams, A. T., Bergemalm, D., Vatn, S., Kennedy, N. A., Ricanek, P., Lindstrom, J., Ocklind, A., Hjelm, F., Ventham, N. T., Ho, G. T., Petren, C., Repsilber, D., Söderholm, Johan D, Pierik, M., DAmato, M., Gomollon, F., Olbjorn, C., Jahnsen, J., Vatn, M. H., Halfvarson, J., and Satsangi, J.
- Abstract
Background: Success in personalized medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay [PEA] to identify diagnostic and prognostic biomarkers in inflammatory bowel disease [IBD]. Methods: We conducted a prospective case-control study in an inception cohort of 552 patients [328 IBD, 224 non-IBD], profiling proteins recruited across six centres. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross-validation was used to examine the performance of diagnostic and prognostic proteins. Results: A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls, including matrix metallopeptidase-12 [MMP-12; Holm-adjusted p=4.1x10(-23)] and oncostatin-M [OSM; p=3.7x10(-16)]. Nine of these proteins are associated with cis-germline variation [59 independent single nucleotide polymorphisms]. Fifteen proteins, all members of tumour necrosis factor-independent pathways including interleukin-1 (IL-1) and OSM, predicted escalation, over a median follow-up of 518 [interquartile range 224-756] days. Nested cross-validation of the entire data set allowed characterization of five-protein models [96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7 and IL8], which define a high-risk subgroup in IBD [hazard ratio 3.90, confidence interval: 2.43-6.26], or allowed distinct two- and three-protein models for ulcerative colitis and Crohns disease respectively. Conclusion: We have characterized a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and to predict future disease course. Further prospective work is required to validate our findings., Funding Agencies|EU FP7 grant: IBD-CHARACTER [2858546]; Wellcome TrustWellcome TrustEuropean Commission
- Published
- 2021
- Full Text
- View/download PDF
3. Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease
- Author
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Kalla, R, primary, Adams, A T, additional, Bergemalm, D, additional, Vatn, S, additional, Kennedy, N A, additional, Ricanek, P, additional, Lindstrom, J, additional, Ocklind, A, additional, Hjelm, F, additional, Ventham, N T, additional, Ho, G T, additional, Petren, C, additional, Repsilber, D, additional, Söderholm, J, additional, Pierik, M, additional, D’Amato, M, additional, Gomollón, F, additional, Olbjorn, C, additional, Jahnsen, J, additional, Vatn, M H, additional, Halfvarson, J, additional, and Satsangi, J, additional
- Published
- 2020
- Full Text
- View/download PDF
4. IgE Enhances Specific Antibody and T-cell Responses in Mice Overexpressing CD23
- Author
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Carlsson, F., Hjelm, F., Conrad, D. H., and Heyman, B.
- Published
- 2007
5. Antibody-Mediated Regulation of the Immune Response
- Author
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Hjelm, F., Carlsson, F., Getahun, A., and Heyman, B.
- Published
- 2006
6. IgG3-Mediated Enhancement of the Antibody Response is Normal in FcγRI-Deficient Mice
- Author
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Hjelm, F., Carlsson, F., Verbeek, S., and Heyman, B.
- Published
- 2005
7. Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease.
- Author
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Kalla, R, Adams, A T, Bergemalm, D, Vatn, S, Kennedy, N A, Ricanek, P, Lindstrom, J, Ocklind, A, Hjelm, F, Ventham, N T, Ho, G T, Petren, C, Repsilber, D, Söderholm, J, Pierik, M, D'Amato, M, Gomollón, F, Olbjorn, C, Jahnsen, J, and Vatn, M H
- Abstract
Background Success in personalized medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay [PEA] to identify diagnostic and prognostic biomarkers in inflammatory bowel disease [IBD]. Methods We conducted a prospective case-control study in an inception cohort of 552 patients [328 IBD, 224 non-IBD], profiling proteins recruited across six centres. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross-validation was used to examine the performance of diagnostic and prognostic proteins. Results A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls, including matrix metallopeptidase-12 [MMP-12; Holm-adjusted p = 4.1 × 10
–23 ] and oncostatin-M [OSM; p = 3.7 × 10–16 ]. Nine of these proteins are associated with cis -germline variation [59 independent single nucleotide polymorphisms]. Fifteen proteins, all members of tumour necrosis factor-independent pathways including interleukin-1 (IL-1) and OSM, predicted escalation, over a median follow-up of 518 [interquartile range 224–756] days. Nested cross-validation of the entire data set allowed characterization of five-protein models [96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7 and IL8], which define a high-risk subgroup in IBD [hazard ratio 3.90, confidence interval: 2.43–6.26], or allowed distinct two- and three-protein models for ulcerative colitis and Crohn's disease respectively. Conclusion We have characterized a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and to predict future disease course. Further prospective work is required to validate our findings. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
8. The prevalence and transcriptional activity of the mucosal microbiota of ulcerative colitis patients
- Author
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Moen, A.E.F., Lindstrøm, J.C., Tannæs, T.M., Vatn, S., Ricanek, P., Vatn, M.H., Jahnsen, J., Frengen, A.B., Dahl, F.A., You, P., Sølvernes, J., Ekeland, G.S., Detlie, T.E., Olbjørn, C., O’Leary, K.R., Ventham, N.T., Kennedy, N.A., Kalla, R., Adams, A., Drummond, H.E., Boyapati, R., Nimmo, E.R., Wilson, D.C., Satsangi, J., Heath, S.C., Gut, M., Merkel, A., Bayes, M., Gut, I.G., Keita, Å.V., Söderholm, J.D., Hjortswang, H., Carstens, A., Bergemalm, D., Halfvarson, J., Andersson, E., Lindqvist, M., Repsilber, D., Pierik, M., Jonkers, D., Gomollón, F., D’Amato, M., Törkvist, L., Hjelm, F., Gullberg, M., Nordberg, N., Ocklind, A., Pettersson, E., Ekman, D., Sundell, M., Modig, E., Bonfiglio, F., Veillard, A.C., Schoemans, R., Poncelet, D., Sabatel, C., Lindahl, T., Ciemniejewska, E., Casén, C., Lees, C., Noble, C.L., Arnott, I., Ho, G.T., Shand, A.G., and The, IBD-Character, Consortium
- Abstract
Active microbes likely have larger impact on gut health status compared to inactive or dormant microbes. We investigate the composition of active and total mucosal microbiota of treatment-naïve ulcerative colitis (UC) patients to determine the microbial picture at the start-up phase of disease, using both a 16S rRNA transcript and gene amplicon sequencing. DNA and RNA were isolated from the same mucosal colonic biopsies. Our aim was to identify active microbial members of the microbiota in early stages of disease and reveal which members are present, but do not act as major players. We demonstrated differences in active and total microbiota of UC patients when comparing inflamed to non-inflamed tissue. Several taxa, among them the Proteobacteria phyla and families therein, revealed lower transcriptional activity despite a high presence. The Bifidobacteriaceae family of the Actinobacteria phylum showed lower abundance in the active microbiota, although no difference in presence was detected. The most abundant microbiota members of the inflamed tissue in UC patients were not the most active. Knowledge of active members of microbiota in UC patients could enhance our understanding of disease etiology. The active microbial community composition did not deviate from the total when comparing UC patients to non-IBD controls.
- Published
- 2018
9. Proximity Extension Assay technology identifies novel serum biomarkers for predicting Inflammatory Bowel Disease : IBD Character Consortium
- Author
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Kalla, R., Kennedy, N., Hjelm, F., Modig, E., Sundell, M., Andreassen, B., Bergemalm, Daniel, Ricanek, P., Söderholm, J., Vatn, M., Halfvarson, Jonas, Gullberg, M., Satsangi, J., Kalla, R., Kennedy, N., Hjelm, F., Modig, E., Sundell, M., Andreassen, B., Bergemalm, Daniel, Ricanek, P., Söderholm, J., Vatn, M., Halfvarson, Jonas, Gullberg, M., and Satsangi, J.
- Published
- 2015
- Full Text
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10. Antibody-mediated regulation of the immune response
- Author
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Hjelm, F, Carlsson, F, Getahun, A, Heyman, B, Hjelm, F, Carlsson, F, Getahun, A, and Heyman, B
- Abstract
Antibodies administered in vivo together with the antigen they are specific for can regulate the immune response to that antigen. This phenomenon is called antibody-mediated feedback regulation and has been known for over 100 years. Both passively administered and actively produced antibodies exert immunoregulatory functions. Feedback regulation can be either positive or negative, resulting in >1000-fold enhancement or >99% suppression of the specific antibody response. Usually, the response to the entire antigen is up- or downregulated, regardless of which epitope the regulating antibody recognizes. IgG of all isotypes can suppress responses to large particulate antigens like erythrocytes, a phenomenon used clinically in Rhesus prophylaxis. IgG suppression works in mice lacking the known Fc-gamma receptors (FcgammaR) and a likely mechanism of action is epitope masking. IgG1, IgG2a and IgG2b administered together with soluble protein antigens will enhance antibody and CD4+ T-cell responses via activating FcgammaR, probably via increased antigen presentation by dendritic cells. IgG3 as well as IgM also enhance antibody responses but their effects are dependent on their ability to activate complement. A possible mechanism is increased B-cell activation caused by immune complexes co-crosslinking the B-cell receptor with the complement-receptor 2/CD19 receptor complex, known to lower the threshold for B-cell activation. IgE-antibodies enhance antibody and CD4+ T-cell responses to small soluble proteins. This effect is entirely dependent on the low-affinity receptor for IgE, CD23, the mechanism probably being increased antigen presentation by CD23+ B cells.
- Published
- 2006
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11. IgG3-mediated enhancement of the antibody response is normal in Fc gammaRI-deficient mice
- Author
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Hjelm, F, Carlsson, F, Verbeek, S, Heyman, B, Hjelm, F, Carlsson, F, Verbeek, S, and Heyman, B
- Abstract
Antibodies, administered together with their specific antigen, can feedback-regulate antibody responses to this antigen. IgG1, IgG2a and IgG2b enhance antibody responses to soluble protein antigens. This effect is primarily mediated by FcRs as enhancement is impaired in FcR gamma-/- mice, reported to lack Fc gammaRI and Fc gammaRIII because of deletion of the common FcR gamma chain. Also IgG3 can enhance antibody responses. However, this effect is unperturbed in FcR gamma-/- mice but severely impaired in complement-depleted animals and in animals lacking complement receptor 1 and 2. Although this argues against involvement of Fc gammaRs, FcR gamma-/- mice may express one-fifth of the normal levels of Fc gammaRI and, in addition, Fc gammaRI has been suggested to bind IgG3. We re-investigated the dependence of IgG3-mediated enhancement on Fc gammaRs using a mouse strain selectively lacking Fc gammaRI and found that IgG3-mediated enhancement is completely normal. Unlike IgE and IgG2a, which are both thought to enhance T-cell proliferation via FcR-mediated antigen presentation, IgG3 was a poor enhancer of T-cell proliferation both in vivo and in vitro. These findings argue against a significant involvement of Fc gammaRs in IgG3-mediated enhancement of antibody responses and support our previous conclusion that complement plays a major role.
- Published
- 2005
- Full Text
- View/download PDF
12. High resolution calorimetry with PWO-II.
- Author
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Novotny, R.W., Doring, W.M., Hjelm, F., Melnychuk, D., Makonyi, K., Reiter, A., Salz, C., Steinacher, M., Thiel, M., and Zwieglinski, B.
- Published
- 2005
- Full Text
- View/download PDF
13. Shb deficient mice display an augmented TH2 response in peripheral CD4+ T cells
- Author
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Grönvik Kjell-Olov, Heyman Birgitta, Hjelm Fredrik, Kriz Vitezslav, Calounova Gabriela, Gustafsson Karin, Mostoslavsky Gustavo, and Welsh Michael
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background Shb, a ubiquitously expressed Src homology 2 domain-containing adaptor protein has previously been implicated in the signaling of various tyrosine kinase receptors including the TCR. Shb associates with SLP76, LAT and Vav, all important components in the signaling cascade governing T cell function and development. A Shb knockout mouse was recently generated and the aim of the current study was to address the importance of Shb deficiency on T cell development and function. Results Shb knockout mice did not display any major changes in thymocyte development despite an aberrant TCR signaling pattern, including increased basal activation and reduced stimulation-induced phosphorylation. The loss of Shb expression did however affect peripheral CD4+ TH cells resulting in an increased proliferative response to TCR stimulation and an elevated IL-4 production of naïve TH cells. This suggests a TH2 skewing of the Shb knockout immune system, seemingly caused by an altered TCR signaling pattern. Conclusion Our results indicate that Shb appears to play an important modulating role on TCR signaling, thus regulating the peripheral CD4+ TH2 cell response.
- Published
- 2011
- Full Text
- View/download PDF
14. Frequency and outcomes of treatment dose escalation with biologics in moderate-to-severe psoriasis: a Swedish register study.
- Author
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Svedbom A, Wennerström C, Hjelm F, Tjärnlund A, and Ståhle M
- Subjects
- Humans, Sweden, Male, Female, Middle Aged, Adult, Treatment Outcome, Dose-Response Relationship, Drug, Biological Products administration & dosage, Biological Products therapeutic use, Psoriasis drug therapy, Adalimumab administration & dosage, Adalimumab therapeutic use, Etanercept administration & dosage, Etanercept therapeutic use, Registries, Ustekinumab administration & dosage, Ustekinumab therapeutic use, Severity of Illness Index, Dermatologic Agents administration & dosage
- Abstract
Background: The advent of biosimilars may increase the frequency of dose escalation with biologics in psoriasis., Objective: To explore the frequency and outcomes of dose escalation with adalimumab etanercept, and ustekinumab., Methods: Data were extracted from DermaReg-Pso, a psoriasis register in Stockholm, Sweden. The main exposure was treatment, and the main outcome was dose escalation. We describe outcomes with dose escalation by estimating drug survival and changes in the Psoriasis Area and Severity Index (PASI)., Results: 554 patients had 946 treatment episodes with adalimumab, etanercept, or ustekinumab. The cumulative incidence of dose escalation was 4.1 per 100 treatment years. The Hazard Ratios (HRs) for dose escalation with ustekinumab vs adalimumab and ustekinumab vs etanercept were 1.93 (95% CI: 1.25-2.98), and 2.20 (95% CI: 1.42-3.41), respectively. After dose escalation, the HRs for treatment discontinuation with adalimumab and etanercept compared with ustekinumab were 3.10 (95% CI: 1.56-6.18) and 7.15 (95% CI: 3.96-12.94), respectively. PASI was higher after compared to before dose escalation for etanercept ( p = 0.036), but not for adalimumab ( p = 0.832) or ustekinumab ( p = 0.300)., Conclusions: Dose escalation was comparatively more frequent with ustekinumab than with adalimumab or etanercept; however, treatment discontinuation after dose escalation was more common with adalimumab and etanercept than ustekinumab.
- Published
- 2024
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15. Ustekinumab Is Associated with Real-World Long-Term Effectiveness and Improved Health-Related Quality of Life in Crohn's Disease.
- Author
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Forss A, Clements M, Myrelid P, Strid H, Söderman C, Wagner A, Andersson D, Hjelm F, Olén O, Halfvarson J, and Ludvigsson JF
- Subjects
- Adult, Humans, Follow-Up Studies, Prospective Studies, Quality of Life, Remission Induction, Interleukin-23, Treatment Outcome, Ustekinumab adverse effects, Crohn Disease diagnosis, Crohn Disease drug therapy, Crohn Disease pathology
- Abstract
Background: Prospectively and systematically collected long-term real-world clinical data on ustekinumab (anti-interleukin-12/23) are still scarce., Aims: To assess the long-term effectiveness of ustekinumab in patients with active Crohn's disease (CD)., Methods: This is a prospective multicenter study of adult patients with CD initiating ustekinumab according to recommended doses at 20 Swedish hospitals. The primary outcome was clinical remission (Harvey-Bradshaw Index (HBI) ≤ 4 points) at weeks 52 and 104. Secondary outcomes included clinical response (≥ 3-point-decrease in HBI among patients with initial HBI ≥ 5 points), treatment retention, and biomarkers (C-reactive protein (CRP), hemoglobin, fecal-calprotectin) at weeks 52 and 104 compared to baseline. We also reported Health-related Quality of Life (HRQoL) measures., Results: Of 114 included patients, 107 (94%) had previously failed ≥ 1 and 58 (51%) ≥ 2 anti-tumor necrosis factor agents. Forty (35%) had failed anti-integrin agents. Ustekinumab retention rates at weeks 52 and 104 were 70% (n = 80/114) and 61% (n = 69/114), respectively. Clinical response was seen in 36% (n = 25/69) and 29% (n = 20/69) of the patients, and remission was achieved in 32% (n = 31/96) and 29% (n = 28/96) at weeks 52 and 104, respectively. Median HBI and CRP levels decreased significantly at both timepoints as compared to baseline. Significant improvements were also observed in HRQoL. Adverse events were reported in 11% (n = 13/114) of the patients, including five cases of severe adverse events. No malignancies were observed., Conclusions: In this nationwide prospective real-world 104-week-follow-up study of adult patients with active CD, ustekinumab was associated with long-term clinical effectiveness and improvement in HRQoL measures when used in routine clinical care., (© 2022. The Author(s).)
- Published
- 2023
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16. Prospective observational study on Stelara (ustekinumab) assessing effectiveness in Crohn's disease (PROSE): a 16-week follow-up.
- Author
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Forss A, Clements M, Myrelid P, Strid H, Söderman C, Wagner A, Andersson D, Hjelm F, Olén O, Ludvigsson JF, and Halfvarson J
- Subjects
- Adult, Follow-Up Studies, Humans, Prospective Studies, Remission Induction, Treatment Outcome, Ustekinumab therapeutic use, Crohn Disease drug therapy, Inflammatory Bowel Diseases
- Abstract
Background: Prospectively and systematically collected real-world data on the effectiveness of ustekinumab (anti-interleukin-12/23) for treating Crohn's disease (CD) are still limited., Aim: To assess the short-term real-world effectiveness of ustekinumab in Swedish patients with active CD., Methods: Prospective multicentre study of adult CD patients initiating ustekinumab according to recommended doses at 20 hospitals, between January 2017 and November 2018. Data were collected through an electronic case report form (eCRF) linked to the Swedish Inflammatory Bowel Disease Registry (SWIBREG). The primary outcomes were clinical response (≥3-point-decrease of Harvey-Bradshaw index (HBI)) and remission (HBI ≤4 points) at week 16. Secondary outcomes included C-reactive protein (CRP) and haemoglobin (Hb) at baseline compared to week 16., Results: Of 114 included patients, 107 (94%) had failed ≥ 1 and 58 (51%) ≥ 2 biological agents (anti-tumour necrosis factor [aTNF] agents or vedolizumab). The 16-week ustekinumab retention rate was 105 (92%). Data on HBI at baseline were available for 96 patients. At week 16, response or remission was achieved in 38/96 (40%) patients (25/96 (26%) achieving clinical remission and 23/96 (24%) showing a clinical response). The median CRP concentration ( N = 65) decreased from 6 to 4 mg/l ( p = .006). No significant changes in Hb were observed. No incident malignancies or infections, requiring antibiotic treatment, were reported., Conclusions: In this nation-wide prospective real-world study of adult patients with CD, ustekinumab was associated with clinical effectiveness when administered according to clinical practice and seemed to represent a safe treatment option.
- Published
- 2021
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17. Shb deficient mice display an augmented TH2 response in peripheral CD4+ T cells.
- Author
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Gustafsson K, Calounova G, Hjelm F, Kriz V, Heyman B, Grönvik KO, Mostoslavsky G, and Welsh M
- Subjects
- Alleles, Animals, Blood Cell Count, Cell Differentiation, Cell Proliferation, Gene Expression Profiling, Gene Expression Regulation, Immunologic Memory, Lymphocyte Activation immunology, Mice, Mice, Knockout, Proto-Oncogene Proteins metabolism, Receptors, Antigen, T-Cell immunology, Signal Transduction, Thymus Gland cytology, Proto-Oncogene Proteins deficiency, Th2 Cells immunology
- Abstract
Background: Shb, a ubiquitously expressed Src homology 2 domain-containing adaptor protein has previously been implicated in the signaling of various tyrosine kinase receptors including the TCR. Shb associates with SLP76, LAT and Vav, all important components in the signaling cascade governing T cell function and development. A Shb knockout mouse was recently generated and the aim of the current study was to address the importance of Shb deficiency on T cell development and function., Results: Shb knockout mice did not display any major changes in thymocyte development despite an aberrant TCR signaling pattern, including increased basal activation and reduced stimulation-induced phosphorylation. The loss of Shb expression did however affect peripheral CD4+ T(H) cells resulting in an increased proliferative response to TCR stimulation and an elevated IL-4 production of naïve T(H) cells. This suggests a T(H)2 skewing of the Shb knockout immune system, seemingly caused by an altered TCR signaling pattern., Conclusion: Our results indicate that Shb appears to play an important modulating role on TCR signaling, thus regulating the peripheral CD4+ T(H)2 cell response.
- Published
- 2011
- Full Text
- View/download PDF
18. Bright-field microscopy visualization of proteins and protein complexes by in situ proximity ligation with peroxidase detection.
- Author
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Zieba A, Wählby C, Hjelm F, Jordan L, Berg J, Landegren U, and Pardali K
- Subjects
- Animals, Cells, Cultured, Estradiol analysis, Immunohistochemistry, Mice, Receptor, ErbB-2 analysis, Receptors, Estradiol analysis, Smad2 Protein analysis, Horseradish Peroxidase metabolism, Microscopy, Fluorescence methods, Protein Interaction Mapping methods, Proteins analysis
- Abstract
Background: The in situ proximity ligation assay (PLA) allows a protein or protein complex to be represented as an amplifiable DNA molecule. Recognition is mediated by proximity probes consisting of antibodies coupled with oligonucleotides. Upon dual binding of the proximity probes, the oligonucleotides direct the formation of a circular DNA molecule, which is then amplified by rolling-circle replication. The localized concatemeric product is then detected with fluorescent probes. The in situ PLA enables localized detection of individual native proteins or interacting protein pairs in fixed cells or tissue sections, thus providing an important tool for basic and clinical research., Methods: We used horseradish peroxidase (HRP)-conjugated oligonucleotides to couple in situ PLA with enzymatic visualization of the localized detection event., Results: We demonstrate the detection of protein complexes, both in cells and in tissue sections, and show that we can quantify the complexes with image-analysis software specially developed for recognizing HRP signals in bright-field microscopy images. We show that fluorescence and HRP signals produce equivalent results, both in cultured cells and in tissue samples., Conclusions: The combination of in situ PLA with bright-field detection and automated image analysis allows the signals present to be counted in an automated fashion and thus provides a sensitive and specific method for quantification of proteins and protein complexes with bright-field microscopy. With this approach, in situ PLA can be used without the requirement for expensive fluorescence microscopes, thereby avoiding problems with nonspecific fluorescence while maintaining compatibility with conventional histologic staining.
- Published
- 2010
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19. A novel B cell-mediated transport of IgE-immune complexes to the follicle of the spleen.
- Author
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Hjelm F, Karlsson MC, and Heyman B
- Subjects
- Adoptive Transfer, Animals, CD4-Positive T-Lymphocytes immunology, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Fluorescent Antibody Technique, Immunoglobulin G immunology, Immunohistochemistry, Lymphocyte Activation immunology, Male, Mice, Mice, Transgenic, Microscopy, Confocal, Ovalbumin immunology, Receptors, IgE immunology, Receptors, IgE metabolism, Trinitrobenzenes immunology, Antigen Presentation immunology, Antigen-Antibody Complex immunology, B-Lymphocytes immunology, Germinal Center immunology, Immunoglobulin E immunology, Spleen immunology
- Abstract
Ag administered i.v. to mice along with specific IgE or IgG2a induces higher Ab- and CD4(+) T cell responses than Ag administered alone. The IgE effect is completely dependent on the low-affinity receptor for IgE, CD23, whereas the IgG2a effect depends on activating FcgammaRs. In vitro studies suggest that IgE/Ag is presented more efficiently than Ag alone to CD4(+) T cells by CD23(+) B cells and that IgG2a/Ag is presented by FcgammaR(+) dendritic cells (DCs). In this study, we investigate in vivo the early events leading to IgE- and IgG2a-mediated enhancement of immune responses. OVA administered i.v. in PBS in combination with specific IgE binds circulating B cells after 5 min and is found in B cell follicles bound to follicular B cells (CD23(high)) after 30 min. This novel B cell-dependent route of entry is specific for IgE because IgG2a-Ag complexes were trapped in the marginal zone. OVA-specific CD4(+) T cells were found at the T-B border in the T cell zones 12 h after immunization both with IgE/OVA or IgG2a/OVA and proliferated vigorously after 3 days. The findings suggest that IgE- and IgG2a-immune complexes are efficient stimulators of early CD4(+) T cell responses and that Ag bound to IgE has a specific route for transportation into follicles.
- Published
- 2008
- Full Text
- View/download PDF
20. IgG3-mediated enhancement of the antibody response is normal in Fc gammaRI-deficient mice.
- Author
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Hjelm F, Carlsson F, Verbeek S, and Heyman B
- Subjects
- Adoptive Transfer, Animals, Antibody Formation drug effects, Antigen Presentation drug effects, Antigen Presentation immunology, CD4-Positive T-Lymphocytes immunology, Hemocyanins immunology, Immunoglobulin G pharmacology, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Transgenic, Ovalbumin immunology, Picrates immunology, Receptors, IgG immunology, Vaccination, Antibody Formation immunology, Immunoglobulin G immunology, Receptors, IgG genetics
- Abstract
Antibodies, administered together with their specific antigen, can feedback-regulate antibody responses to this antigen. IgG1, IgG2a and IgG2b enhance antibody responses to soluble protein antigens. This effect is primarily mediated by FcRs as enhancement is impaired in FcR gamma-/- mice, reported to lack Fc gammaRI and Fc gammaRIII because of deletion of the common FcR gamma chain. Also IgG3 can enhance antibody responses. However, this effect is unperturbed in FcR gamma-/- mice but severely impaired in complement-depleted animals and in animals lacking complement receptor 1 and 2. Although this argues against involvement of Fc gammaRs, FcR gamma-/- mice may express one-fifth of the normal levels of Fc gammaRI and, in addition, Fc gammaRI has been suggested to bind IgG3. We re-investigated the dependence of IgG3-mediated enhancement on Fc gammaRs using a mouse strain selectively lacking Fc gammaRI and found that IgG3-mediated enhancement is completely normal. Unlike IgE and IgG2a, which are both thought to enhance T-cell proliferation via FcR-mediated antigen presentation, IgG3 was a poor enhancer of T-cell proliferation both in vivo and in vitro. These findings argue against a significant involvement of Fc gammaRs in IgG3-mediated enhancement of antibody responses and support our previous conclusion that complement plays a major role.
- Published
- 2005
- Full Text
- View/download PDF
21. IgE enhances antibody and T cell responses in vivo via CD23+ B cells.
- Author
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Getahun A, Hjelm F, and Heyman B
- Subjects
- Animals, Antigen Presentation genetics, Antigen-Antibody Complex administration & dosage, Antigen-Antibody Complex physiology, B-Lymphocyte Subsets metabolism, B-Lymphocyte Subsets transplantation, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes transplantation, Epitopes, T-Lymphocyte metabolism, Haptens administration & dosage, Haptens immunology, Immunoglobulin E metabolism, Lymphocyte Activation genetics, Lymphocyte Activation immunology, Mice, Mice, Congenic, Mice, Inbred BALB C, Mice, Transgenic, Ovalbumin administration & dosage, Ovalbumin immunology, Receptors, IgE deficiency, Receptors, IgE genetics, T-Lymphocytes metabolism, Trinitrobenzenes administration & dosage, Trinitrobenzenes immunology, Adjuvants, Immunologic administration & dosage, Adjuvants, Immunologic physiology, Antibody Formation genetics, B-Lymphocyte Subsets immunology, Epitopes, T-Lymphocyte immunology, Immunoglobulin E administration & dosage, Immunoglobulin E physiology, Receptors, IgE biosynthesis, T-Lymphocytes immunology
- Abstract
IgE Abs, passively administered together with their specific Ag, can enhance the production of Abs recognizing this Ag by >100-fold. IgE-mediated feedback enhancement requires the low affinity receptor for IgE, CD23. One possible mechanism is that B cells take up IgE-Ag via CD23 and efficiently present Ag to Th cells, resulting in better Ab responses. To test whether IgE Abs have an effect on Th cells in vivo, mice were adoptively transferred with CD4+ T cells expressing a transgenic OVA-specific TCR, before immunization with IgE anti-TNP (2,4,6-trinitrophenyl) plus OVA-TNP or with OVA-TNP alone. IgE induced a 6- to 21-fold increase in the number of OVA-specific T cells. These cells acquired an activated phenotype and were visible in splenic T cell zones. The T cell response peaked 3 days after immunization and preceded the OVA-specific Ab response by a few days. Transfer of CD23+ B cells to CD23-deficient mice rescued their ability to respond to IgE-Ag. Interestingly, in this situation also CD23-negative B cells produce enhanced levels of OVA-specific Abs. The data are compatible with the Ag presentation model and suggest that B cells can take up Ag via "unspecific" receptors and activate naive T cells in vivo.
- Published
- 2005
- Full Text
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