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Lobell, Anna
Publications (10 of 22) Show all publications
Eriksson, D., Bianchi, M., Landegren, N., Nordin, J., Dalin, F., Mathioudaki, A., . . . Pielberg, G. R. (2016). Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease. Journal of Internal Medicine, 286(6), 595-608
Open this publication in new window or tab >>Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease
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2016 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 286, no 6, p. 595-608Article in journal (Refereed) Published
Abstract [en]

BackgroundAutoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. MethodsTo understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls. ResultsWe identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 x 10(-15), MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex. ConclusionWhilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.

Keywords
Addison Disease, BACH2 protein, genetic, genetic association studies, genetic predisposition to disease, human, polymorphism
National Category
General Practice
Identifiers
urn:nbn:se:uu:diva-311491 (URN)10.1111/joim.12569 (DOI)000388573300007 ()27807919 (PubMedID)
Funder
Swedish Research CouncilRagnar Söderbergs stiftelseTorsten Söderbergs stiftelseEU, European Research Council, 201167Stockholm County CouncilThe Karolinska Institutet's Research FoundationSwedish Society for Medical Research (SSMF)Swedish Society of MedicineNovo NordiskSwedish Research Council FormasSwedish Rheumatism AssociationÅke Wiberg FoundationAstraZeneca
Available from: 2016-12-28 Created: 2016-12-28 Last updated: 2018-01-13Bibliographically approved
Mitchell, A. L., Macarthur, K. D. R., Gan, E. H., Baggott, L. E., Wolff, A. S. B., Skinningsrud, B., . . . Pearce, S. H. S. (2014). Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts. PLoS ONE, 9(3), e88991
Open this publication in new window or tab >>Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 3, p. e88991-Article in journal (Refereed) Published
Abstract [en]

Background: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. Aim: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. Methods: A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. Results: We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-kappa B1 and IL23A genes in the UK and Italian cohorts respectively. Conclusions: Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-223893 (URN)10.1371/journal.pone.0088991 (DOI)000332839300009 ()
Available from: 2014-05-05 Created: 2014-04-28 Last updated: 2017-12-05Bibliographically approved
Ahlgren, K. M., Fall, T., Landegren, N., Grimelius, L., von Euler, H., Sundberg, K., . . . Kämpe, O. (2014). Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus. PLoS ONE, 9(8), e105473
Open this publication in new window or tab >>Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e105473-Article in journal (Refereed) Published
Abstract [en]

AIMS/HYPOTHESIS:

Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.

METHODS:

Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.

RESULTS:

None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.

CONCLUSIONS/INTERPRETATIONS:

Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-232422 (URN)10.1371/journal.pone.0105473 (DOI)000340952200053 ()25153886 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2014-09-17 Created: 2014-09-17 Last updated: 2017-12-05Bibliographically approved
Isaksson, M., Ardesjö Lundgren, B., Ahlgren, K. M., Kämpe, O. & Lobell, A. (2012). Conditional DC depletion does not affect priming of encephalitogenic Th cells in EAE. European Journal of Immunology, 42(10), 2555-2563
Open this publication in new window or tab >>Conditional DC depletion does not affect priming of encephalitogenic Th cells in EAE
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2012 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 42, no 10, p. 2555-2563Article in journal (Refereed) Published
Abstract [en]

EAE, an animal model for multiple sclerosis, is a Th17- and Th1-cell-mediated auto-immune disease, but the mechanisms leading to priming of encephalitogenicTcells in autoimmune neuroinflammation are poorly understood. To investigate the role of dendritic cells (DCs) in the initiation of autoimmuneTh17- andTh1-cell responses andEAE, we used mice transgenic for a simian diphtheria toxin receptor (DTR) expressed under the control of the murineCD11c promoter (CD11c-DTRmice onC57BL/6 background).EAEwas induced by immunization with myelin oligodendrocyte glycoprotein (MOG) protein in CFA. DCs were depleted on the day before and 8 days afterMOG immunization. The mean clinicalEAEscore was only mildly reduced inDC-depleted mice when DCs were ablated beforeEAEinduction. The frequency of activatedTh cells was not altered, andMOG-inducedTh17 orTh1-cell responses were not altered, in the spleens ofDC-depleted mice. Similar results were obtained ifDCswere ablated the first 10 days afterMOGimmunization with repeatedDCdepletions. Unexpectedly, transient depletion of DCs did not affect priming or differentiation of MOG-inducedTh17 andTh1-cell responses or the incidence ofEAE. Thus, the mechansim of priming ofTh cells inEAEremains to be elucidated.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-173266 (URN)10.1002/eji.201142239 (DOI)000309610200004 ()22806332 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2012-04-23 Created: 2012-04-21 Last updated: 2018-01-12Bibliographically approved
Ahlgren, K. M., Moretti, S., Lundgren, B. A., Karlsson, I., Åhlin, E., Norling, A., . . . Lobell, A. (2011). Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. European Journal of Immunology, 41(1), 235-245
Open this publication in new window or tab >>Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model
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2011 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 41, no 1, p. 235-245Article in journal (Refereed) Published
Abstract [en]

Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal failure are hallmarks of the disease. The critical mechanisms causing chronic mucocutaneous candidiasis in APS-1 patients have not been identified although autoantibodies to cytokines are implicated in the pathogenesis. To investigate whether the Th reactivity to Candida albicans (C. albicans) and other stimuli was altered, we isolated PBMC from APS-1 patients and matched healthy controls. The Th17 pathway was upregulated in response to C. albicans in APS-1 patients, whereas the IL-22 secretion was reduced. Autoantibodies against IL-22, IL-17A and IL-17F were detected in sera from APS-1 patients by immunoprecipitation. In addition, Aire-deficient (Aire(0/0) ) mice were much more susceptible than Aire(+/+) mice to mucosal candidiasis and C. albicans-induced Th17- and Th1-cell responses were increased in Aire(0/0) mice. Thus an excessive IL-17A reactivity towards C. albicans was observed in APS-1 patients and Aire(0/0) mice.

Keywords
Autoimmunity, Cytokines, Fungal, T cells
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-140180 (URN)10.1002/eji.200939883 (DOI)000285933000024 ()21182094 (PubMedID)
Available from: 2011-01-04 Created: 2011-01-04 Last updated: 2017-12-11Bibliographically approved
Israelsson, C., Bengtsson, H., Lobell, A., Nilsson, L. N. G., Kylberg, A., Isaksson, M., . . . Ebendal, T. (2010). Appearance of Cxcl10-expressing cell clusters is common for traumatic brain injury and neurodegenerative disorders. European Journal of Neuroscience, 31(5), 852-863
Open this publication in new window or tab >>Appearance of Cxcl10-expressing cell clusters is common for traumatic brain injury and neurodegenerative disorders
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2010 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 31, no 5, p. 852-863Article in journal (Refereed) Published
Abstract [en]

Traumatic brain injury (TBI) in the mouse results in the rapid appearance of scattered clusters of cells expressing the chemokine Cxcl10 in cortical and subcortical areas. To extend the observation of this unique pattern, we used neuropathological mouse models using quantitative reverse transcriptase-polymerase chain reaction, gene array analysis, in-situ hybridization and flow cytometry. As for TBI, cell clusters of 150–200 μm expressing Cxcl10 characterize the cerebral cortex of mice carrying a transgene encoding the Swedish mutation of amyloid precursor protein, a model of amyloid Alzheimer pathology. The same pattern was found in experimental autoimmune encephalomyelitis in mice modelling multiple sclerosis. In contrast, mice carrying a SOD1G93A mutant mimicking amyotrophic lateral sclerosis pathology lacked such cell clusters in the cerebral cortex, whereas clusters appeared in the brainstem and spinal cord. Mice homozygous for a null mutation of the Cxcl10 gene did not show detectable levels of Cxcl10 transcript after TBI, confirming the quantitative reverse transcriptase-polymerase chain reaction and in-situ hybridization signals. Moreover, unbiased microarray expression analysis showed that Cxcl10 was among 112 transcripts in the neocortex upregulated at least threefold in both TBI and ageing TgSwe mice, many of them involved in inflammation. The identity of the Cxcl10+ cells remains unclear but flow cytometry showed increased numbers of activated microglia/macrophages as well as myeloid dendritic cells in the TBI and experimental autoimmune encephalomyelitis models. It is concluded that the Cxcl10+ cells appear in the inflamed central nervous system and may represent a novel population of cells that it may be possible to target pharmacologically in a broad range of neurodegenerative conditions.

Keywords
Alzheimer's disease, chemokines, dendritic cells, experimental autoimmune encephalomyelitis, inflammation, mouse
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-123055 (URN)10.1111/j.1460-9568.2010.07105.x (DOI)000275096500008 ()20374285 (PubMedID)
Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2017-12-12Bibliographically approved
Isaksson, M., Ardesjö, B., Rönnblom, L., Kämpe, O., Lassmann, H., Eloranta, M.-L. & Lobell, A. (2009). Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE. European Journal of Immunology, 39(10), 2925-2935
Open this publication in new window or tab >>Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE
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2009 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 39, no 10, p. 2925-2935Article in journal (Refereed) Published
Abstract [en]

EAE, an animal model for MS, is a Th17 and Th1-cell-mediated autoimmune disease, but the mechanisms leading to priming of encephalitogenic T cells in autoimmune neuroinflammation are poorly understood. To investigate the role of plasmacytoid DC (pDC) in the initiation of autoimmune Th17- and Th1-cell responses and EAE, we depleted pDC with anti-pDC Ag-1 (anti-PDCA1) mAb prior to immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG). pDC-depleted mice developed less severe clinical and histopathological signs of EAE than control mice, which demonstrates a promoting role for pDC in the initiation of EAE. The levels of type I IFN were much lower in the sera from anti-PDCA1-treated mice. However, neutralization of type I IFN ameliorated the early phase of EAE but did not alter the severity of disease. Thus, only a minor part of the EAE-promoting effect of pDC appears to be mediated by IFN-alpha/beta secretion. The numbers of MOG-specific Th17 cells, but not Th1 cells, were lower in spleen from anti-PDCA1-treated mice compared with controls. In contrast, pDC depletion a week after MOG immunization resulted in more severe clinical signs of EAE. In conclusion, we demonstrate that pDC promote initiation of MOG-induced Th17-cell responses and EAE.

Keywords
Autoimmunity, DC, EAE/MS, T cells, Type I IFN
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-108362 (URN)10.1002/eji.200839179 (DOI)000271151000030 ()19637225 (PubMedID)
Available from: 2009-09-16 Created: 2009-09-16 Last updated: 2017-12-13Bibliographically approved
Marta, M., Meier, U. C. & Lobell, A. (2009). Regulation of autoimmune encephalomyelitis by toll-like receptors. Autoimmunity Reviews, 8(6), 506-509
Open this publication in new window or tab >>Regulation of autoimmune encephalomyelitis by toll-like receptors
2009 (English)In: Autoimmunity Reviews, ISSN 1568-9972, E-ISSN 1873-0183, Vol. 8, no 6, p. 506-509Article in journal (Refereed) Published
Abstract [en]

Experimental autoimmune encephalomyelitis (EAE) is a Th17-mediated autoimmune disease and an animal model for multiple sclerosis (MS). Complete Freund's adjuvant (CFA) contains pathogen-associated molecular patterns (PAMPs) that bind toll-like receptors (TLRs), and is necessary to induce EAE. Upstream TLR signals modify innate and adaptive immune responses in EAE. In detail, the common TLR adaptor molecule MyD88 is necessary for induction of EAE, and mediates activation of peripheral myeloid dendritic cells (mDCs) and differentiation of autoimmune Th17 cells. The stimulatory TLRs have not yet been identified for Th17 cells. TLR4 down regulates disease severity in EAE and Th17 cell responses, but promotes Th1 cell responses, which may inhibit the differentiation of Th17 cells. Moreover, treatment with a TLR4 ligand tolerizes mice and prevents EAE. TLR9 down regulates disease severity in myelin oligodendrocyte glycoprotein (MOG)-induced EAE, whereas it promotes disease in MOG(35-55)-induced EAE. Thus MyD88, TLR4 and TLR9 modify the disease process in EAE. Both endogenous and CFA-derived TLR ligands are implicated to modulate the disease process.

Keywords
central nervous system, b-cells, multiple-sclerosis, innate immunity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-102744 (URN)10.1016/j.autrev.2009.01.006 (DOI)000266683100013 ()19211042 (PubMedID)1873-0183 (Electronic) (ISBN)
Available from: 2009-05-12 Created: 2009-05-11 Last updated: 2017-12-13Bibliographically approved
Andersson, Å., Isaksson, M., Wefer, J., Norling, A., Flores-Morales, A., Rorsman, F., . . . Lobell, A. (2008). Impaired autoimmune T helper 17 cell responses following DNA vaccination against rat experimental autoimmune encephalomyelitis. PLoS ONE, 3(11), e3682
Open this publication in new window or tab >>Impaired autoimmune T helper 17 cell responses following DNA vaccination against rat experimental autoimmune encephalomyelitis
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2008 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 3, no 11, p. e3682-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: We have previously shown that vaccination with DNA encoding the encephalitogenic peptide myelin oligodendrocyte glycoprotein (MOG)(91-108) (pMOG) suppresses MOG(91-108)-induced rat Experimental Autoimmune Encephalomyelitis (EAE), a model for human Multiple Sclerosis (MS). The suppressive effect of pMOG is dependent on inclusion of CpG DNA in the plasmid backbone and is associated with early induction of Interferon (IFN)-beta. PRINCIPAL FINDINGS: In this study we examined the mechanisms underlying pMOG-induced protection. We found that in the DNA vaccinated cohort proinflammatory Interleukin (IL)-17 and IL-21 responses were dramatically reduced compared to in the control group, but that the expression of Foxp3 and Tumor Growth Factor (TGF)-beta1, which are associated with regulatory T cells, was not enhanced. Moreover, genes associated with Type I IFNs were upregulated. To delineate the role of IFN-beta in the protective mechanism we employed short interfering RNA (siRNA) to IFN-beta in the DNA vaccine. SiRNA to IFN-beta completely abrogated the protective effects of the vaccine, demonstrating that a local early elaboration of IFN-beta is important for EAE protection. IL-17 responses comparable to those in control rats developed in rats injected with the IFN-beta-silencing DNA vaccine. CONCLUSIONS: We herein demonstrate that DNA vaccination protects from proinflammatory Th17 cell responses during induction of EAE. The mechanism involves IFN-beta as IL-17 responses are rescued by silencing of IFN-beta during DNA vaccination.

Place, publisher, year, edition, pages
PLoS, 2008
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-102743 (URN)10.1371/journal.pone.0003682 (DOI)000265165500005 ()18997868 (PubMedID)1932-6203 (Electronic) (ISBN)
Available from: 2009-05-12 Created: 2009-05-11 Last updated: 2012-08-01Bibliographically approved
Kisand, K., Link, M., Wolff, A. S., Meager, A., Tserel, L., Org, T., . . . Peterson, P. (2008). Interferon autoantibodies associated with AIRE-deficiency decrease the expression of IFN-stimulated genes. Blood, 112(7), 2657-2666
Open this publication in new window or tab >>Interferon autoantibodies associated with AIRE-deficiency decrease the expression of IFN-stimulated genes
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2008 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 112, no 7, p. 2657-2666Article in journal (Refereed) Published
Abstract [en]

Neutralizing autoantibodies to type I, but not type II, interferons (IFNs) are found at high titers in almost every patient with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a disease caused by AIRE gene mutations that lead to defects in thymic T-cell selection. Combining genome-wide expression array with real time RT-PCR assays, we here demonstrate that antibodies against IFN-alpha cause highly significant down-regulation of interferon-stimulated gene expression in cells from APECED patients' blood by blocking their highly dilute endogenous IFNs. This down-regulation was lost progressively as these APECED cells matured in cultures without neutralizing autoantibodies. Most interestingly, a rare APECED patient with autoantibodies to IFN-omega but not IFN-alpha showed a marked increase in expression of the same interferon-stimulated genes. We also report unexpected increases in serum CXCL10 levels in APECED. Our results argue that the breakdown of tolerance to IFNs in AIRE deficiency is associated with impaired responses to them in thymus, and highlight APECED as another autoimmune disease with associated dysregulation of IFN activity.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-17670 (URN)10.1182/blood-2008-03-144634 (DOI)000259402600018 ()18606876 (PubMedID)
Available from: 2008-08-12 Created: 2008-08-12 Last updated: 2017-12-08Bibliographically approved
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