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Publications (10 of 96) Show all publications
Lundtoft, C., Eriksson, D., Bianchi, M., Aranda-Guillen, M., Landegren, N., Rantapää-Dahlqvist, S., . . . Kämpe, O. (2023). Relation between HLA and copy number variation of steroid 21-hydroxylase in a Swedish cohort of patients with autoimmune Addison's disease. European Journal of Endocrinology, 189(2), 235-241
Open this publication in new window or tab >>Relation between HLA and copy number variation of steroid 21-hydroxylase in a Swedish cohort of patients with autoimmune Addison's disease
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2023 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 189, no 2, p. 235-241Article in journal (Refereed) Published
Abstract [en]

Objective Autoantibodies against the adrenal enzyme 21-hydroxylase is a hallmark manifestation in autoimmune Addison's disease (AAD). Steroid 21-hydroxylase is encoded by CYP21A2, which is located in the human leucocyte antigen (HLA) region together with the highly similar pseudogene CYP21A1P. A high level of copy number variation is seen for the 2 genes, and therefore, we asked whether genetic variation of the CYP21 genes is associated with AAD.

Design Case-control study on patients with AAD and healthy controls.

Methods Using next-generation DNA sequencing, we estimated the copy number of CYP21A2 and CYP21A1P, together with HLA alleles, in 479 Swedish patients with AAD and autoantibodies against 21-hydroxylase and in 1393 healthy controls.

Results With 95% of individuals carrying 2 functional 21-hydroxylase genes, no difference in CYP21A2 copy number was found when comparing patients and controls. In contrast, we discovered a lower copy number of the pseudogene CYP21A1P among AAD patients (P = 5 x 10(-44)), together with associations of additional nucleotide variants, in the CYP21 region. However, the strongest association was found for HLA-DQB1*02:01 (P = 9 x 10(-63)), which, in combination with the DRB1*04:04-DQB1*03:02 haplotype, imposed the greatest risk of AAD.

Conclusions We identified strong associations between copy number variants in the CYP21 region and risk of AAD, although these associations most likely are due to linkage disequilibrium with disease-associated HLA class II alleles.

Place, publisher, year, edition, pages
Oxford University Press, 2023
Keywords
Addison's disease, autoimmune disease, autoantibodies, genetics
National Category
Endocrinology and Diabetes Medical Genetics
Identifiers
urn:nbn:se:uu:diva-511065 (URN)10.1093/ejendo/lvad102 (DOI)001051537400001 ()37553728 (PubMedID)
Funder
Science for Life Laboratory, SciLifeLabKnut and Alice Wallenberg FoundationNovo Nordisk Foundation
Available from: 2023-09-07 Created: 2023-09-07 Last updated: 2023-09-07Bibliographically approved
Lind, A., Eriksson, D., Akel, O., Ramelius, A., Palm, L., Lernmark, A., . . . Landegren, N. (2020). Screening for autoantibody targets in post-vaccination narcolepsy using proteome arrays. Scandinavian Journal of Immunology, 91(4), Article ID e12864.
Open this publication in new window or tab >>Screening for autoantibody targets in post-vaccination narcolepsy using proteome arrays
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2020 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 91, no 4, article id e12864Article in journal (Refereed) Published
Abstract [en]

Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a specific loss of hypocretin‐producing neurons. The incidence of NT1 increased in Sweden, Finland and Norway following Pandemrix®‐vaccination, initiated to prevent the 2009 influenza pandemic. The pathogenesis of NT1 is poorly understood, and causal links to vaccination are yet to be clarified. The strong association with Human leukocyte antigen (HLA) DQB1*06:02 suggests an autoimmune pathogenesis, but proposed autoantigens remain controversial. We used a two‐step approach to identify autoantigens in patients that acquired NT1 after Pandemrix®‐vaccination. Using arrays of more than 9000 full‐length human proteins, we screened the sera of 10 patients and 24 healthy subjects for autoantibodies. Identified candidate antigens were expressed in vitro to enable validation studies with radiobinding assays (RBA). The validation cohort included NT1 patients (n = 39), their first‐degree relatives (FDR) (n = 66), population controls (n = 188), and disease controls representing multiple sclerosis (n = 100) and FDR to type 1 diabetes patients (n = 41). Reactivity towards previously suggested NT1 autoantigen candidates including Tribbles homolog 2, Prostaglandin D2 receptor, Hypocretin receptor 2 and α‐MSH/proopiomelanocortin was not replicated in the protein array screen. By comparing case to control signals, three novel candidate autoantigens were identified in the protein array screen; LOC401464, PARP3 and FAM63B. However, the RBA did not confirm elevated reactivity towards either of these proteins. In summary, three putative autoantigens in NT1 were identified by protein array screening. Autoantibodies against these candidates could not be verified with independent methods. Further studies are warranted to identify hypothetical autoantigens related to the pathogenesis of Pandemrix®‐induced NT1.

Place, publisher, year, edition, pages
Wiley, 2020
Keywords
antigens, peptides, epitopes, autoantibodies, autoimmunity
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-424409 (URN)10.1111/sji.12864 (DOI)000513207500001 ()32056243 (PubMedID)
Funder
Magnus Bergvall FoundationFredrik och Ingrid Thurings StiftelseSven Jerring FoundationSwedish Research Council, Dnr 2009-1039Swedish Foundation for Strategic Research , Dnr IRC15-0067Swedish Society of MedicineRegion SkåneSwedish Foundation for Strategic Research , Dnr IRC15-0067Swedish Research Council, Dnr 2009-1039Gun och Bertil Stohnes StiftelseThe Crafoord Foundation
Available from: 2020-11-04 Created: 2020-11-04 Last updated: 2020-11-04Bibliographically approved
Eriksson, D., Dalin, F., Eriksson, G. N., Landegren, N., Bianchi, M., Hallgren, Å., . . . Kämpe, O. (2018). Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1. Journal of Clinical Endocrinology and Metabolism, 103(1), 179-186
Open this publication in new window or tab >>Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1
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2018 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 1, p. 179-186Article in journal (Refereed) Published
Abstract [en]

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1.

Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease.

Design: We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE.

Results: In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure.

Conclusion: We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.

National Category
Endocrinology and Diabetes Immunology in the medical area Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-343355 (URN)10.1210/jc.2017-01957 (DOI)000424934300021 ()29069385 (PubMedID)
Funder
Swedish Research CouncilRagnar Söderbergs stiftelseTorsten Söderbergs stiftelseEU, FP7, Seventh Framework Programme, 201167Stockholm County CouncilSwedish Society for Medical Research (SSMF)Swedish Society of MedicineNovo NordiskÅke Wiberg Foundation
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2020-11-04Bibliographically approved
Bremer, H. D., Landegren, N., Sjöberg, R., Hallgren, Å., Renneker, S., Lattwein, E., . . . Hansson-Hamlin, H. (2018). ILF2 and ILF3 are autoantigens in canine systemic autoimmune disease. Scientific Reports, 8, Article ID 4852.
Open this publication in new window or tab >>ILF2 and ILF3 are autoantigens in canine systemic autoimmune disease
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2018 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 8, article id 4852Article in journal (Refereed) Published
Abstract [en]

Dogs can spontaneously develop complex systemic autoimmune disorders, with similarities to human autoimmune disease. Autoantibodies directed at self-antigens are a key feature of these autoimmune diseases. Here we report the identification of interleukin enhancer-binding factors 2 and 3 (ILF2 and ILF3) as autoantigens in canine immune-mediated rheumatic disease. The ILF2 autoantibodies were discovered in a small, selected canine cohort through the use of human protein arrays; a method not previously described in dogs. Subsequently, ILF3 autoantibodies were also identified in the same cohort. The results were validated with an independent method in a larger cohort of dogs. ILF2 and ILF3 autoantibodies were found exclusively, and at a high frequency, in dogs that showed a speckled pattern of antinuclear antibodies on immunofluorescence. ILF2 and ILF3 autoantibodies were also found at low frequency in human patients with SLE and Sjogren's syndrome. These autoantibodies have the potential to be used as diagnostic biomarkers for canine, and possibly also human, autoimmune disease.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-351425 (URN)10.1038/s41598-018-23034-w (DOI)000427688100045 ()29556082 (PubMedID)
Funder
Swedish Research CouncilSwedish Research Council Formas, 2011-1404Novo NordiskRagnar Söderbergs stiftelseSwedish Rheumatism Association
Available from: 2018-06-01 Created: 2018-06-01 Last updated: 2022-09-15Bibliographically approved
Zaidi, G., Bhatia, V., Sahoo, S. K., Sarangi, A. N., Bharti, N., Zhang, L., . . . Bhatia, E. (2017). Autoimmune polyendocrine syndrome type 1 in an Indian cohort: a longitudinal study. Endocrine Connections, 6(5), 289-296
Open this publication in new window or tab >>Autoimmune polyendocrine syndrome type 1 in an Indian cohort: a longitudinal study
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2017 (English)In: Endocrine Connections, E-ISSN 2049-3614, Vol. 6, no 5, p. 289-296Article in journal (Refereed) Published
Abstract [en]

Objective: Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive disorder characterized by progressive organ-specific autoimmunity. There is scant information on APS1 in ethnic groups other than European Caucasians. We studied clinical aspects and autoimmune regulator (AIRE) gene mutations in a cohort of Indian APS1 patients. Design: Twenty-three patients (19 families) from six referral centres in India, diagnosed between 1996 and 2016, were followed for [median (range)] 4 (0.2-19) years. Methods: Clinical features, mortality, organ-specific autoantibodies and AIRE gene mutations were studied. Results: Patients varied widely in their age of presentation [3.5 (0.1-17) years] and number of clinical manifestations [5 (2-11)]. Despite genetic heterogeneity, the frequencies of the major APS1 components (mucocutaneous candidiasis: 96%; hypoparathyroidism: 91%; primary adrenal insufficiency: 55%) were similar to reports in European series. In contrast, primary hypothyroidism (23%) occurred more frequently and at an early age, while kerato-conjunctivitis, urticarial rash and autoimmune hepatitis were uncommon (9% each). Six (26%) patients died at a young age [5.8 (3-23) years] due to septicaemia, hepatic failure and adrenal/hypocalcaemic crisis from non-compliance/unexplained cause. Interferon-a and/or interleukin-22 antibodies were elevated in all 19 patients tested, including an asymptomatic infant. Eleven AIRE mutations were detected, the most common being p.C322fsX372 (haplotype frequency 37%). Four mutations were novel, while six others were previously described in European Caucasians. Conclusions: Indian APS1 patients exhibited considerable genetic heterogeneity and had highly variable clinical features. While the frequency of major manifestations was similar to that of European Caucasians, other features showed significant differences. A high mortality at a young age was observed.

Keywords
autoimmune polyendocrine syndrome 1, APECED syndrome, autoimmune regulator gene, India
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-330021 (URN)10.1530/EC-17-0022 (DOI)000404929500002 ()28446514 (PubMedID)
Funder
Swedish Research CouncilTorsten Söderbergs stiftelseRagnar Söderbergs stiftelse
Available from: 2017-10-11 Created: 2017-10-11 Last updated: 2023-08-28Bibliographically approved
Smith-Anttila, C. J. A., Bensing, S., Alimohammadi, M., Dalin, F., Oscarson, M., Zhang, M.-D., . . . Kämpe, O. (2017). Identification of endothelin-converting enzyme-2 as an autoantigen in autoimmune polyendocrine syndrome type 1. Autoimmunity, 50(4), 223-231
Open this publication in new window or tab >>Identification of endothelin-converting enzyme-2 as an autoantigen in autoimmune polyendocrine syndrome type 1
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2017 (English)In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 50, no 4, p. 223-231Article in journal (Refereed) Published
Abstract [en]

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in up to 7% of all APS1 patients, with immunoreactivity to pituitary tissue frequently reported. We aimed to isolate and identify specific pituitary autoantigens in patients with APS1. Immunoscreening of a pituitary cDNA expression library identified endothelin-converting enzyme (ECE)-2 as a potential candidate autoantigen. Immunoreactivity against ECE-2 was detected in 46% APS1 patient sera, with no immunoreactivity detectable in patients with other autoimmune disorders or healthy controls. Quantitative-PCR showed ECE-2 mRNA to be most abundantly expressed in the pancreas with high levels also in the pituitary and brain. In the pancreas ECE-2 was co-expressed with insulin or somatostatin, but not glucagon and was widely expressed in GH producing cells in the guinea pig pituitary. The correlation between immunoreactivity against ECE-2 and the major recognized clinical phenotypes of APS1 including hypopituitarism was not apparent. Our results identify ECE-2 as a specific autoantigen in APS1 with a restricted neuroendocrine distribution.

Keywords
APS1, endothelin-converting enzyme-2, ECE-2, pituitary autoantibodies, pancreas
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-333619 (URN)10.1080/08916934.2017.1332183 (DOI)000407564500005 ()28557628 (PubMedID)
Available from: 2017-11-16 Created: 2017-11-16 Last updated: 2020-11-04Bibliographically approved
Navarini, A. A., Hruz, P., Berger, C. T., Hou, T. Z., Schwab, C., Gabrysch, A., . . . Recher, M. (2017). Vedolizumab as a successful treatment of CTLA-4-associated autoimmune enterocolitis [Letter to the editor]. Journal of Allergy and Clinical Immunology, 139(3), 1043-1046
Open this publication in new window or tab >>Vedolizumab as a successful treatment of CTLA-4-associated autoimmune enterocolitis
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2017 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 139, no 3, p. 1043-1046Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
MOSBY-ELSEVIER, 2017
National Category
Respiratory Medicine and Allergy Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-320972 (URN)10.1016/j.jaci.2016.08.042 (DOI)000397295800041 ()27908448 (PubMedID)
Available from: 2017-04-27 Created: 2017-04-27 Last updated: 2020-11-04Bibliographically approved
Dalin, F., Adamus, G., Yang, S., Landgren, E., Palle, J., Hallgren, Å., . . . Alimohammadi, M. (2016). Aryl Hydrocarbon Receptor-Interacting Protein-Like 1 in Cancer-Associated Retinopathy. Ophthalmology, 123(6), 1401-1404
Open this publication in new window or tab >>Aryl Hydrocarbon Receptor-Interacting Protein-Like 1 in Cancer-Associated Retinopathy
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2016 (English)In: Ophthalmology, ISSN 0161-6420, E-ISSN 1549-4713, Vol. 123, no 6, p. 1401-1404Article in journal (Refereed) Published
Abstract
National Category
Cancer and Oncology
Research subject
Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-279019 (URN)10.1016/j.ophtha.2015.12.031 (DOI)
Available from: 2016-02-27 Created: 2016-02-27 Last updated: 2023-03-28Bibliographically approved
Dalin, F., Adamus, G., Yang, S., Landgren, E., Palle, J., Hallgren, Å., . . . Alimohammadi, M. (2016). Aryl Hydrocarbon Receptor-Interacting Protein-Like 1 in Cancer-Associated Retinopathy. Ophthalmology, 123(6), 1401-1404
Open this publication in new window or tab >>Aryl Hydrocarbon Receptor-Interacting Protein-Like 1 in Cancer-Associated Retinopathy
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2016 (English)In: Ophthalmology, ISSN 0161-6420, E-ISSN 1549-4713, Vol. 123, no 6, p. 1401-1404Article in journal, Editorial material (Other academic) Published
National Category
Ophthalmology
Identifiers
urn:nbn:se:uu:diva-299646 (URN)10.1016/j.ophtha.2015.12.031 (DOI)000376506400041 ()26854037 (PubMedID)
Available from: 2016-07-26 Created: 2016-07-25 Last updated: 2023-03-28Bibliographically approved
Landegren, N., Pourmousa Lindberg, M., Skov, J., Hallgren, Å., Eriksson, D., Lisberg Toft-Bertelsen, T., . . . Kämpe, O. (2016). Autoantibodies Targeting a Collecting Duct-Specific Water Channel in Tubulointerstitial Nephritis.. Journal of the American Society of Nephrology, 27(10), 3220-3228
Open this publication in new window or tab >>Autoantibodies Targeting a Collecting Duct-Specific Water Channel in Tubulointerstitial Nephritis.
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2016 (English)In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 27, no 10, p. 3220-3228Article in journal (Refereed) Published
Abstract [en]

Tubulointerstitial nephritis is a common cause of kidney failure and may have diverse etiologies. This form of nephritis is sometimes associated with autoimmune disease, but the role of autoimmune mechanisms in disease development is not well understood. Here, we present the cases of three patients with autoimmune polyendocrine syndrome type 1 who developed tubulointerstitial nephritis and ESRD in association with autoantibodies against kidney collecting duct cells. One of the patients developed autoantibodies targeting the collecting duct-specific water channel aquaporin 2, whereas autoantibodies of the two other patients reacted against the HOXB7 or NFAT5 transcription factors, which regulate the aquaporin 2 promoter. Our findings suggest that tubulointerstitial nephritis developed in these patients as a result of an autoimmune insult on the kidney collecting duct cells.

National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-300411 (URN)10.1681/ASN.2015101126 (DOI)000384628500030 ()26984885 (PubMedID)
Funder
Swedish Research CouncilSwedish Research Council FormasSwedish Rheumatism AssociationNovo NordiskTorsten Söderbergs stiftelseRagnar Söderbergs stiftelse
Available from: 2016-08-08 Created: 2016-08-08 Last updated: 2022-01-29Bibliographically approved
Projects
Organ-specific autoimmunity - immunological, genetic and epidemiological aspects [2010-03243_VR]; Uppsala University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6091-9914

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