27 results on '"Landegren N"'
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2. Sex dimorphism in the tumor microenvironment - From bench to bedside and back
- Author
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He, F., Rodgers Furones, A., Landegren, N., Fuxe, J., Sarhan, D., He, F., Rodgers Furones, A., Landegren, N., Fuxe, J., and Sarhan, D.
- Abstract
Item does not contain fulltext, Cancer represents a significant cause of death and suffering in both the developed and developing countries. Key underlying issues in the mortality of cancer are delayed diagnosis and resistance to treatments. However, improvements in biomarkers represent one important step that can be taken for alleviating the suffering caused by malignancy. Precision-based medicine is promising for revolutionizing diagnostic and treatment strategies for cancer patients worldwide. Contemporary methods, including various omics and systems biology approaches, as well as advanced digital imaging and artificial intelligence, allow more accurate assessment of tumor characteristics at the patient level. As a result, treatment strategies can be specifically tailored and adapted for individual and/or groups of patients that carry certain tumor characteristics. This includes immunotherapy, which is based on characterization of the immunosuppressive tumor microenvironment (TME) and, more specifically, the presence and activity of immune cell subsets. Unfortunately, while it is increasingly clear that gender strongly affects immune regulation and response, there is a knowledge gap concerning differences in sex-specific immune responses and how these contribute to the immunosuppressive TME and the response to immunotherapy. In fact, sex dimorphism is poorly understood in cancer progression and is typically ignored in current clinical practice. In this review, we aim to survey the available literature and highlight the existing knowledge gap in order to encourage further studies that would contribute to understanding both gender-biased immunosuppression in the TME and the driver of tumor progression towards invasive and metastatic disease. The review highlights the need to include sex optimized/genderized medicine as a new concept in future medicine cancer diagnostics and treatments.
- Published
- 2022
3. GWAS for autoimmune Addison's disease identifies multiple risk loci and highlights AIRE in disease susceptibility
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Eriksson, D., Royrvik, E. C., Aranda-Guillen, M., Berger, A. H., Landegren, N., Artaza, H., Hallgren, A., Grytaas, M. A., Strom, S., Bratland, E., Botusan, I. R., Oftedal, B. E., Breivik, L., Vaudel, M., Helgeland, O., Falorni, A., Jorgensen, A. P., Hulting, A. -L., Svartberg, J., Ekwall, O., Fougner, K. J., Wahlberg, J., Nedrebo, B. G., Dahlqvist, P., Raeder, H., Jovanovic, N., Reisegg, S. C., Holleland, G., Carlsen, S., Berg, T. J., Eggesbo, J. B., Svendsen, T., Lima, K., Nermoen, I., Whitfield, R., Sollid, S., Aarskog, D., Korsgaard, E., Saeta, S., Finnes, T., Valland, S. F., Fossum, C., Brevik, E., Moe, R. B., Svendsen, M., Debowska, A., Milova, P., Holte, S., Tomkowicz, A. E., Sormo, D. E., Svare, A., Rensvik, M. L., Revheim, R., Haug, T., Blix, I., Jensen, L. P., Akerman, A. -K., Lindberg, B., Kristrom, B., Waldenstrom, E., Johannsson, G., Skov, J., Duchen, K., Isaksson, M., Elfving, M., Stenlid, M. H., Nilsson, O., Kampe, O., Bergthorsdottir, R., Nergardh, R., Bjornsdottir, S., Bensing, S., Olsson, T., Knappskog, P. M., Wolff, A. S. B., Johansson, S., and Husebye, E. S.
- Subjects
Male ,Models, Molecular ,Risk ,0301 basic medicine ,endocrine system diseases ,Science ,General Physics and Astronomy ,Genome-wide association study ,Disease ,Human leukocyte antigen ,Endocrinology and Diabetes ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,PTPN22 ,03 medical and health sciences ,Disease susceptibility ,0302 clinical medicine ,Addison Disease ,Models ,Humans ,CTLA-4 Antigen ,Gene ,Rheumatology and Autoimmunity ,Medicinsk genetik ,Genetics ,Reumatologi och inflammation ,Adrenal gland diseases ,Multidisciplinary ,Disease genetics ,Molecular ,VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710 ,Protein Tyrosine Phosphatase, Non-Receptor Type 22 ,General Chemistry ,Heritability ,Autoimmune regulator ,Non-Receptor Type 22 ,VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710 ,Basic-Leucine Zipper Transcription Factors ,030104 developmental biology ,Endokrinologi och diabetes ,Female ,Protein Tyrosine Phosphatase ,Medical Genetics ,Genome-Wide Association Study ,030215 immunology - Abstract
Autoimmune Addison’s disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P, Autoimmune Addison’s disease is a rare complex disease, which has not yet been characterized by non-biased genetic studies. Here, the authors perform the first GWAS for the disease, identifying nine loci including two coding variants in the gene Autoimmune Regulator (AIRE).
- Published
- 2021
4. Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease
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Eriksson, D., primary, Bianchi, M., additional, Landegren, N., additional, Nordin, J., additional, Dalin, F., additional, Mathioudaki, A., additional, Eriksson, G. N., additional, Hultin‐Rosenberg, L., additional, Dahlqvist, J., additional, Zetterqvist, H., additional, Karlsson, Å., additional, Hallgren, Å., additional, Farias, F. H. G., additional, Murén, E., additional, Ahlgren, K. M., additional, Lobell, A., additional, Andersson, G., additional, Tandre, K., additional, Dahlqvist, S. R., additional, Söderkvist, P., additional, Rönnblom, L., additional, Hulting, A.‐L., additional, Wahlberg, J., additional, Ekwall, O., additional, Dahlqvist, P., additional, Meadows, J. R. S., additional, Bensing, S., additional, Lindblad‐Toh, K., additional, Kämpe, O., additional, and Pielberg, G. R., additional
- Published
- 2016
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5. Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease
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Eriksson, D, Bianchi, M, Landegren, N, Nordin, J, Dalin, F, Mathioudaki, A, Eriksson, G N, Hultin-Rosenberg, L, Dahlqvist, J, Zetterqvist, H, Karlsson, Å, Hallgren, Å, Farias, F H G, Murén, E, Ahlgren, K M, Lobell, A, Andersson, G, Tandre, K, Rantapää Dahlqvist, Solbritt, Söderkvist, P, Rönnblom, L, Hulting, A-L, Wahlberg, J, Ekwall, O, Dahlqvist, Per, Meadows, J R S, Bensing, S, Lindblad-Toh, K, Kämpe, O, Pielberg, G R, Eriksson, D, Bianchi, M, Landegren, N, Nordin, J, Dalin, F, Mathioudaki, A, Eriksson, G N, Hultin-Rosenberg, L, Dahlqvist, J, Zetterqvist, H, Karlsson, Å, Hallgren, Å, Farias, F H G, Murén, E, Ahlgren, K M, Lobell, A, Andersson, G, Tandre, K, Rantapää Dahlqvist, Solbritt, Söderkvist, P, Rönnblom, L, Hulting, A-L, Wahlberg, J, Ekwall, O, Dahlqvist, Per, Meadows, J R S, Bensing, S, Lindblad-Toh, K, Kämpe, O, and Pielberg, G R
- Abstract
BACKGROUND: Autoimmune 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. METHODS: To 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. RESULTS: We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 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. CONCLUSION: Whilst 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.
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- 2016
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6. Hypomorphic Rag1mutations alter the preimmune repertoire at early stages of lymphoid development
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Ott de Bruin, L.M., Bosticardo, M., Barbieri, A., Lin, S.G., Rowe, J.H., Poliani, P.L., Ching, K., Eriksson, D., Landegren, N., Kämpe, O., Manis, J.P., and Notarangelo, L.D.
- Abstract
Hypomorphic RAG1mutations allowing residual T- and B-cell development have been found in patients presenting with delayed-onset combined immune deficiency with granulomas and/or autoimmunity (CID-G/AI) and abnormalities of the peripheral T- and B-cell repertoire. To examine how hypomorphic Rag1mutations affect the earliest stages of lymphocyte development, we used CRISPR/Cas9 to generate mouse models with mutations equivalent to those found in patients with CID-G/AI. Immunological characterization showed partial development of T and B lymphocytes, with persistence of naïve cells and preserved serum immunoglobulin but impaired antibody responses and presence of autoantibodies, thereby recapitulating the phenotype seen in patients with CID-G/AI. By using high-throughput sequencing, we identified marked skewing of Igh Vand Trb Vgene usage in early progenitors, with a bias for productive Ighand Trbrearrangements after selection occurred and increased apoptosis of B-cell progenitors. Rearrangement at the Igklocus was impaired, and polyreactive immunoglobulin M antibodies were detected. This study provides novel insights into how hypomorphic Rag1mutations alter the primary repertoire of T and B cells, setting the stage for immune dysregulation frequently seen in patients.
- Published
- 2018
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7. Author Correction: Immune system adaptation during gender-affirming testosterone treatment.
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Lakshmikanth T, Consiglio C, Sardh F, Forlin R, Wang J, Tan Z, Barcenilla H, Rodriguez L, Sugrue J, Noori P, Ivanchenko M, Piñero Páez L, Gonzalez L, Habimana Mugabo C, Johnsson A, Ryberg H, Hallgren Å, Pou C, Chen Y, Mikeš J, James A, Dahlqvist P, Wahlberg J, Hagelin A, Holmberg M, Degerblad M, Isaksson M, Duffy D, Kämpe O, Landegren N, and Brodin P
- Published
- 2024
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8. Inherited human RelB deficiency impairs innate and adaptive immunity to infection.
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Le Voyer T, Maglorius Renkilaraj MRL, Moriya K, Pérez Lorenzo M, Nguyen T, Gao L, Rubin T, Cederholm A, Ogishi M, Arango-Franco CA, Béziat V, Lévy R, Migaud M, Rapaport F, Itan Y, Deenick EK, Cortese I, Lisco A, Boztug K, Abel L, Boisson-Dupuis S, Boisson B, Frosk P, Ma CS, Landegren N, Celmeli F, Casanova JL, Tangye SG, and Puel A
- Subjects
- Humans, Female, Male, B-Lymphocytes immunology, NF-kappa B p52 Subunit genetics, NF-kappa B p52 Subunit metabolism, Adult, Fibroblasts metabolism, Fibroblasts immunology, Interferon Type I immunology, Interferon Type I metabolism, Transcription Factor RelB genetics, Transcription Factor RelB metabolism, Immunity, Innate, Adaptive Immunity genetics
- Abstract
We report two unrelated adults with homozygous (P1) or compound heterozygous (P2) private loss-of-function variants of V-Rel Reticuloendotheliosis Viral Oncogene Homolog B ( RELB). The resulting deficiency of functional RelB impairs the induction of NFKB2 mRNA and NF-κB2 (p100/p52) protein by lymphotoxin in the fibroblasts of the patients. These defects are rescued by transduction with wild-type RELB complementary DNA (cDNA). By contrast, the response of RelB-deficient fibroblasts to Tumor Necrosis Factor (TNF) or IL-1β via the canonical NF-κB pathway remains intact. P1 and P2 have low proportions of naïve CD4
+ and CD8+ T cells and of memory B cells. Moreover, their naïve B cells cannot differentiate into immunoglobulin G (IgG)- or immunoglobulin A (IgA)-secreting cells in response to CD40L/IL-21, and the development of IL-17A/F-producing T cells is strongly impaired in vitro. Finally, the patients produce neutralizing autoantibodies against type I interferons (IFNs), even after hematopoietic stem cell transplantation, attesting to a persistent dysfunction of thymic epithelial cells in T cell selection and central tolerance to some autoantigens. Thus, inherited human RelB deficiency disrupts the alternative NF-κB pathway, underlying a T- and B cell immunodeficiency, which, together with neutralizing autoantibodies against type I IFNs, confers a predisposition to viral, bacterial, and fungal infections., Competing Interests: Competing interests statement:Tim Niehues was a co-author on publications with the following co-authors within the last 4 y: K.B., C.S.M., and S.G.T. (https://doi.org/10.1182/blood.2020006738) and K.B. (https://doi.org/10.1016/j.jaci.2019.11.051; https://doi.org/10.1002/eji.202048713). Andrew R. Gennery was a co-author with S.G.T. (https://doi.org/10.1016/j.jaci.2020.09.010; https://doi.org/10.1016/j.jaci.2022.09.002) within the last 4 y.- Published
- 2024
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9. Immune system adaptation during gender-affirming testosterone treatment.
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Lakshmikanth T, Consiglio C, Sardh F, Forlin R, Wang J, Tan Z, Barcenilla H, Rodriguez L, Sugrue J, Noori P, Ivanchenko M, Piñero Páez L, Gonzalez L, Habimana Mugabo C, Johnsson A, Ryberg H, Hallgren Å, Pou C, Chen Y, Mikeš J, James A, Dahlqvist P, Wahlberg J, Hagelin A, Holmberg M, Degerblad M, Isaksson M, Duffy D, Kämpe O, Landegren N, and Brodin P
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- Adult, Female, Humans, Male, Datasets as Topic, Dendritic Cells immunology, Dendritic Cells metabolism, Dendritic Cells drug effects, Immune System drug effects, Immune System metabolism, Interferon Type I immunology, Interferon Type I metabolism, Interferon-gamma immunology, Interferon-gamma metabolism, Interleukin-15 immunology, Interleukin-15 metabolism, Killer Cells, Natural immunology, Killer Cells, Natural drug effects, Monocytes immunology, Monocytes drug effects, Monocytes metabolism, NF-kappa B metabolism, Sex Characteristics, Tumor Necrosis Factor-alpha metabolism, Testosterone adverse effects, Testosterone immunology, Testosterone pharmacology, Testosterone therapeutic use, Transgender Persons
- Abstract
Infectious, inflammatory and autoimmune conditions present differently in males and females. SARS-CoV-2 infection in naive males is associated with increased risk of death, whereas females are at increased risk of long COVID
1 , similar to observations in other infections2 . Females respond more strongly to vaccines, and adverse reactions are more frequent3 , like most autoimmune diseases4 . Immunological sex differences stem from genetic, hormonal and behavioural factors5 but their relative importance is only partially understood6-8 . In individuals assigned female sex at birth and undergoing gender-affirming testosterone therapy (trans men), hormone concentrations change markedly but the immunological consequences are poorly understood. Here we performed longitudinal systems-level analyses in 23 trans men and found that testosterone modulates a cross-regulated axis between type-I interferon and tumour necrosis factor. This is mediated by functional attenuation of type-I interferon responses in both plasmacytoid dendritic cells and monocytes. Conversely, testosterone potentiates monocyte responses leading to increased tumour necrosis factor, interleukin-6 and interleukin-15 production and downstream activation of nuclear factor kappa B-regulated genes and potentiation of interferon-γ responses, primarily in natural killer cells. These findings in trans men are corroborated by sex-divergent responses in public datasets and illustrate the dynamic regulation of human immunity by sex hormones, with implications for the health of individuals undergoing hormone therapy and our understanding of sex-divergent immune responses in cisgender individuals., (© 2024. The Author(s).)- Published
- 2024
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10. Neutralizing IFN-γ autoantibodies are rare and pathogenic in HLA-DRB1*15:02 or 16:02 individuals.
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Peel JN, Yang R, Le Voyer T, Gervais A, Rosain J, Bastard P, Behere A, Cederholm A, Bodansky A, Seeleuthner Y, Conil C, Ding JY, Lei WT, Bizien L, Soudee C, Migaud M, Ogishi M, Yatim A, Lee D, Bohlen J, Perpoint T, Perez L, Messina F, Genet R, Karkowski L, Blot M, Lafont E, Toullec L, Goulvestre C, Mehlal-Sedkaoui S, Sallette J, Martin F, Puel A, Jouanguy E, Anderson MS, Landegren N, Tiberghien P, Abel L, Boisson-Dupuis S, Bustamante J, Ku CL, and Casanova JL
- Subjects
- Adult, Humans, Genetic Predisposition to Disease, Genotype, HLA-DRB1 Chains genetics, Mycobacterium Infections, Nontuberculous, Autoantibodies, Autoimmune Diseases
- Abstract
BACKGROUNDWeakly virulent environmental mycobacteria (EM) can cause severe disease in HLA-DRB1*15:02 or 16:02 adults harboring neutralizing anti-IFN-γ autoantibodies (nAIGAs). The overall prevalence of nAIGAs in the general population is unknown, as are the penetrance of nAIGAs in HLA-DRB1*15:02 or 16:02 individuals and the proportion of patients with unexplained, adult-onset EM infections carrying nAIGAs.METHODSThis study analyzed the detection and neutralization of anti-IFN-γ autoantibodies (auto-Abs) from 8,430 healthy individuals of the general population, 257 HLA-DRB1*15:02 or 16:02 carriers, 1,063 patients with autoimmune disease, and 497 patients with unexplained severe disease due to EM.RESULTSWe found that anti-IFN-γ auto-Abs detected in 4,148 of 8,430 healthy individuals (49.2%) from the general population of an unknown HLA-DRB1 genotype were not neutralizing. Moreover, we did not find nAIGAs in 257 individuals carrying HLA-DRB1* 15:02 or 16:02. Additionally, nAIGAs were absent in 1,063 patients with an autoimmune disease. Finally, 7 of 497 patients (1.4%) with unexplained severe disease due to EM harbored nAIGAs.CONCLUSIONThese findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are the cause of EM disease.FUNDINGThe Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI095983 and U19AIN1625568), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), the French National Research Agency (ANR) under the "Investments for the Future" program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), ANR-GENMSMD (ANR-16-CE17-0005-01), ANR-MAFMACRO (ANR-22-CE92-0008), ANRSECTZ170784, the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AI2D (ANR-22-CE15-0046) projects, the ANR-RHU program (ANR-21-RHUS-08-COVIFERON), the European Union's Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics), the Square Foundation, Grandir - Fonds de solidarité pour l'enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the Battersea & Bowery Advisory Group, William E. Ford, General Atlantic's Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantic's Co-President, Managing Director, and Head of business in EMEA, and the General Atlantic Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM) and of Paris Cité University. JR was supported by the INSERM PhD program for doctors of pharmacy (poste d'accueil INSERM). JR and TLV were supported by the Bettencourt-Schueller Foundation and the MD-PhD program of the Imagine Institute. MO was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the New York Hideyo Noguchi Memorial Society (HNMS).
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- 2024
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11. No link between type I interferon autoantibody positivity and adverse reactions to COVID-19 vaccines.
- Author
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Yalcinkaya A, Cavalli M, Cederholm A, Aranda-Guillén M, Behere A, Mildner H, Lakshmikanth T, Gonzalez L, Mugabo CH, Johnsson A, Ekwall O, Kämpe O, Bensing S, Brodin P, Hallberg P, Wadelius M, and Landegren N
- Abstract
Type I interferons act as gatekeepers against viral infection, and autoantibodies that neutralize these signaling molecules have been associated with COVID-19 severity and adverse reactions to the live-attenuated yellow fever vaccine. On this background, we sought to examine whether autoantibodies against type I interferons were associated with adverse events following COVID-19 vaccination. Our nationwide analysis suggests that type I interferon autoantibodies were not associated with adverse events after mRNA or viral-vector COVID-19 vaccines., (© 2024. The Author(s).)
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- 2024
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12. Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency.
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Le Voyer T, Parent AV, Liu X, Cederholm A, Gervais A, Rosain J, Nguyen T, Perez Lorenzo M, Rackaityte E, Rinchai D, Zhang P, Bizien L, Hancioglu G, Ghillani-Dalbin P, Charuel JL, Philippot Q, Gueye MS, Maglorius Renkilaraj MRL, Ogishi M, Soudée C, Migaud M, Rozenberg F, Momenilandi M, Riller Q, Imberti L, Delmonte OM, Müller G, Keller B, Orrego J, Franco Gallego WA, Rubin T, Emiroglu M, Parvaneh N, Eriksson D, Aranda-Guillen M, Berrios DI, Vong L, Katelaris CH, Mustillo P, Raedler J, Bohlen J, Bengi Celik J, Astudillo C, Winter S, McLean C, Guffroy A, DeRisi JL, Yu D, Miller C, Feng Y, Guichard A, Béziat V, Bustamante J, Pan-Hammarström Q, Zhang Y, Rosen LB, Holland SM, Bosticardo M, Kenney H, Castagnoli R, Slade CA, Boztuğ K, Mahlaoui N, Latour S, Abraham RS, Lougaris V, Hauck F, Sediva A, Atschekzei F, Sogkas G, Poli MC, Slatter MA, Palterer B, Keller MD, Pinzon-Charry A, Sullivan A, Droney L, Suan D, Wong M, Kane A, Hu H, Ma C, Grombiříková H, Ciznar P, Dalal I, Aladjidi N, Hie M, Lazaro E, Franco J, Keles S, Malphettes M, Pasquet M, Maccari ME, Meinhardt A, Ikinciogullari A, Shahrooei M, Celmeli F, Frosk P, Goodnow CC, Gray PE, Belot A, Kuehn HS, Rosenzweig SD, Miyara M, Licciardi F, Servettaz A, Barlogis V, Le Guenno G, Herrmann VM, Kuijpers T, Ducoux G, Sarrot-Reynauld F, Schuetz C, Cunningham-Rundles C, Rieux-Laucat F, Tangye SG, Sobacchi C, Doffinger R, Warnatz K, Grimbacher B, Fieschi C, Berteloot L, Bryant VL, Trouillet Assant S, Su H, Neven B, Abel L, Zhang Q, Boisson B, Cobat A, Jouanguy E, Kampe O, Bastard P, Roifman CM, Landegren N, Notarangelo LD, Anderson MS, Casanova JL, and Puel A
- Subjects
- Humans, COVID-19 genetics, COVID-19 immunology, Gain of Function Mutation, Heterozygote, I-kappa B Proteins deficiency, I-kappa B Proteins genetics, Loss of Function Mutation, NF-kappa B p52 Subunit deficiency, NF-kappa B p52 Subunit genetics, Pneumonia, Viral genetics, Pneumonia, Viral immunology, Thymus Gland abnormalities, Thymus Gland immunology, Thymus Gland pathology, Thyroid Epithelial Cells metabolism, Thyroid Epithelial Cells pathology, AIRE Protein, NF-kappaB-Inducing Kinase, Autoantibodies immunology, Genetic Predisposition to Disease, Interferon Type I antagonists & inhibitors, Interferon Type I immunology, NF-kappa B deficiency, NF-kappa B genetics
- Abstract
Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)
1,2 , conferring a predisposition to life-threatening COVID-19 pneumonia3 . Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF /IκBδGOF ). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF /IκBδLOF ) or gain-of-function of p52 (hereafter, p52GOF /IκBδLOF ). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases., (© 2023. The Author(s).)- Published
- 2023
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13. Monitoring drug-target interactions through target engagement-mediated amplification on arrays and in situ.
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Al-Amin RA, Johansson L, Abdurakhmanov E, Landegren N, Löf L, Arngården L, Blokzijl A, Svensson R, Hammond M, Lönn P, Haybaeck J, Kamali-Moghaddam M, Jensen AJ, Danielson UH, Artursson P, Lundbäck T, and Landegren U
- Subjects
- Dasatinib pharmacology, Oligonucleotide Probes, Protein Array Analysis, Proteins, Gefitinib pharmacology, Protein Kinase Inhibitors pharmacology, Molecular Targeted Therapy methods
- Abstract
Drugs are designed to bind their target proteins in physiologically relevant tissues and organs to modulate biological functions and elicit desirable clinical outcomes. Information about target engagement at cellular and subcellular resolution is therefore critical for guiding compound optimization in drug discovery, and for probing resistance mechanisms to targeted therapies in clinical samples. We describe a target engagement-mediated amplification (TEMA) technology, where oligonucleotide-conjugated drugs are used to visualize and measure target engagement in situ, amplified via rolling-circle replication of circularized oligonucleotide probes. We illustrate the TEMA technique using dasatinib and gefitinib, two kinase inhibitors with distinct selectivity profiles. In vitro binding by the dasatinib probe to arrays of displayed proteins accurately reproduced known selectivity profiles, while their differential binding to fixed adherent cells agreed with expectations from expression profiles of the cells. We also introduce a proximity ligation variant of TEMA to selectively investigate binding to specific target proteins of interest. This form of the assay serves to improve resolution of binding to on- and off-target proteins. In conclusion, TEMA has the potential to aid in drug development and clinical routine by conferring valuable insights in drug-target interactions at spatial resolution in protein arrays, cells and in tissues., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2022
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14. Autoantibody discovery across monogenic, acquired, and COVID-19-associated autoimmunity with scalable PhIP-seq.
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Vazquez SE, Mann SA, Bodansky A, Kung AF, Quandt Z, Ferré EMN, Landegren N, Eriksson D, Bastard P, Zhang SY, Liu J, Mitchell A, Proekt I, Yu D, Mandel-Brehm C, Wang CY, Miao B, Sowa G, Zorn K, Chan AY, Tagi VM, Shimizu C, Tremoulet A, Lynch K, Wilson MR, Kämpe O, Dobbs K, Delmonte OM, Bacchetta R, Notarangelo LD, Burns JC, Casanova JL, Lionakis MS, Torgerson TR, Anderson MS, and DeRisi JL
- Subjects
- Humans, Autoantibodies, Autoantigens metabolism, Autoimmunity, Homeodomain Proteins, Immunoprecipitation, Proteome, Autoimmune Diseases, Bacteriophages metabolism, COVID-19
- Abstract
Phage immunoprecipitation sequencing (PhIP-seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-seq for autoantigen discovery, including our previous work (Vazquez et al., 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki disease (KD), multisystem inflammatory syndrome in children (MIS-C), and finally, mild and severe forms of COVID-19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as prodynorphin (PDYN) in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in two patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID-19, including the endosomal protein EEA1. Together, scaled PhIP-seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies., Competing Interests: SV, SM, AB, AK, ZQ, EF, NL, DE, PB, SZ, JL, AM, IP, DY, CM, CW, BM, GS, KZ, AC, VT, CS, AT, KL, MW, OK, KD, OD, RB, LN, JB, JC, ML, TT, MA, JD No competing interests declared
- Published
- 2022
- Full Text
- View/download PDF
15. Autoantibody discovery across monogenic, acquired, and COVID19-associated autoimmunity with scalable PhIP-Seq.
- Author
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Vazquez SE, Mann SA, Bodansky A, Kung AF, Quandt Z, Ferré EMN, Landegren N, Eriksson D, Bastard P, Zhang SY, Liu J, Mitchell A, Mandel-Brehm C, Miao B, Sowa G, Zorn K, Chan AY, Shimizu C, Tremoulet A, Lynch K, Wilson MR, Kampe O, Dobbs K, Delmonte OM, Notarangelo LD, Burns JC, Casanova JL, Lionakis MS, Torgerson TR, Anderson MS, and DeRisi JL
- Abstract
Phage Immunoprecipitation-Sequencing (PhIP-Seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-Seq for autoantigen discovery, including our previous work (Vazquez et al. 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki Disease (KD), Multisystem Inflammatory Syndrome in Children (MIS-C), and finally, mild and severe forms of COVID19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as PDYN in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in 2 patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-Seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID19, including the endosomal protein EEA1. Together, scaled PhIP-Seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies.
- Published
- 2022
- Full Text
- View/download PDF
16. A gene-centric approach to biomarker discovery identifies transglutaminase 1 as an epidermal autoantigen.
- Author
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Landegren N, Ishii N, Aranda-Guillén M, Gunnarsson HI, Sardh F, Hallgren Å, Ståhle M, Hagforsen E, Bradley M, Edqvist PD, Pontén F, Mäkitie O, Eidsmo L, Norlén L, Achour A, Dahlbom I, Korponay-Szabó I, Agardh D, Alimohammadi M, Eriksson D, Hashimoto T, and Kämpe O
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers blood, Case-Control Studies, Child, Female, Humans, Male, Middle Aged, Paraneoplastic Syndromes blood, Pemphigus blood, Young Adult, Autoantigens blood, Paraneoplastic Syndromes immunology, Pemphigus immunology, Transglutaminases immunology
- Abstract
Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases., Competing Interests: Competing interest statement: N.L., T.H., and O.K. are preparing to file a patent related to the use of transglutaminase 1 autoantibodies as a diagnostic marker., (Copyright © 2021 the Author(s). Published by PNAS.)
- Published
- 2021
- Full Text
- View/download PDF
17. GWAS for autoimmune Addison's disease identifies multiple risk loci and highlights AIRE in disease susceptibility.
- Author
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Eriksson D, Røyrvik EC, Aranda-Guillén M, Berger AH, Landegren N, Artaza H, Hallgren Å, Grytaas MA, Ström S, Bratland E, Botusan IR, Oftedal BE, Breivik L, Vaudel M, Helgeland Ø, Falorni A, Jørgensen AP, Hulting AL, Svartberg J, Ekwall O, Fougner KJ, Wahlberg J, Nedrebø BG, Dahlqvist P, Knappskog PM, Wolff ASB, Bensing S, Johansson S, Kämpe O, and Husebye ES
- Subjects
- Basic-Leucine Zipper Transcription Factors genetics, CTLA-4 Antigen genetics, Female, Humans, Male, Models, Molecular, Protein Tyrosine Phosphatase, Non-Receptor Type 22 genetics, Risk, Addison Disease genetics, Genome-Wide Association Study
- Abstract
Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10
-8 ). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7-4.3), P = 9.0 × 10-25 ) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h2 ).- Published
- 2021
- Full Text
- View/download PDF
18. The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.
- Author
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Consiglio CR, Cotugno N, Sardh F, Pou C, Amodio D, Rodriguez L, Tan Z, Zicari S, Ruggiero A, Pascucci GR, Santilli V, Campbell T, Bryceson Y, Eriksson D, Wang J, Marchesi A, Lakshmikanth T, Campana A, Villani A, Rossi P, Landegren N, Palma P, and Brodin P
- Subjects
- Autoantibodies blood, Betacoronavirus isolation & purification, COVID-19, Child, Child, Preschool, Coronavirus Infections complications, Coronavirus Infections virology, Cytokines metabolism, Female, Humans, Immunity, Humoral, Infant, Male, Mucocutaneous Lymph Node Syndrome complications, Mucocutaneous Lymph Node Syndrome immunology, Mucocutaneous Lymph Node Syndrome pathology, Pandemics, Pneumonia, Viral complications, Pneumonia, Viral virology, Principal Component Analysis, Proteome analysis, SARS-CoV-2, Severity of Illness Index, Systemic Inflammatory Response Syndrome etiology, Systemic Inflammatory Response Syndrome immunology, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Coronavirus Infections pathology, Pneumonia, Viral pathology, Systemic Inflammatory Response Syndrome pathology
- Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is typically very mild and often asymptomatic in children. A complication is the rare multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction, and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines, and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2, and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T cell subsets, interleukin (IL)-17A, and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C., Competing Interests: Declaration of Interests P.B. and T.L. are founders and shareholders of Cytodelics AB (Stockholm, Sweden). P.B. is an advisor Scailyte AG (Switzerland)., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
19. Comment on 'AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies'.
- Author
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Landegren N, Rosen LB, Freyhult E, Eriksson D, Fall T, Smith G, Ferre EMN, Brodin P, Sharon D, Snyder M, Lionakis M, Anderson M, and Kämpe O
- Subjects
- Autoantibodies, Humans, Transcription Factors, Diabetes Mellitus, Type 1, Interferon Type I, Polyendocrinopathies, Autoimmune
- Abstract
The AIRE gene plays a key role in the development of central immune tolerance by promoting thymic presentation of tissue-specific molecules. Patients with AIRE -deficiency develop multiple autoimmune manifestations and display autoantibodies against the affected tissues. In 2016 it was reported that: i) the spectrum of autoantibodies in patients with AIRE -deficiency is much broader than previously appreciated; ii) neutralizing autoantibodies to type I interferons (IFNs) could provide protection against type 1 diabetes in these patients (Meyer et al., 2016). We attempted to replicate these new findings using a similar experimental approach in an independent patient cohort, and found no evidence for either conclusion., Competing Interests: NL, LR, EF, DE, TF, GS, EF, PB, DS, ML, MA No competing interests declared, MS Serves as founder and consultant for Personalis, is a member of the scientific advisory board of GenapSys, and a consultant for Illumina. OK Is a board member of Olink Bioscience.
- Published
- 2019
- Full Text
- View/download PDF
20. Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison's disease in Sweden.
- Author
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Eriksson D, Bianchi M, Landegren N, Dalin F, Skov J, Hultin-Rosenberg L, Mathioudaki A, Nordin J, Hallgren Å, Andersson G, Tandre K, Rantapää Dahlqvist S, Söderkvist P, Rönnblom L, Hulting AL, Wahlberg J, Dahlqvist P, Ekwall O, Meadows JRS, Lindblad-Toh K, Bensing S, Rosengren Pielberg G, and Kämpe O
- Subjects
- Basic-Leucine Zipper Transcription Factors genetics, CTLA-4 Antigen genetics, Genomics, Haplotypes, Humans, Lectins, C-Type genetics, Monosaccharide Transport Proteins genetics, Protein Tyrosine Phosphatase, Non-Receptor Type 22 genetics, Sweden, AIRE Protein, Addison Disease genetics, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Genetic Variation, Transcription Factors genetics
- Abstract
Autoimmune Addison's disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.
- Published
- 2018
- Full Text
- View/download PDF
21. ILF2 and ILF3 are autoantigens in canine systemic autoimmune disease.
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Bremer HD, Landegren N, Sjöberg R, Hallgren Å, Renneker S, Lattwein E, Leonard D, Eloranta ML, Rönnblom L, Nordmark G, Nilsson P, Andersson G, Lilliehöök I, Lindblad-Toh K, Kämpe O, and Hansson-Hamlin H
- Subjects
- Animals, Antibodies, Antinuclear immunology, Dogs, Humans, Autoantigens immunology, Autoimmune Diseases immunology, Nuclear Factor 45 Protein immunology, Nuclear Factor 90 Proteins immunology
- Abstract
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 Sjögren's syndrome. These autoantibodies have the potential to be used as diagnostic biomarkers for canine, and possibly also human, autoimmune disease.
- Published
- 2018
- Full Text
- View/download PDF
22. Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1.
- Author
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Eriksson D, Dalin F, Eriksson GN, Landegren N, Bianchi M, Hallgren Å, Dahlqvist P, Wahlberg J, Ekwall O, Winqvist O, Catrina SB, Rönnelid J, Hulting AL, Lindblad-Toh K, Alimohammadi M, Husebye ES, Knappskog PM, Rosengren Pielberg G, Bensing S, and Kämpe O
- Subjects
- Addison Disease blood, Addison Disease immunology, Autoantibodies immunology, Case-Control Studies, Follow-Up Studies, Humans, Polyendocrinopathies, Autoimmune blood, Polyendocrinopathies, Autoimmune immunology, Prognosis, Sweden, Addison Disease diagnosis, Autoantibodies blood, Biomarkers blood, Cytokines immunology, Mass Screening, Polyendocrinopathies, Autoimmune diagnosis, Registries
- Abstract
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., (Copyright © 2017 Endocrine Society)
- Published
- 2018
- Full Text
- View/download PDF
23. Autoantibodies Targeting a Collecting Duct-Specific Water Channel in Tubulointerstitial Nephritis.
- Author
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Landegren N, Pourmousa Lindberg M, Skov J, Hallgren Å, Eriksson D, Lisberg Toft-Bertelsen T, MacAulay N, Hagforsen E, Räisänen-Sokolowski A, Saha H, Nilsson T, Nordmark G, Ohlsson S, Gustafsson J, Husebye ES, Larsson E, Anderson MS, Perheentupa J, Rorsman F, Fenton RA, and Kämpe O
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Young Adult, Aquaporins immunology, Autoantibodies immunology, Kidney Tubules, Collecting immunology, Nephritis, Interstitial immunology
- Abstract
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., (Copyright © 2016 by the American Society of Nephrology.)
- Published
- 2016
- Full Text
- View/download PDF
24. A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 1.
- Author
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Bruserud Ø, Oftedal BE, Landegren N, Erichsen MM, Bratland E, Lima K, Jørgensen AP, Myhre AG, Svartberg J, Fougner KJ, Bakke Å, Nedrebø BG, Mella B, Breivik L, Viken MK, Knappskog PM, Marthinussen MC, Løvås K, Kämpe O, Wolff AB, and Husebye ES
- Subjects
- Adolescent, Adult, Autoantibodies blood, Child, Child, Preschool, DNA Mutational Analysis, Disease Progression, Female, Follow-Up Studies, Genetic Association Studies, Humans, Infant, Longitudinal Studies, Male, Middle Aged, Norway epidemiology, Phenotype, Prognosis, Registries, Survival Analysis, Transcription Factors genetics, Young Adult, AIRE Protein, Polyendocrinopathies, Autoimmune diagnosis, Polyendocrinopathies, Autoimmune genetics, Polyendocrinopathies, Autoimmune mortality, Polyendocrinopathies, Autoimmune therapy
- Abstract
Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (CMC). Information on longitudinal follow-up of APS1 is sparse., Objective: To describe the phenotypes of APS1 and correlate the clinical features with autoantibody profiles and autoimmune regulator (AIRE) mutations during extended follow-up (1996-2016)., Patients: All known Norwegian patients with APS1., Results: Fifty-two patients from 34 families were identified. The majority presented with one of the major disease components during childhood. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. With age, most patients presented three to five disease manifestations, although some had milder phenotypes diagnosed in adulthood. Fifteen of the patients died during follow-up (median age at death, 34 years) or were deceased siblings with a high probability of undisclosed APS1. All except three had interferon-ω) autoantibodies, and all had organ-specific autoantibodies. The most common AIRE mutation was c.967_979del13, found in homozygosity in 15 patients. A mild phenotype was associated with the splice mutation c.879+1G>A. Primary adrenocortical insufficiency and type 1 diabetes were associated with protective human leucocyte antigen genotypes., Conclusions: Multiple presumable autoimmune manifestations, in particular hypoparathyroidism, CMC, and enamel hypoplasia, should prompt further diagnostic workup using autoantibody analyses (eg, interferon-ω) and AIRE sequencing to reveal APS1, even in adults. Treatment is complicated, and mortality is high. Structured follow-up should be performed in a specialized center.
- Published
- 2016
- Full Text
- View/download PDF
25. Proteome-wide survey of the autoimmune target repertoire in autoimmune polyendocrine syndrome type 1.
- Author
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Landegren N, Sharon D, Freyhult E, Hallgren Å, Eriksson D, Edqvist PH, Bensing S, Wahlberg J, Nelson LM, Gustafsson J, Husebye ES, Anderson MS, Snyder M, and Kämpe O
- Subjects
- Antigens, Neoplasm blood, Autoantibodies blood, Autoantigens blood, Female, Humans, Male, Neoplasm Proteins blood, Polyendocrinopathies, Autoimmune blood, Protein Array Analysis, Protein Disulfide-Isomerases blood, Proteome metabolism, Scandinavian and Nordic Countries, Antigens, Neoplasm immunology, Autoantibodies immunology, Autoantigens immunology, Neoplasm Proteins immunology, Polyendocrinopathies, Autoimmune immunology, Protein Disulfide-Isomerases immunology, Proteome immunology
- Abstract
Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features multiple autoimmune disease manifestations. It is caused by mutations in the Autoimmune regulator (AIRE) gene, which promote thymic display of thousands of peripheral tissue antigens in a process critical for establishing central immune tolerance. We here used proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Interrogation of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of more than 9000 proteins we further identified MAGEB2 and PDILT as novel major autoantigens in APS1. Our proteome-wide assessment revealed a marked enrichment for tissue-specific immune targets, mirroring AIRE's selectiveness for this category of genes. Our findings also suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1, which contrasts the broad defect of thymic presentation associated with AIRE-deficiency and raises novel questions what other factors are needed for break of tolerance.
- Published
- 2016
- Full Text
- View/download PDF
26. Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies.
- Author
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Albrecht I, Wick C, Hallgren Å, Tjärnlund A, Nagaraju K, Andrade F, Thompson K, Coley W, Phadke A, Diaz-Gallo LM, Bottai M, Nennesmo I, Chemin K, Herrath J, Johansson K, Wikberg A, Ytterberg AJ, Zubarev RA, Danielsson O, Krystufkova O, Vencovsky J, Landegren N, Wahren-Herlenius M, Padyukov L, Kämpe O, and Lundberg IE
- Subjects
- Animals, Autoantibodies blood, Autoimmune Diseases blood, Autoimmune Diseases genetics, Autoimmune Diseases pathology, Female, Granzymes genetics, Granzymes immunology, Granzymes metabolism, Humans, Inflammation blood, Inflammation genetics, Inflammation immunology, Inflammation pathology, Intracellular Signaling Peptides and Proteins blood, Intracellular Signaling Peptides and Proteins genetics, LIM Domain Proteins blood, LIM Domain Proteins genetics, Male, Mice, Muscle Fibers, Skeletal metabolism, Muscle Fibers, Skeletal pathology, Muscle Proteins blood, Muscle Proteins genetics, Muscular Diseases blood, Muscular Diseases genetics, Muscular Diseases pathology, Autoantibodies immunology, Autoimmune Diseases immunology, Intracellular Signaling Peptides and Proteins immunology, LIM Domain Proteins immunology, Muscle Fibers, Skeletal immunology, Muscle Proteins immunology, Muscular Diseases immunology
- Abstract
Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1-negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.
- Published
- 2015
- Full Text
- View/download PDF
27. Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus.
- Author
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Ahlgren KM, Fall T, Landegren N, Grimelius L, von Euler H, Sundberg K, Lindblad-Toh K, Lobell A, Hedhammar Å, Andersson G, Hansson-Hamlin H, Lernmark Å, and Kämpe O
- Subjects
- Animals, Autoantibodies metabolism, Diabetes Mellitus blood, Diabetes Mellitus immunology, Dog Diseases blood, Dogs, Fluorescent Antibody Technique, Humans, Islets of Langerhans metabolism, Diabetes Mellitus veterinary, Dog Diseases immunology, Islets of Langerhans immunology
- Abstract
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.
- Published
- 2014
- Full Text
- View/download PDF
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