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  • 151.
    Andreasson, H
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Allen, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Rapid quantification and sex determination of forensic evidence materials.2003In: J Forensic Sci, Vol. 48, p. 1280-Article in journal (Refereed)
  • 152.
    Andreasson, H
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Asp, A
    Alderborn, A
    Gyllensten, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Allen, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Mitochondrial sequence analysis for forensic identification using pyrosequencing technology.2002In: Biotechniques, Vol. 32, p. 124-Article in journal (Refereed)
  • 153. Andreasson, Ulrika
    et al.
    Edén, Patrik
    Peterson, Carsten
    Högerkorp, Carl-Magnus
    Jerkeman, Mats
    Andersen, Niels
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Borrebaeck, Carl A. K.
    Ek, Sara
    Identification of uniquely expressed transcription factors in highly purified B-cell lymphoma samples2010In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 85, no 6, p. 418-425Article in journal (Refereed)
    Abstract [en]

    Transcription factors (TFs) are critical for B-cell differentiation, affecting gene expression both by repression and transcriptional activation. Still, this information is not used for classification of B-cell lymphomas (BCLs). Traditionally, BCLs are diagnosed based on a phenotypic resemblance to normal B-cells; assessed by immunohistochemistry or flow cytometry, by using a handful of phenotypic markers. In the last decade, diagnostic and prognostic evaluation has been facilitated by global gene expression profiling (GEP), providing a new powerful means for the classification, prediction of survival, and response to treatment of lymphomas. However, most GEP studies have typically been performed on whole tissue samples, containing varying degrees of tumor cell content, which results in uncertainties in data analysis. In this study, global GEP analyses were performed on highly purified, flow-cytometry sorted tumor-cells from eight subgroups of BCLs. This enabled identification of TFs that can be uniquely associated to the tumor cells of chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hairy cell leukemia (HCL), and mantle cell lymphoma (MCL). The identified transcription factors influence both the global and specific gene expression of the BCLs and have possible implications for diagnosis and treatment.

  • 154.
    Andræ, Johanna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    PDGF in cerebellar development and tumorigenesis2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Medulloblastoma is a highly malignant cerebellar childhood tumor. As in many other brain tumors, expression of platelet-derived growth factor (PDGF) and its receptors has been shown in medulloblastoma. To reveal the importance of this growth factor in cerebellar development and tumorigenesis, analyses were performed on human medulloblastoma cell lines and on tissue from normal mouse brain at different stages of development. The in vivo effect of a forced expression of PDGF-B in the cerebellar primordium was examined in transgenic mice.

    In the normal mouse embryo, we found PDGF receptor-α-positive cells in the early neuroepithelium and on neuronal precursors. In the postnatal cerebellum, cells in the external germinal layer and Purkinje cells expressed the receptor. In the medulloblastoma cells, expression of all the three PDGF isoforms and PDGF receptors was seen and correlated to neuronal differentiation. Endogenously activated, i.e. tyrosine phosphorylated, PDGF receptors were identified. To reveal the role of PDGF in normal cerebellar development, we established transgenic mice where a PDGF-B cDNA was introduced via homologous recombination into the engrailed-1 gene. Engrailed-1 is specifically expressed at the mid-/hindbrain boundary of the early neural tube, i.e. in an area from which the cerebellar primordium develops. The ectopic expression of PDGF-B caused a disturbance of cerebellar development. Midline fusion of the cerebellar primordium did not occur properly, which resulted in cerebellar dysplasia in the adult mouse.

    In a parallel study, the expression pattern of a glial fibrillary acidic protein (GFAP)-lacZ transgene was followed in the embryonic mouse central nervous system. It was shown that the human GFAP promoter was already active by embryonic day 9.5 and as development proceeded, expression occured in different, independent cell populations. Among these cell populations were the radial glial cells in the neocortex.

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  • 155.
    Andréasson, Hanna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Sensitive Forensic DNA Analysis: Application of Pyrosequencing and Real-time PCR Quantification2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The field of forensic genetics is growing fast and the development and optimisation of more sensitive, faster and more discriminating forensic DNA analysis methods is highly important. In this thesis, an evaluation of the use of novel DNA technologies and the development of specific applications for use in forensic casework investigations are presented.

    In order to maximise the use of valuable limited DNA samples, a fast and user-friendly Real-time PCR quantification assay, of nuclear and mitochondrial DNA copies, was developed. The system is based on the 5’ exonuclease detection assay and was evaluated and successfully used for quantification of a number of different evidence material types commonly found on crime scenes. Furthermore, a system is described that allows both nuclear DNA quantification and sex determination in limited samples, based on intercalation of the SYBR Green dye to double stranded DNA.

    To enable highly sensitive DNA analysis, Pyrosequencing of short stretches of mitochondrial DNA was developed. The system covers both control region and coding region variation, thus providing increased discrimination power for mitochondrial DNA analysis. Finally, due to the lack of optimal assays for quantification of mitochondrial DNA mixture, an alternative use of the Pyrosequencing system was developed. This assay allows precise ratio quantification of mitochondrial DNA in samples showing contribution from more than one individual.

    In conclusion, the development of optimised forensic DNA analysis methods in this thesis provides several novel quantification assays and increased knowledge of typical DNA amounts in various forensic samples. The new, fast and sensitive mitochondrial DNA Pyrosequencing assay was developed and has the potential for increased discrimination power.

    List of papers
    1.
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    2. Nuclear and mitochondrial DNA quantification of various forensic materials
    Open this publication in new window or tab >>Nuclear and mitochondrial DNA quantification of various forensic materials
    2006 (English)In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 164, no 1, p. 56-64Article in journal (Refereed) Published
    Abstract [en]

    Due to the different types and quality of forensic evidence materials, their DNA content can vary substantially, and particularly low quantities can impact the results in an identification analysis. In this study, the quantity of mitochondrial and nuclear DNA was determined in a variety of materials using a previously described real-time PCR method. DNA quantification in the roots and distal sections of plucked and shed head hairs revealed large variations in DNA content particularly between the root and the shaft of plucked hairs. Also large intra- and inter-individual variations were found among hairs. In additions DNA content was estimated in samples collected from fingerprints and accessories. The quantification of DNA on various items also displayed large variations, with some materials containing large amounts of nuclear DNA while no detectable nuclear DNA and only limited amounts of mitochondrial DNA were seen in others. Using this sensitive real-time PCR quantification assay, a better understanding was obtained regarding DNA content and variation in commonly analysed forensic evidence materials and this may guide the forensic scientist as to the best molecular biology approach for analysing various forensic evidence materials.

    Keywords
    quantification, real-time PCR, forensic materials, hair, nuclear DNA, mitochondrial DNA
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-92985 (URN)10.1016/j.forsciint.2005.11.024 (DOI)000242666700006 ()16427750 (PubMedID)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2017-12-14Bibliographically approved
    3. Rapid quantification and sex determination of forensic evidence materials
    Open this publication in new window or tab >>Rapid quantification and sex determination of forensic evidence materials
    2003 (English)In: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 48, no 6, p. 1280-1287Article in journal (Refereed) Published
    Abstract [en]

    DNA quantification of forensic evidence is very valuable for an optimal use of the available biological material. Moreover, sex determination is of great importance as additional information in criminal investigations as well as in identification of missing persons, no suspect cases, and ancient DNA studies. While routine forensic DNA analysis based on short tandem repeat markers includes a marker for sex determination, analysis of samples containing scarce amounts of DNA is often based on mitochondrial DNA, and sex determination is not performed. In order to allow quantification and simultaneous sex determination on minute amounts of DNA, an assay based on real-time PCR analysis of a marker within the human amelogenin gene has been developed. The sex determination is based on melting curve analysis, while an externally standardized kinetic analysis allows quantification of the nuclear DNA copy number in the sample. This real-time DNA quantification assay has proven to be highly sensitive, enabling quantification of single DNA copies. Although certain limitations were apparent, the system is a rapid, cost-effective, and flexible assay for analysis of forensic casework samples.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-92986 (URN)14640271 (PubMedID)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2017-12-14Bibliographically approved
    4. Mitochondrial sequence analysis for forensic identification using Pyrosequencing technology
    Open this publication in new window or tab >>Mitochondrial sequence analysis for forensic identification using Pyrosequencing technology
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    2002 (English)In: BioTechniques, ISSN 0736-6205, E-ISSN 1940-9818, Vol. 32, no 1, p. 124-6, 128, 130-3Article in journal (Refereed) Published
    Abstract [en]

    Over recent years, requests for mtDNA analysis in the field of forensic medicine have notably increased, and the results of such analyses have proved to be very useful in forensic cases where nuclear DNA analysis cannot be performed. Traditionally, mtDNA has been analyzed by DNA sequencing of the two hypervariable regions, HVI and HVII, in the D-loop. DNA sequence analysis using the conventional Sanger sequencing is very robust but time consuming and labor intensive. By contrast, mtDNA analysis based on the pyrosequencing technology provides fast and accurate results from the human mtDNA present in many types of evidence materials in forensic casework. The assay has been developed to determine polymorphic sites in the mitochondrial D-loop as well as the coding region to further increase the discrimination power of mtDNA analysis. The pyrosequencing technology for analysis of mtDNA polymorphisms has been tested with regard to sensitivity, reproducibility, and success rate when applied to control samples and actual casework materials. The results show that the method is very accurate and sensitive; the results are easily interpreted and provide a high success rate on casework samples. The panel of pyrosequencing reactions for the mtDNA polymorphisms were chosen to result in an optimal discrimination power in relation to the number of bases determined.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-92987 (URN)11808686 (PubMedID)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2017-12-14Bibliographically approved
    5. Coding mtDNA analysis for increased forensic discrimination power using Pyrosequencing technology
    Open this publication in new window or tab >>Coding mtDNA analysis for increased forensic discrimination power using Pyrosequencing technology
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-92988 (URN)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2010-01-13Bibliographically approved
    6. Quantification of mtDNA mixtures in forensic evidence material using pyrosequencing
    Open this publication in new window or tab >>Quantification of mtDNA mixtures in forensic evidence material using pyrosequencing
    Show others...
    2006 (English)In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 120, no 6, p. 383-390Article in journal (Refereed) Published
    Abstract [en]

    Analysis of mtDNA variation using Sanger sequencing does not allow accurate quantification of the components of mtDNA mixtures. An alternative method to determine the specific mixture ratios in samples displaying heteroplasmy, consisting of DNA contributions from several individuals, or containing contamination would therefore be valuable. A novel quantification system for mtDNA mixture analysis has been developed based on pyrosequencing technology, in which the linear relationship between incorporated nucleotides and released light allows quantification of the components of a sample. Within five polymerase chain reaction fragments, seven variable positions in the mtDNA control and coding region were evaluated using this quantification analysis. For all single nucleotide polymorphisms quantified in this study, a linear relationship was observed between the measured and expected mixture ratios. This mtDNA quantification assay is an easy to use, fast and accurate quantification system, with the ability to resolve and interpret major and minor mtDNA components in forensic mixture samples.

    Keywords
    mixtures, mitochondrial DNA, pyrosequencing, quantification, forensic material
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-92989 (URN)10.1007/s00414-005-0072-8 (DOI)000241522300013 ()16453148 (PubMedID)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2017-12-14Bibliographically approved
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    COVER01
  • 156.
    Andréasson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nilsson, Martina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Budowle, B.
    Frisk, Stine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Quantification of mtDNA mixtures in forensic evidence material using pyrosequencing2006In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 120, no 6, p. 383-390Article in journal (Refereed)
    Abstract [en]

    Analysis of mtDNA variation using Sanger sequencing does not allow accurate quantification of the components of mtDNA mixtures. An alternative method to determine the specific mixture ratios in samples displaying heteroplasmy, consisting of DNA contributions from several individuals, or containing contamination would therefore be valuable. A novel quantification system for mtDNA mixture analysis has been developed based on pyrosequencing technology, in which the linear relationship between incorporated nucleotides and released light allows quantification of the components of a sample. Within five polymerase chain reaction fragments, seven variable positions in the mtDNA control and coding region were evaluated using this quantification analysis. For all single nucleotide polymorphisms quantified in this study, a linear relationship was observed between the measured and expected mixture ratios. This mtDNA quantification assay is an easy to use, fast and accurate quantification system, with the ability to resolve and interpret major and minor mtDNA components in forensic mixture samples.

  • 157.
    Andréasson, Hanna
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Nilsson, Martina
    Styrman, Hanna
    Allen, Marie
    Coding mtDNA analysis for increased forensic discrimination power using Pyrosequencing technologyManuscript (Other academic)
  • 158.
    Andréasson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Nilsson, Martina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Styrman, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Allen, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Forensic mitochondrial coding region analysis for increased discrimination using pyrosequencing technology2007In: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 1, no 1, p. 35-43Article in journal (Refereed)
    Abstract [en]

    Analysis of mitochondrial DNA (mtDNA) is very useful when nuclear DNA analysis fails due to degradation or insufficient amounts of DNA in forensic analysis. However, mtDNA analysis has a lower discrimination power compared to what can be obtained by nuclear DNA (nDNA) analysis, potentially resulting in multiple individuals showing identical mtDNA types in the HVI/HVII region. In this study, the increase in discrimination by analysis of mitochondrial coding regions has been evaluated for identical or similar HVI/HVII sequences. A pyrosequencing-based system for coding region analysis, comprising 17 pyrosequencing reactions performed on 15 PCR fragments, was utilised. This assay was evaluated in 135 samples, resulting in an average read length of 81 nucleotides in the pyrosequencing analysis. In the sample set, a total of 52 coding region SNPs were identified, of which 18 were singletons. In a group of 60 samples with 0 or 1 control region difference from the revised Cambridge reference sequence (rCRS), only 12 samples could not be resolved by at least two differences using the pyrosequencing assay. Thus, the use of this pyrosequencing-based coding region assay has the potential to substantially increase the discriminatory power of mtDNA analysis.

  • 159. Andréasson, Ulrika
    et al.
    Dictor, Michael
    Jerkeman, Mats
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Linderoth, Johan
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Borrebaeck, Carl A K
    Ek, Sara
    Identification of molecular targets associated with transformed diffuse large B cell lymphoma using highly purified tumor cells2009In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 84, no 12, p. 803-808Article in journal (Refereed)
    Abstract [en]

    Follicular lymphoma (FL) frequently transforms into the more aggressive diffuse large B cell lymphoma (DLBCL-tr), but no protein biomarkers have been identified for predictive or early diagnosis. Gene expression analyses have identified genes changing on transformation but have failed to be reproducible in different studies, reflecting the heterogeneity within the tumor tissue and between tumor samples. Gene expression analyses on Affymetrix Human Genome U133 Plus 2.0 arrays were performed, using flow cytometry sorted tumor cells derived from FL and transformed DLBCL. To identify molecular targets associated with the transformation, subsequent immunohistochemistry (IHC) analyses of the corresponding proteins were performed. Using highly purified cells, this study identified 163 genes, which were significantly deregulated during the transformation in a majority of cases. Among the upregulated transcripts, 13 genes were selected for validation using IHC, based on the availability of commercial antibodies, and galectin-3 and NEK2 proteins specifically identify DLBCL-tr, when compared with FL. We demonstrate that by purifying tumor cells through cell sorting, thereby reducing the heterogeneity due to infiltrating cells, it was possible to identify distinct differences between tumor entities rather than variations due to cellular composition. Galectin-3 and NEK2 both identified a subgroup of DLBCL-tr, and the function of these protein markers also suggests a biological role in the transformation process.

  • 160. Andréasson, Ulrika
    et al.
    Ek, Sara
    Merz, Hartmut
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Andersen, Niels
    Jerkeman, Mats
    Dictor, Michael
    Borrebaeck, Carl A K
    B cell lymphomas express CX(3)CR1 a non-B cell lineage adhesion molecule2008In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 259, no 2, p. 138-145Article in journal (Refereed)
    Abstract [en]

    To study the differential expression of cell membrane-bound receptors and their potential role in growth and/or survival of the tumor cells, highly purified follicular lymphoma cells were analyzed, using gene expression analysis, and compared to non-malignant B cell populations. Filtering the genome for overexpressed genes coding for cell membrane-bound proteins/receptors resulted in a hit list of 27 identified genes. Among these, we have focused on the aberrant over expression of CX3CR1, in different types of B cell lymphoma, as compared to non-malignant B cells. We show that CX3CR1, which normally is not expressed on B cells, is expressed both at the mRNA and protein level in several subtypes of lymphoma. CX3CR1 has also shown to be involved in the homing to specific tissues that express the ligand, CX3CL1, in breast and prostate cancer and may thus be involved in dissemination of lymphoma.

  • 161.
    Andrén, M
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Xiang, Z
    Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Nilsson, G
    Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Kleinau, S
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
    FcgammaRIII-expressing macrophages are essential for development of collagen-induced arthritis.2006In: Scand J Immunol, ISSN 0300-9475, Vol. 63, no 4, p. 282-9Article in journal (Refereed)
  • 162.
    Andrén, Maria
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    The Role of Fc Gamma Receptors in Experimental Arthritis2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Induction of collagen-induced arthritis (CIA), an animal model for human rheumatoid arthritis, is dependent on anti-collagen type II (CII) antibodies. The effector mechanism by which autoantibodies contribute to inflammatory reactions in autoimmune diseases is not well understood. In this thesis I have studied the effector pathways used by IgG anti-CII antibodies to initiate arthritis, namely the IgG Fc receptors (FcγRs) and the complement system. We have found that FcγRIII is crucial for development of CIA, as CII-immunized mice lacking this receptor do not develop arthritis and IgG1 and IgG2b anti-CII antibodies require FcγRIII to trigger arthritis when transferred to naïve mice. The antibody-mediated arthritis was further enhanced in mice deficient in the inhibitory FcγRIIB, indicating that FcγRIIB regulates the activation of FcγRIII. Furthermore, we demonstrate that FcγRIII exist as three distinct haplotypes in mice, FcγRIII:H, FcγRIII:V and FcγRIII:T. Mice expressing the FcγRIII:H haplotype are more susceptible to CIA than mice expressing the FcγRIII:V haplotype, indicating that certain FcγRIII haplotype predisposes for CIA. We also show that the most likely FcγRIII-expressing effector cell in CIA is the macrophage, since FcγRIII-expressing macrophages exclusively can induce arthritis in FcγRIII-deficient mice challenged for CIA.

    The complement system was also investigated in development of CIA. We found that this effector pathway is also necessary for onset of arthritis, as CIA was inhibited by treatment with anti-complement factor 5 (C5) antibodies. C5-deficient mice could neither develop CIA unless provided with C5-containing sera.

    Taken together, the work presented in this thesis indicates that FcγRs and the complement system are crucial for the induction of experimental arthritis. These findings are important for understanding the mechanisms behind rheumatoid arthritis and blocking of these effector pathways may in the future be used as treatment of rheumatoid arthritis.

    List of papers
    1. Expression of FcγRIII is required for development of collagen-induced arthritis
    Open this publication in new window or tab >>Expression of FcγRIII is required for development of collagen-induced arthritis
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    2002 In: European Journal of Immunology, Vol. 32, p. 2915-2922Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92480 (URN)
    Available from: 2005-01-14 Created: 2005-01-14Bibliographically approved
    2. FcγRIII-expressing macrophages are essential for the development of collagen-induced arthritis
    Open this publication in new window or tab >>FcγRIII-expressing macrophages are essential for the development of collagen-induced arthritis
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-92481 (URN)
    Available from: 2005-01-14 Created: 2005-01-14 Last updated: 2010-01-13Bibliographically approved
    3. Induction of arthritis by single monoclonal IgG anti-collagen type II antibodies and enhancement of arthritis in mice lacking inhibitory FcγRIIB
    Open this publication in new window or tab >>Induction of arthritis by single monoclonal IgG anti-collagen type II antibodies and enhancement of arthritis in mice lacking inhibitory FcγRIIB
    Show others...
    2003 In: European Journal of Immunology, Vol. 33, p. 2269-2277Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92482 (URN)
    Available from: 2005-01-14 Created: 2005-01-14Bibliographically approved
    4. IgG Fc receptor polymorphisms and C5 influence susceptibility to collagen-induced arthritis
    Open this publication in new window or tab >>IgG Fc receptor polymorphisms and C5 influence susceptibility to collagen-induced arthritis
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-92483 (URN)
    Available from: 2005-01-14 Created: 2005-01-14Bibliographically approved
    Download full text (pdf)
    FULLTEXT01
  • 163.
    Andrén, Maria
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Molekylär immunologi.
    Johanneson, Bo
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Alarcon Riquelme, Marta E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Medicinsk Genetik.
    Kleinau, Sandra
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology. Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Molekylär immunologi.
    IgG Fc receptor polymorphisms and association with autoimmune disease.2005In: Eur J Immunol, ISSN 0014-2980, Vol. 35, no 10, p. 3020-9Article in journal (Other (popular scientific, debate etc.))
  • 164.
    Andrén, Maria
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Johanneson, Bo
    Alarcón-Riquelme, Marta
    Kleinau, Sandra
    IgG Fc receptor polymorphisms and C5 influence susceptibility to collagen-induced arthritisArticle in journal (Refereed)
  • 165.
    Andrén, Maria
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Xiang, Zou
    Nilsson, Gunnar
    Kleinau, Sandra
    FcγRIII-expressing macrophages are essential for the development of collagen-induced arthritisManuscript (Other academic)
  • 166.
    Anneren, G.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Folsyra bör ges till alla gravida. God försäkring mot neuralrörsdefekt hos barnet.1995In: Läkartidningen, Vol. 92, p. 499-Article in journal (Other scientific)
  • 167.
    Anneren, G.
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Bull, MJ
    Guyda, HJ
    Mortimer, J
    Pueschel, SM
    Statement for parents on Growth Hormone treatment for children with Down syndrome.1996In: Down syndrome quartely, Vol. 1, p. 9-Article in journal (Refereed)
  • 168.
    Anneren, G
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Tuvemo, T
    Department of Women's and Children's Health.
    Carlsson-Skwirut, C
    Lonnerholm, T
    Department of Oncology, Radiology and Clinical Immunology.
    Bang, P
    Sara, VR
    Gustafsson, J
    Department of Women's and Children's Health.
    Growth hormone treatment in young children with Down's syndrome: effects on growth and psychomotor development.1999In: Arch. Dis. Child., Vol. 80, p. 334-Article in journal (Refereed)
  • 169.
    Anneren, G
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Tuvemo, T
    Department of Women's and Children's Health.
    Gustafsson, J
    Department of Women's and Children's Health.
    Growth hormone therapy in young children with Down's syndome and a clinical comparison of Down and Prader-Willi syndromes2000In: Growth Hormone & IGF Research, Vol. suppl B, p. 87-Article in journal (Refereed)
  • 170.
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    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
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    Department of Women's and Children's Health.
    Thyroid function in Down syndrome: relation to age and thyroid autoimmunity.1999In: Arch. Dis. Child., Vol. 81Article in journal (Refereed)
  • 171.
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    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Downs syndrom.1997In: En bok för föräldrar och personal.Book (Other scientific)
  • 172.
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    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Medicinskt och psykologiskt omhändertagande av Downs syndrom. Sävstaholmsföreningen, Mot bättre vetande!? - hur använda ökade kunskaper i en sämre samhällsekonomi?1996In: Symposium Linköping -95 Stockholm -96, SävstaholmsföreningenOther (Other scientific)
  • 173.
    Annerén, G.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Mental retardation. In: Barnhabilitering1998Book (Other scientific)
  • 174.
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    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
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    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Genetik, utredning och rådgivning vid neuromuskelära sjukdomar. In. Barnhabilitering. Eds Bille B, Olow I1999Book (Other scientific)
  • 175.
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    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    The genetic basis of severe mental retardation2001In: European J Paediatr Neurol, Vol. 5, p. A32-Article, book review (Other scientific)
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    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Uddenfeldt, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Janols, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Asperger syndrome in a boy with a balanced de novo translocation: t(17;19)(p13.3;p11)1995In: American Journal of Medical Genetics, ISSN 0148-7299, E-ISSN 1096-8628, Vol. 56, no 3, p. 330p. 330-1Article in journal (Other academic)
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    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hedov, Gerth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wester, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Downs syndrom: ny kunskap ställer höga krav på medicinsk vård och habilitering1999In: Socialmedicinsk Tidskrift, ISSN 0037-833X, Vol. 76, no 1, p. 71-79Article in journal (Other academic)
  • 179.
    Annerén, Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Meurling, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lilja, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wallander, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    von Döbeln, Ulrika
    Lethal autosomal recessive syndrome with intrauterine growth retardation, intra- and extrahepatic biliary atresia, and esophageal and duodenal atresia1998In: American Journal of Medical Genetics, ISSN 0148-7299, E-ISSN 1096-8628, Vol. 78, no 3, p. 306-307Article in journal (Refereed)
  • 180. Antoniou, Antonis C
    et al.
    Sinilnikova, M
    McGuffog, Lesley
    Healey, Sue
    Nevanlinna, Heli
    Heikkinen, Tuomas
    Simard, Jacques
    Spurdle, B
    Beesley, Jonathan
    Chen, Xiaoqing
    Neuhausen, L
    Ding, C
    Couch, J
    Wang, Xianshu
    Fredericksen, Zachary
    Peterlongo, Paolo
    Peissel, Bernard
    Bonanni, Bernardo
    Viel, Alessandra
    Bernard, Loris
    Radice, Paolo
    Szabo, I
    Foretova, Lenka
    Zikan, Michal
    Claes, Kathleen
    Greene, H
    Mai, L
    Rennert, Gad
    Lejbkowicz, Flavio
    Andrulis, L
    Ozcelik, Hilmi
    Glendon, Gord
    Gerdes, Anne-Marie
    Thomassen, Mads
    Sunde, Lone
    Caligo, A
    Laitman, Yael
    Kontorovich, Tair
    Cohen, Shimrit
    Kaufman, Bella
    Dagan, Efrat
    Baruch, Gershoni
    Friedman, Eitan
    Harbst, Katja
    Barbany-Bustinza, Gisela
    Rantala, Johanna
    Ehrencrona, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Karlsson, Per
    Domchek, M
    Nathanson, L
    Osorio, Ana
    Blanco, Ignacio
    Lasa, Adriana
    Benitez, Javier
    Hamann, Ute
    Hogervorst, L
    Rookus, A
    Collee, Margriet
    Devilee, Peter
    Ligtenberg, J
    van der Luijt, B
    Aalfs, M
    Waisfisz, Quinten
    Wijnen, Juul
    van Roozendaal, P
    Peock, Susan
    Cook, Margaret
    Frost, Debra
    Oliver, Clare
    Platte, Radka
    Evans, Gareth
    Lalloo, Fiona
    Eeles, Rosalind
    Izatt, Louise
    Davidson, Rosemarie
    Chu, Carol
    Eccles, Diana
    Cole, Trevor
    Hodgson, Shirley
    Godwin, K
    Stoppa-Lyonnet, Dominique
    Buecher, Bruno
    Leone, Melanie
    Bressac-de Paillerets, Brigitte
    Remenieras, Audrey
    Caron, Olivier
    Lenoir, M
    Sevenet, Nicolas
    Longy, Michel
    Ferrer, Fert
    Prieur, Fabienne
    Goldgar, David
    Miron, Alexander
    John, M
    Buys, S
    Daly, B
    Hopper, L
    Terry, Beth
    Yassin, Yosuf
    Singer, Christian
    Gschwantler-Kaulich, Daphne
    Staudigl, Christine
    Hansen, O
    Barkardottir, Bjork
    Kirchhoff, Tomas
    Pal, Prodipto
    Kosarin, Kristi
    Offit, Kenneth
    Piedmonte, Marion
    Rodriguez, C
    Wakeley, Katie
    Boggess, F
    Basil, Jack
    Schwartz, E
    Blank, V
    Toland, E
    Montagna, Marco
    Casella, Cinzia
    Imyanitov, N
    Allavena, Anna
    Schmutzler, K
    Versmold, Beatrix
    Engel, Christoph
    Meindl, Alfons
    Ditsch, Nina
    Arnold, Norbert
    Niederacher, Dieter
    Deissler, Helmut
    Fiebig, Britta
    Suttner, Christian
    Schoenbuchner, Ines
    Gadzicki, Dorothea
    Caldes, Trinidad
    de la Hoya, Miguel
    Pooley, A
    Easton, F
    Chenevix-Trench, Georgia
    Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers2009In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 18, no 22, p. 4442-4456Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

  • 181. Antoniou, Antonis C.
    et al.
    Wang, Xianshu
    Fredericksen, Zachary S.
    McGuffog, Lesley
    Tarrell, Robert
    Sinilnikova, Olga M.
    Healey, Sue
    Morrison, Jonathan
    Kartsonaki, Christiana
    Lesnick, Timothy
    Ghoussaini, Maya
    Barrowdale, Daniel
    Peock, Susan
    Cook, Margaret
    Oliver, Clare
    Frost, Debra
    Eccles, Diana
    Evans, D. Gareth
    Eeles, Ros
    Izatt, Louise
    Chu, Carol
    Douglas, Fiona
    Paterson, Joan
    Stoppa-Lyonnet, Dominique
    Houdayer, Claude
    Mazoyer, Sylvie
    Giraud, Sophie
    Lasset, Christine
    Remenieras, Audrey
    Caron, Olivier
    Hardouin, Agnes
    Berthet, Pascaline
    Hogervorst, Frans B. L.
    Rookus, Matti A.
    Jager, Agnes
    van den Ouweland, Ans
    Hoogerbrugge, Nicoline
    van der Luijt, Rob B.
    Meijers-Heijboer, Hanne
    Garcia, Encarna B. Gomez
    Devilee, Peter
    Vreeswijk, Maaike P. G.
    Lubinski, Jan
    Jakubowska, Anna
    Gronwald, Jacek
    Huzarski, Tomasz
    Byrski, Tomasz
    Gorski, Bohdan
    Cybulski, Cezary
    Spurdle, Amanda B.
    Holland, Helene
    Goldgar, David E.
    John, Esther M.
    Hopper, John L.
    Southey, Melissa
    Buys, Saundra S.
    Daly, Mary B.
    Terry, Mary-Beth
    Schmutzler, Rita K.
    Wappenschmidt, Barbara
    Engel, Christoph
    Meindl, Alfons
    Preisler-Adams, Sabine
    Arnold, Norbert
    Niederacher, Dieter
    Sutter, Christian
    Domchek, Susan M.
    Nathanson, Katherine L.
    Rebbeck, Timothy
    Blum, Joanne L.
    Piedmonte, Marion
    Rodriguez, Gustavo C.
    Wakeley, Katie
    Boggess, John F.
    Basil, Jack
    Blank, Stephanie V.
    Friedman, Eitan
    Kaufman, Bella
    Laitman, Yael
    Milgrom, Roni
    Andrulis, Irene L.
    Glendon, Gord
    Ozcelik, Hilmi
    Kirchhoff, Tomas
    Vijai, Joseph
    Gaudet, Mia M.
    Altshuler, David
    Guiducci, Candace
    Loman, Niklas
    Harbst, Katja
    Rantala, Johanna
    Ehrencrona, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Gerdes, Anne-Marie
    Thomassen, Mads
    Sunde, Lone
    Peterlongo, Paolo
    Manoukian, Siranoush
    Bonanni, Bernardo
    Viel, Alessandra
    Radice, Paolo
    Caldes, Trinidad
    de la Hoya, Miguel
    Singer, Christian F.
    Fink-Retter, Anneliese
    Greene, Mark H.
    Mai, Phuong L.
    Loud, Jennifer T.
    Guidugli, Lucia
    Lindor, Noralane M.
    Hansen, Thomas V. O.
    Nielsen, Finn C.
    Blanco, Ignacio
    Lazaro, Conxi
    Garber, Judy
    Ramus, Susan J.
    Gayther, Simon A.
    Phelan, Catherine
    Narod, Stephen
    Szabo, Csilla I.
    Benitez, Javier
    Osorio, Ana
    Nevanlinna, Heli
    Heikkinen, Tuomas
    Caligo, Maria A.
    Beattie, Mary S.
    Hamann, Ute
    Godwin, Andrew K.
    Montagna, Marco
    Casella, Cinzia
    Neuhausen, Susan L.
    Karlan, Beth Y.
    Tung, Nadine
    Toland, Amanda E.
    Weitzel, Jeffrey
    Olopade, Olofunmilayo
    Simard, Jacques
    Soucy, Penny
    Rubinstein, Wendy S.
    Arason, Adalgeir
    Rennert, Gad
    Martin, Nicholas G.
    Montgomery, Grant W.
    Chang-Claude, Jenny
    Flesch-Janys, Dieter
    Brauch, Hiltrud
    Severi, Gianluca
    Baglietto, Laura
    Cox, Angela
    Cross, Simon S.
    Miron, Penelope
    Gerty, Sue M.
    Tapper, William
    Yannoukakos, Drakoulis
    Fountzilas, George
    Fasching, Peter A.
    Beckmann, Matthias W.
    Silva, Isabel dos Santos
    Peto, Julian
    Lambrechts, Diether
    Paridaens, Robert
    Ruediger, Thomas
    Foersti, Asta
    Winqvist, Robert
    Pylkaes, Katri
    Diasio, Robert B.
    Lee, Adam M.
    Eckel-Passow, Jeanette
    Vachon, Celine
    Blows, Fiona
    Driver, Kristy
    Dunning, Alison
    Pharoah, Paul P. D.
    Offit, Kenneth
    Pankratz, V. Shane
    Hakonarson, Hakon
    Chenevix-Trench, Georgia
    Easton, Douglas F.
    Couch, Fergus J.
    A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population2010In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 42, no 10, p. 885-892Article in journal (Refereed)
    Abstract [en]

    Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P-trend = 2.3 x 10(-9) to Ptrend = 3.9 x 10(-7)), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P-trend = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P-trend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 x 10(-7) to Ptrend = 8 x 10(-5); rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P-trend = 1.1 x 10(-7)).

  • 182.
    Antson, Dan-Oscar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Genotyping RNA and DNA using padlock probes2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Novel techniques are needed to investigate the genetic variation revealed in the first draft of the human genome sequence. Padlock probes are recently developed reagents, suitable for detecting single-nucleotide variations of DNA and RNA in situ or in solution. The probes are oligonucleotides of about 70-140 nucleotides that can be circularized by ligation in the presence of a correct target sequence. Standard chemical synthesis of padlock probes is difficult due to the requirement for intact 5' and 3' ends of these long oligonucleotides.

    A novel PCR-based method is presented in this thesis, whereby longer, densely labeled padlock probes can be made as compared to conventional chemical synthesis. PCR-generated padlock probes produced a stronger signal and a more resolved staining pattern, compared to chemically synthesized probes in fluorescence in situ analysis of an alpha-satellite sequence variant present in human chromosomes 13 and 21. Padlock probes used for in situ analysis of metaphase chromosomes had an optimal length of 140 nucleotides. They were used to identify individual chromosomes 7 and 15, and to follow the transmission of chromosome homologues for two consecutive generations. The specificity of the padlock probes to detect single copy genes in genomic DNA samples was demonstrated by detecting a single-nucleotide mutation in the ATP7B gene.

    It has not previously been known if T4 DNA ligase can be used for RNA sequence analysis. In this thesis, it is demonstrated that T4 DNA ligase can be used for distinguishing single-nucleotide RNA sequence variants. Reaction conditions were defined where most mismatches could be discriminated by a factor of 80 and all mismatches by a factor of at least 20. Under these conditions padlock probes could detect and distinguish RNA sequence variants with ligation efficiency almost as high as on the corresponding DNA sequence.

    A detailed study of the parameters influencing RNA-templated DNA ligation revealed that DNA ligation on RNA templates proceeds at a much slower rate compared to the same reaction on DNA, and that a molar excess of enzyme is required. Furthermore, the ligation reaction is inhibited by high concentrations of the cofactor ATP and NaCl.

    The work presented in this thesis demonstrates that PCR-generated padlock probes can detect and distinguish single-nucleotide variation in both RNA and DNA.

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  • 183.
    Antson, D.O.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Isaksson, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    PCR-generated padlock probes detect single nucleotide variation in genomic DNA2000In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 28, no 12, p. E58-Article in journal (Refereed)
    Abstract [en]

    Circularizing oligonucleotide probes, so-called padlock probes, have properties that should prove valuable in a wide range of genetic investigations, including in situ analyses, genotyping and measurement of gene expression. However, padlock probes can be difficult to obtain by standard oligonucleotide synthesis because they are relatively long and require intact 5'- and 3'-end sequences to function. We describe a PCR-based protocol for flexible small-scale enzymatic synthesis of such probes. The protocol also offers the advantage over chemical synthesis that longer probes can be made that are densely labeled with detectable functions, resulting in an increased detection signal. The utility of probes synthesized according to this protocol is demonstrated for the analysis of single nucleotide variations in human genomic DNA both in situ and in solution.

  • 184.
    Antson, DO
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Mendel-Hartvig, M
    Landegren, U
    Nilsson, M
    PCR-generated padlock probes distinguish homologous chromosomes throughquantitative fluorescence analysis.2003In: Eur J Hum Genet, Vol. 11, p. 357-Article in journal (Refereed)
  • 185. Anttonen, Anna-Kaisa
    et al.
    Mahjneh, Ibrahim
    Hämäläinen, Riikka H
    Lagier-Tourenne, Clotilde
    Kopra, Outi
    Waris, Laura
    Anttonen, Mikko
    Joensuu, Tarja
    Kalimo, Hannu
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Paetau, Anders
    Tranebjaerg, Lisbeth
    Chaigne, Denys
    Koenig, Michel
    Eeg-Olofsson, Orvar
    Department of Women's and Children's Health.
    Udd, Bjarne
    Somer, Mirja
    Somer, Hannu
    Lehesjoki, Anna-Elina
    The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone.2005In: Nat Genet, ISSN 1061-4036, Vol. 37, no 12, p. 1309-11Article in journal (Refereed)
  • 186.
    Applequist, SE
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Dahlstrom, J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Jiang, N
    Molina, H
    Heyman, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Antibody production in mice deficient for complement receptors 1 and 2 canbe induced by IgG/Ag and IgE/Ag, but not IgM/Ag complexes.2000In: J Immunol, Vol. 165, p. 2398-Article in journal (Refereed)
  • 187. Apweiler, Rolf
    et al.
    Aslanidis, Charalampos
    Deufel, Thomas
    Gerstner, Andreas
    Hansen, Jens
    Hochstrasser, Dennis
    Kellner, Roland
    Kubicek, Markus
    Lottspeich, Friedrich
    Maser, Edmund
    Mewes, Hans-Werner
    Meyer, Helmut E.
    Müllner, Stefan
    Mutter, Wolfgang
    Neumaier, Michael
    Nollau, Peter
    Nothwang, Hans G.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Radbruch, Andreas
    Reinert, Knut
    Rothe, Gregor
    Stockinger, Hannes
    Tarnok, Attila
    Taussig, Mike J.
    Thiel, Andreas
    Thiery, Joachim
    Ueffing, Marius
    Valet, Günther
    Vandekerckhove, Joel
    Verhuven, Wiltrud
    Wagener, Christoph
    Wagner, Oswald
    Schmitz, Gerd
    Approaching clinical proteomics: current state and future fields of application in fluid proteomics2009In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 47, no 6, p. 724-744Article, review/survey (Refereed)
    Abstract [en]

    The field of clinical proteomics offers opportunities to identify new disease biomarkers in body fluids, cells and tissues. These biomarkers can be used in clinical applications for diagnosis, stratification of patients for specific treatment, or therapy monitoring. New protein array formats and improved spectrometry technologies have brought these analyses to a level with potential for use in clinical diagnostics. The nature of the human body fluid proteome with its large dynamic range of protein concentrations presents problems with quantitation. The extreme complexity of the proteome in body fluids presents enormous challenges and requires the establishment of standard operating procedures for handling of specimens, increasing sensitivity for detection and bioinformatical tools for distribution of proteomic data into the public domain. From studies of in vitro diagnostics, especially in clinical chemistry, it is evident that most errors occur in the preanalytical phase and during implementation of the diagnostic strategy. This is also true for clinical proteomics, and especially for fluid proteomics because of the multiple pretreatment processes. These processes include depletion of high-abundance proteins from plasma or enrichment processes for urine where biological variation or differences in proteolytic activities in the sample along with preanalytical variables such as inter- and intra-assay variability will likely influence the results of proteomics studies. However, before proteomic analysis can be introduced at a broader level into the clinical setting, standardization of the preanalytical phase including patient preparation, sample collection, sample preparation, sample storage, measurement and data analysis needs to be improved. In this review, we discuss the recent technological advances and applications that fulfil the criteria for clinical proteomics, with the focus on fluid proteomics. These advances relate to preanalytical factors, analytical standardization and quality-control measures required for effective implementation into routine laboratory testing in order to generate clinically useful information. With new disease biomarker candidates, it will be crucial to design and perform clinical studies that can identify novel diagnostic strategies based on these techniques, and to validate their impact on clinical decision-making.

  • 188. Apweiler, Rolf
    et al.
    Aslanidis, Charalampos
    Deufel, Thomas
    Gerstner, Andreas
    Hansen, Jens
    Hochstrasser, Dennis
    Kellner, Roland
    Kubicek, Markus
    Lottspeich, Friedrich
    Maser, Edmund
    Mewes, Hans-Werner
    Meyer, Helmut E.
    Müllner, Stefan
    Mutter, Wolfgang
    Neumaier, Michael
    Nollau, Peter
    Nothwang, Hans G.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Radbruch, Andreas
    Reinert, Knut
    Rothe, Gregor
    Stockinger, Hannes
    Tárnok, Attila
    Taussig, Mike J.
    Thiel, Andreas
    Thiery, Joachim
    Ueffing, Marius
    Valet, Günther
    Vandekerckhove, Joel
    Wagener, Christoph
    Wagner, Oswald
    Schmitz, Gerd
    Approaching clinical proteomics: current state and future fields of application in cellular proteomics2009In: Cytometry. Part A : the journal of the International Society for Analytical Cytology, ISSN 1552-4922, Vol. 75A, no 10, p. 816-832Article, review/survey (Refereed)
    Abstract [en]

    Recent developments in proteomics technology offer new opportunities for clinical applications in hospital or specialized laboratories including the identification of novel biomarkers, monitoring of disease, detecting adverse effects of drugs, and environmental hazards. Advanced spectrometry technologies and the development of new protein array formats have brought these analyses to a standard, which now has the potential to be used in clinical diagnostics. Besides standardization of methodologies and distribution of proteomic data into public databases, the nature of the human body fluid proteome with its high dynamic range in protein concentrations, its quantitation problems, and its extreme complexity present enormous challenges. Molecular cell biology (cytomics) with its link to proteomics is a new fast moving scientific field, which addresses functional cell analysis and bioinformatic approaches to search for novel cellular proteomic biomarkers or their release products into body fluids that provide better insight into the enormous biocomplexity of disease processes and are suitable for patient stratification, therapeutic monitoring, and prediction of prognosis. Experience from studies of in vitro diagnostics and especially in clinical chemistry showed that the majority of errors occurs in the preanalytical phase and the setup of the diagnostic strategy. This is also true for clinical proteomics where similar preanalytical variables such as inter- and intra-assay variability due to biological variations or proteolytical activities in the sample will most likely also influence the results of proteomics studies. However, before complex proteomic analysis can be introduced at a broader level into the clinic, standardization of the preanalytical phase including patient preparation, sample collection, sample preparation, sample storage, measurement, and data analysis is another issue which has to be improved. In this report, we discuss the recent advances and applications that fulfill the criteria for clinical proteomics with the focus on cellular proteomics (cytoproteomics) as related to preanalytical and analytical standardization and to quality control measures required for effective implementation of these technologies and analytes into routine laboratory testing to generate novel actionable health information. It will then be crucial to design and carry out clinical studies that can eventually identify novel clinical diagnostic strategies based on these techniques and validate their impact on clinical decision making.

  • 189. Arabi, Azadeh
    et al.
    Wu, Siqin
    Ridderstråle, Karin
    Bierhoff, Holger
    Shiue, Chiounan
    Fatyol, Karoly
    Fahlén, Sara
    Hydbring, Per
    Söderberg, Ola
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Grummt, Ingrid
    Larsson, Lars-Gunnar
    Wright, Anthony P H
    c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription.2005In: Nat Cell Biol, ISSN 1465-7392, Vol. 7, no 3, p. 303-10Article in journal (Refereed)
  • 190. Arbiser, Jack L.
    et al.
    Govindarajan, Baskaran
    Bai, Xianhe
    Onda, Hiroaki
    Kazlauskas, Andrius
    Lim, So Dug
    Amin, Mahuk B.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Functional tyrosine kinase inhibitor profiling: a generally applicable method points to a novel role of platelet-derived growth factor receptor-beta in tuberous sclerosis2002In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 161, no 3, p. 781-786Article in journal (Refereed)
    Abstract [en]

    Tumors often exhibit activation of specific tyrosine kinases, which may allow targeting of therapy through inhibition of tyrosine kinase signaling. This strategy has been used successfully in the development of STI571 (gleevec), an inhibitor of bcr-abl tyrosine kinase that has been used successfully in the treatment of chronic myelogenous leukemia. STI571 also shows activity against c-kit and platelet-derived growth factor receptor-beta (PDGFRbeta) tyrosine kinase signaling, thus potentially expanding the number of tumors that may respond to it. We describe a simple and rapid method to assess functional activity of tyrosine kinase signaling that is broadly applicable to tumor types. As proof of principle, we have applied it to cells that serve as models of the autosomal-dominant tumor syndrome tuberous sclerosis (TS). We found that TS model cells derived from tuberin heterozygous mice and from a human renal angiomyolipoma are highly sensitive to PDGFR antagonists and that these cells express PDGFRbeta. Given that PDGFRbeta signaling is inhibited by STI571, we found that SV7tert human angiomyolipoma cells are sensitive to STI571. Thus, we describe a novel but simple method of determining the functional tyrosine kinase profile of a neoplastic cell and our results suggest that STI571 might be useful in the treatment of neoplasms commonly seen in patients with TS.

  • 191. Arbiser, JL
    et al.
    Larsson, H
    Claesson-Welsh, Lena
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Bai, X
    LaMontagne, K
    Weiss, SW
    Soker, S
    Flynn, E
    Brown, LF
    Overexpression of VEGF 121 in inmortalized endothelial cells causes conversion to slowly growing angiosarcoma and high level expression of the VEGF receptors VEGFR-1 and VEGFR-2 in vivo.2000In: Am. J. Pathol., Vol. 156, p. 1469-Article in journal (Refereed)
  • 192.
    Ardesjö, Brita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hansson, Caisa M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bruder, Carl E.G.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Betterle, Corrado
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Autoantibodies to Glutathione S-transferase theta 1 in patients with primary sclerosing cholangitis and other autoimmune diseases2008In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 30, no 4, p. 273-282Article in journal (Refereed)
    Abstract [en]

    Primary sclerosing cholangitis (PSC) is an enigmatic disorder with a suggested autoimmune basis. A variety of autoantigens have been suggested but no specific or highly directed epitope has been identified. To address this issue, we constructed a cDNA library from normal human choledochus and screened expressing clones with serum from a patient with PSC and inflammatory bowel disease (IBD). Based on this screening, glutathione S-transferase theta 1 (GSTT1) was identified as a potential autoantigenic target. To study the specificity of GSTT1, we determined immunoreactivity using a panel of 58 patients with PSC, with and without IBD, 57 patients with IBD, 31 patients with Hashimoto's thyroiditis, 30 patients with primary biliary cirrhosis (PBC), 20 patients with insulin dependent diabetes mellitus, 22 patients with autoimmune polyendocrine syndrome type 1, 10 patients with systemic lupus erythematosus (SLE), 20 patients with Sjogren's syndrome, 12 patients with autoimmune pancreatitis, 28 patients with Addison's disease, 27 patients with Grave's disease, 17 with myasthenia gravis, and 118 healthy controls. Reactivity against GSTT1 was found with PSC and IBD as well as some patients with other autoimmune pathology, indicating that this population of antibodies is neither specific nor a sensitive serologic marker for PSC, but the frequency was clearly higher in autoimmune patients than controls. GSTT1-antibodies have been described in persons with GSTT1-null genotype and are suggested to develop as an alloimmune response to blood transfusions from GSTT1-positive donors or pregnancies with GSTT1-positive children. Therefore, two IBD patients with and 15 PSC patients without GSTT1-antibodies were genotyped for GSTT1 to investigate if the presence of GSTT1-antibodies was associated with the GSTT1-null genotype and possibly caused by an alloimmune response. Both IBD patients and three of the PSC patients were of the GSTT1-null genotype. We note that the frequency of GSTT1-antibodies in this study is more than 100-fold higher than the frequency described earlier in patients with autoimmune diseases. We also observe an increased frequency of GSTT1-antibodies in patients with autoimmune diseases compared to healthy controls. This increased frequency can be explained by an autoimmune phenotype which increases susceptibility to such autoantibodies, or by a high frequency of the GSTT1-null genotype in autoimmune disease.

  • 193.
    Ardesjö, Brita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Portela-Gomes, Guida M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gerdin, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Lööf, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Immunoreactivity against goblet cells in patients with inflammatory bowel disease2008In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 14, no 5, p. 652-661Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A number of autoantibodies have been reported in inflammatory bowel disease (IBD). The aim of this study was to investigate to what extent sera from patients with IBD contain autoantibodies directed against normal human gastrointestinal mucosa. METHODS: Samples of sera from 50 patients with IBD and 50 healthy subjects were used for immunostaining of normal and affected human gastrointestinal tissues. RESULTS: Eighty-four percent of the sera from IBD patients showed immunoreactivity against goblet cells in the appendix compared with 8% of the sera from healthy subjects. Goblet cell reactivity of IBD patient sera varied between regions in the gastrointestinal tract. Sera from healthy subjects only reacted with goblet cells in the appendix. In the colon and the appendix, goblet cell reactivity of IBD sera was generally weak at the base of the crypts and gradually increased toward the lumen. Three IBD sera samples reacted with gastrin cells in the antrum. In colon biopsies from patients with ulcerative colitis, immunoreactivity against the remaining goblet cells showed an inverse correlation with inflammatory activity. CONCLUSIONS: These findings suggest that immunoreactivity against goblet cells may be of central importance in the pathogenesis of IBD. Identification of goblet cell antigens could lead to a better understanding of IBD and provide a new diagnostic tool.

  • 194.
    Ardesjö, Brita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Portela-Gomes, Guida M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Identification of a novel staining pattern of bile duct epithelial cells in primary sclerosing cholangitis2010In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 16, no 2, p. 305-311Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Primary sclerosing cholangitis (PSC) is an inflammatory disease of the bile ducts with an unknown etiology. A number of autoantigens have been proposed, but an early diagnostic marker is still lacking. Our aim was to identify such an autoantigen. METHODS: Immunostaining was performed on normal human bile duct with sera from patients with PSC and controls. To identify an autoantigen a cDNA library from normal human choledochus was constructed and immunoscreened with patient sera. Using in vitro transcription and translation and immunoprecipitation we examined the immunoreactivity against PDZ domain containing 1 (PDZK1) in 35 patients with PSC, 198 control patients, and 94 healthy controls. RESULTS: We observed a previously unpublished staining pattern in which cytoplasmatic granules and apical cell membranes of biliary epithelial cells were stained by PSC sera. Strong immunoreactivity to these structures was obtained with 12 out of 35 PSC sera (34%) but not with sera from healthy controls. By screening the cDNA library we identified PDZK1 as a candidate antigen. Immunoreactivity against PDZK1 was detected in 9% of PSC patients, 2% of inflammatory bowel disease (IBD) patients, 8% of autoimmune pancreatitis patients, 18% of Grave's disease patients, and 1% of healthy controls. CONCLUSIONS: Previously unpublished, specific, and strong autoantibodies against epithelial cells of the bile duct in PSC sera were identified. Furthermore, PDZK1 is suggested as a potential new autoantigen.

  • 195.
    Ardesjö Lundgren, Brita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Portela-Gomes, Guida M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ekwall, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Identification of complement C3 as an autoantigen in inflammatory bowel disease2010In: European Journal of Gastroenterology and Hepathology, ISSN 0954-691X, E-ISSN 1473-5687, Vol. 22, no 4, p. 429-436Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Autoantibodies against goblet cells in the gastrointestinal mucosa have been described in patients with inflammatory bowel disease (IBD) but a corresponding autoantigen has not yet been identified. The aim of this study was to identify such an antigen. METHODS: First, 10 candidate autoantigens were discarded based on double stainings of appendiceal sections and a mucin-producing cell line (HT29-mtx). Second, an appendiceal cDNA library was immunoscreened with IBD sera. RESULTS: Three out of 48 positive clones were identified as complement C3. Using immunoprecipitation of in vitro transcribed and translated C3, seven of 17 primary sclerosing cholangitis patient sera, 15 of 65 IBD sera, and none out of 54 sera from healthy blood donors showed C3 immunoreactivity. The results were confirmed using western blot and an enzyme-linked immunosorbent assay with alternative sources of C3 protein. CONCLUSION: In conclusion, we have identified complement C3 as a potential autoantigen in IBD and primary sclerosing cholangitis.

  • 196. Arkhammar, P
    et al.
    Juntti-Berggren, L
    Larsson, O
    Welsh, M
    Nanberg, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Sjoholm, A
    Kohler, M
    Berggren, PO
    Protein kinase C modulates the insulin secretory process by maintaining aproper function of the beta-cell voltage-activated Ca2+ channels.1994In: J Biol Chem, Vol. 269, p. 2743-Article in journal (Refereed)
  • 197.
    Arnell, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hjalmas, Kelm
    Jagervall, Martin
    Läckgren, Göran
    Stenberg, Arne
    Bengtsson, Bengt
    Wassen, Christer
    Emahazion, Tesfai
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sundvall, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    The genetics of primary nocturnal enuresis: inheritance and suggestion of a second major gene on chromosome 12q1997In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 34, no 5, p. 360-5Article in journal (Refereed)
    Abstract [en]

    Primary nocturnal enuresis (PNE), or bedwetting at night, affects approximately 10% of 6 year old children. Genetic components contribute to the pathogenesis and recently one locus was assigned to chromosome 13q. We evaluated the genetic factors and the pattern of inheritance for PNE in 392 families. Dominant transmission was observed in 43% and an apparent recessive mode of inheritance was observed in 9% of the families. Among the 392 probands the ratio of males to females was 3:1 indicating sex linked or sex influenced factors. Linkage to candidate regions was tested in 16 larger families segregating for autosomal dominant PNE. A gene for PNE was excluded from chromosome 13q in 11 families, whereas linkage to the interval D13S263-D13S291 was suggested (Zmax = 2.1) in three families. Further linkage analyses excluded about 1/3 of the genome at a 10 cM resolution except the region around D12S80 on chromosome 12q that showed a positive two point lod score in six of the families (Zmax = 4.2). This locus remains suggestive because the material was not sufficiently large to give evidence for heterogeneity. Our pedigree analysis indicates that major genes are involved in a large proportion of PNE families and the linkage results suggest that such a gene is located on chromosome 12q.

  • 198.
    Arnell, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mäntyjärvi, Maija
    Tuppurainen, Kaija
    Andreasson, Sten
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stargardt disease: linkage to the ABCR gene region on 1p21-p22 in Scandinavian families1998In: Acta Ophthalmologica Scandinavica, ISSN 1395-3907, E-ISSN 1600-0420, Vol. 76, no 6, p. 649-52Article in journal (Refereed)
    Abstract [en]

    Stargardt disease (STGD) or fundus flavimaculatus (FFM) is one of the most frequent causes of macular degeneration in childhood. The disease is inherited as an autosomal recessive trait and the corresponding gene has been localized to chromosome 1p21-22 and subsequently identified as the ATP-binding cassette transporter (ABCR) gene. PURPOSE: To characterize Finnish and Swedish STGD families genetically, with special reference to chromosome region 1p21-22. METHODS: We performed genetic linkage and haplotype analyses in five families of Finnish and Swedish origin with members affected by STGD or FFM. RESULTS: Evidence for linkage between STGD and the ABCR gene region on chromosome 1p was found with a maximum cumulative two-point lod score for marker D1S188 (Z=4.04, theta=0.001). The affected individuals of all families, including the offspring of a consanguineous family, were found heterozygous for haplotypes spanning the ABCR gene. CONCLUSION: The results support genetic homogeneity for a STGD/FFM gene defect on chromosome 1p21-22. A variety of haplotypes tightly linked to the ABCR gene region were found among affected individuals which indicate the presence of several independent STGD mutations in the Scandinavian population.

  • 199.
    Arnell, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Nemeth, Antal
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Progressive familial intrahepatic cholestasis (PFIC): evidence for genetic heterogeneity by exclusion of linkage to chromosome 18q21-q221997In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 100, no 3-4, p. 378-381Article in journal (Refereed)
    Abstract [en]

    Progressive familial intrahepatic cholestasis (PFIC) is the second most common form of familial intrahepatic cholestasis. The genes for PFIC and for a milder form of the disease, benign recurrent intrahepatic cholestasis (BRIC), were recently mapped to a 19-cM region on chromosome 18q21-q22. The results suggest that PFIC and BRIC are allelic diseases. We have studied 11 Swedish patients from eight families with clinical and biochemical features consistent with PFIC. The families were genotyped for markers D18S69, D18S64, D18S55 and D18S68, spanning the PFIC candidate region. Unexpectedly, the segregation of haplotypes excluded the entire region in three families, and no indications for shared haplotypes were found in the patients of the six remaining families. A four-point linkage analysis of all families excluded linkage from D18S69 to D18S55 (Zmax < -5). Thus, our data strongly suggest the presence of a second, yet unknown, locus for PFIC. The results indicate that great care should be taken when using 18q markers for prenatal diagnosis and genetic counseling for the disease.

  • 200. Arnelo, U
    et al.
    Blevins, JE
    Larsson, J
    Permert, J
    Westermark, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
    Reidelberger, RD
    Adrian, TE
    Effects of acute and chronic infusion of islet amyloid polypeptide on food intake in rats.1996In: Scand J Gastroenterol, Vol. 31, p. 83-Article in journal (Refereed)
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