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Segerberg, F., Lundtoft, C., Reid, S., Hjorton, K., Leonard, D., Nordmark, G., . . . Hagberg, N. (2019). Autoantibodies to Killer Cell Immunoglobulin-Like Receptors in Patients With Systemic Lupus Erythematosus Induce Natural Killer Cell Hyporesponsiveness. Frontiers in Immunology, 10, Article ID 2164.
Open this publication in new window or tab >>Autoantibodies to Killer Cell Immunoglobulin-Like Receptors in Patients With Systemic Lupus Erythematosus Induce Natural Killer Cell Hyporesponsiveness
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 2164Article in journal (Refereed) Published
Abstract [en]

Natural killer (NK) cell cytotoxicity toward self-cells is restrained by the inhibitory HLA class I-binding receptors CD94/NKG2A and the killer cell immunoglobulin-like receptors (KIRs). CD94/NKG2A and KIRs are also essential for NK cell education, which is a dynamic functional maturation process where a constitutive binding of inhibitory receptors to cognate HLA class I molecules is required for NK cells to maintain their full cytotoxic capacity. Previously, we described autoantibodies to CD94/NKG2A in patients with systemic lupus erythematosus (SLE). In this study we analyzed sera from 191 patients with SLE, 119 patients with primary Sjogren's syndrome (pSS), 48 patients with systemic sclerosis (SSc), and 100 healthy donors (HD) for autoantibodies to eight different KIRs. Anti-KIR autoantibodies were identified in sera from 23.0% of patients with SLE, 10.9% of patients with pSS, 12.5% of patients with SSc, and 3.0% of HD. IgG from anti-KIR-positive SLE patients reduced the degranulation and cytotoxicity of NK cells toward K562 tumor cells. The presence of anti-KIR-autoantibodies reacting with >3 KIRs was associated with an increased disease activity (p < 0.0001), elevated serum levels of IFN-alpha (p < 0.0001), nephritis (p = 0.001), and the presence of anti-Sm (p = 0.007), and anti-RNP (p = 0.003) autoantibodies in serum. Together these findings suggest that anti-KIR autoantibodies may contribute to the reduced function of NK cells in SLE patients, and that a defective NK cell function may be a risk factor for the development of lupus nephritis.

Keywords
autoantibody, killer cell immunoglobulin-like receptor, systemic lupus erythematosus, nephritis, natural killer cells, primary Sjogren's syndrome
National Category
Immunology in the medical area Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-394956 (URN)10.3389/fimmu.2019.02164 (DOI)000485181000001 ()
Funder
Swedish Cancer SocietySwedish Society of MedicineSwedish Rheumatism Association
Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2019-10-21Bibliographically approved
Hagberg, N. & Rönnblom, L. (2019). Interferon-α enhances the IL-12-induced STAT4 activation selectively in carriers of the STAT4 SLE risk allele rs7574865[T] [Letter to the editor]. Annals of the Rheumatic Diseases, 78(3), 429-431
Open this publication in new window or tab >>Interferon-α enhances the IL-12-induced STAT4 activation selectively in carriers of the STAT4 SLE risk allele rs7574865[T]
2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 3, p. 429-431Article in journal, Letter (Refereed) Published
Keywords
T cells, gene polymorphism, systemic lupus erythematosus
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-366407 (URN)10.1136/annrheumdis-2018-213836 (DOI)000471061000023 ()30269051 (PubMedID)
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-06-28Bibliographically approved
Hjorton, K., Hagberg, N., Israelsson, E., Jinton, L., Berggren, O., Sandling, J. K., . . . Rönnblom, L. (2018). Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor. Arthritis Research & Therapy, 20, Article ID 238.
Open this publication in new window or tab >>Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor
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2018 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 20, article id 238Article in journal (Refereed) Published
Abstract [en]

Background: In systemic lupus erythematosus (SLE), immune complexes (ICs) containing self-derived nucleic acids trigger the synthesis of proinflammatory cytokines by immune cells. We asked how an interleukin (IL)-1 receptor-associated kinase 4 small molecule inhibitor (IRAK4i) affects RNA-IC-induced cytokine production compared with hydroxychloroquine (HCQ).

Methods: Plasmacytoid dendritic cells (pDCs) and natural killer (NK) cells were isolated from peripheral blood mononuclear cells (PBMCs) of healthy individuals. PBMCs from SLE patients and healthy individuals were depleted of monocytes. Cells were stimulated with RNA-containing IC (RNA-IC) in the presence or absence of IRAK4i I92 or HCQ, and cytokines were measured by immunoassay or flow cytometry. Transcriptome sequencing was performed on RNA-IC-stimulated pDCs from healthy individuals to assess the effect of IRAK4i and HCQ.

Results: In healthy individuals, RNA-IC induced interferon (IFN)-α, tumor necrosis factor (TNF)-α, IL-6, IL-8, IFN-γ, macrophage inflammatory protein (MIP)1-α, and MIP1-β production in pDC and NK cell cocultures. IFN-α production was selective for pDCs, whereas both pDCs and NK cells produced TNF-α. IRAK4i reduced the pDC and NK cell-derived cytokine production by 74–95%. HCQ interfered with cytokine production in pDCs but not in NK cells. In monocyte-depleted PBMCs, IRAK4i blocked cytokine production more efficiently than HCQ. Following RNA-IC activation of pDCs, 975 differentially expressed genes were observed (false discovery rate (FDR) < 0.05), with many connected to cytokine pathways, cell regulation, and apoptosis. IRAK4i altered the expression of a larger number of RNA-IC-induced genes than did HCQ (492 versus 65 genes).

Conclusions: The IRAK4i I92 exhibits a broader inhibitory effect than HCQ on proinflammatory pathways triggered by RNA-IC, suggesting IRAK4 inhibition as a therapeutic option in SLE.

Keywords
HCQ, IRAK4, NK, SLE, pDC
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-366403 (URN)10.1186/s13075-018-1702-0 (DOI)000448243100001 ()30355354 (PubMedID)
Funder
Swedish Rheumatism AssociationAstraZenecaSwedish Research CouncilSwedish Society of Medicine
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-01-08Bibliographically approved
Hjorton, K., Hagberg, N., Israelsson, E., Berggren, O., Sandling, J. K., Thorn, K., . . . Rönnblom, L. (2018). Cytokine production by activated plasmacytoid dendritic cells and NK cells is suppressed by an IRAK4 inhibitor. Paper presented at Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS. Annals of the Rheumatic Diseases, 77, 1268-1269
Open this publication in new window or tab >>Cytokine production by activated plasmacytoid dendritic cells and NK cells is suppressed by an IRAK4 inhibitor
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, p. 1268-1269Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-368669 (URN)10.1136/annrheumdis-2018-eular.6369 (DOI)000444351003561 ()
Conference
Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS
Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2018-12-10Bibliographically approved
Hagberg, N., Joelsson, M., Leonard, D., Reid, S., Eloranta, M.-L., Mo, J., . . . Rönnblom, L. (2018). The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE. Paper presented at Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS. Annals of the Rheumatic Diseases, 77(7), 1070-1077
Open this publication in new window or tab >>The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 7, p. 1070-1077Article in journal (Refereed) Published
Abstract [en]

Objectives Genetic variants in the transcription factor STAT4 are associated with increased susceptibility to systemic lupus erythematosus (SLE) and a more severe disease phenotype. This study aimed to clarify how the SLE-associated intronic STAT4 risk allele rs7574865[T] affects the function of immune cells in SLE.

Methods Peripheral blood mononuclear cells (PBMCs) were isolated from 52 genotyped patients with SLE. Phosphorylation of STAT4 (pSTAT4) and STAT1 (pSTAT1) in response to interferon (IFN)-α, IFN-γ or interleukin (IL)-12, total levels of STAT4, STAT1 and T-bet, and frequency of IFN-γ+ cells on IL-12 stimulation were determined by flow cytometry in subsets of immune cells before and after preactivation of cells with phytohaemagglutinin (PHA) and IL-2. Cellular responses and phenotypes were correlated to STAT4 risk allele carriership. Janus kinase inhibitors (JAKi) selective for TYK2 (TYK2i) or JAK2 (JAK2i) were evaluated for inhibition of IL-12 or IFN-γ-induced activation of SLE PBMCs.

Results In resting PBMCs, the STAT4 risk allele was neither associated with total levels of STAT4 or STAT1, nor cytokine-induced pSTAT4 or pSTAT1. Following PHA/IL-2 activation, CD8+ T cells from STAT4 risk allele carriers displayed increased levels of STAT4 resulting in increased pSTAT4 in response to IL-12 and IFN-α, and an augmented IL-12-induced IFN-γ production in CD8+ and CD4+ T cells. The TYK2i and the JAK2i efficiently blocked IL-12 and IFN-γ-induced activation of PBMCs from STAT4 risk patients, respectively.

Conclusions T cells from patients with SLE carrying the STAT4 risk allele rs7574865[T] display an augmented response to IL-12 and IFN-α. This subset of patients may benefit from JAKi treatment.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-368664 (URN)10.1136/annrheumdis-2017-212794 (DOI)000438037000030 ()29475858 (PubMedID)
Conference
Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS
Funder
Swedish Research Council, D0283001, A0258801Swedish Rheumatism AssociationKing Gustaf V Jubilee FundKnut and Alice Wallenberg Foundation, 2011.0073AstraZenecaSwedish Society of MedicineErik, Karin och Gösta Selanders FoundationThe Research Council of Norway
Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2019-07-03Bibliographically approved
Berggren, O., Hagberg, N., Alexsson, A., Weber, G., Rönnblom, L. & Eloranta, M.-L. (2017). Plasmacytoid dendritic cells and RNA-containing immune complexes drive expansion of peripheral B cell subsets with an SLE-like phenotype. PLoS ONE, 12(8), Article ID e0183946.
Open this publication in new window or tab >>Plasmacytoid dendritic cells and RNA-containing immune complexes drive expansion of peripheral B cell subsets with an SLE-like phenotype
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 8, article id e0183946Article in journal (Refereed) Published
Abstract [en]

Background Hyperactive B cells and a continuous interferon (IFN)-alpha production by plasmacytoid dendritic cells (pDCs) play a key role in systemic lupus erythematosus (SLE). We asked whether the interaction between B cells and pDCs stimulated with RNA-containing immune complexes affects peripheral B cell subsets. Methods B cells and pDCs were isolated from blood of healthy individuals and stimulated with immune complexes consisting of SLE-IgG and U1snRNP (RNA-IC). Expression of cell surface molecules as well as IL-6 and IL-10 production were determined by flow cytometry and immunoassays. Gene expression profiles were determined by a NanoString nCounter expression array. Results We found a remarkable increase of double negative CD27-IgD-B cells, from 7% within fresh CD19+B cells to 37% in the RNA-IC-stimulated co-cultures of B cells and pDCs, comparable to the frequency of double negative B cells in SLE patients. Gene expression analysis of the double negative CD27-IgD -and the CD27 + IgD-memory B cells revealed that twenty-one genes were differentially expressed between the two B cell subsets (>= 2-fold, p< 0.001). The, IL21R, IL4R, CCL4, CCL3, CD83 and the IKAROS Family Zinc Finger 2 (IKZ2) showed higher expression in the double negative CD27-IgD-B cells. Conclusion The interactions between B cells and pDCs together with RNA-containing IC led to an expansion of B cells with similar phenotype as seen in SLE, suggesting that the pDC-B cell crosstalk contributes to the autoimmune feed-forward loop in SLE.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-335229 (URN)10.1371/journal.pone.0183946 (DOI)000408438600061 ()28846748 (PubMedID)
Available from: 2017-12-05 Created: 2017-12-05 Last updated: 2017-12-05Bibliographically approved
Hjorton, K., Hagberg, N., Berggren, O., Mo, J., Sandling, J. K., Eloranta, M.-L. & Rönnblom, L. (2016). The Effect of Hydroxychloroquine and IRAK4 Inhibition on The IFN-A and TNF-A Production Induced by Sle Related Immune Complexes. Paper presented at Annual European Congress of Rheumatology (EULAR), JUN 08-11, 2016, London, ENGLAND. Annals of the Rheumatic Diseases, 75, 277-277
Open this publication in new window or tab >>The Effect of Hydroxychloroquine and IRAK4 Inhibition on The IFN-A and TNF-A Production Induced by Sle Related Immune Complexes
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2016 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, p. 277-277Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP, 2016
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-347374 (URN)10.1136/annrheumdis-2016-eular.4663 (DOI)000401523101229 ()
Conference
Annual European Congress of Rheumatology (EULAR), JUN 08-11, 2016, London, ENGLAND
Available from: 2018-04-09 Created: 2018-04-09 Last updated: 2018-04-09Bibliographically approved
Hagberg, N. & Rönnblom, L. (2016). The Interferon System in Lupus Erythematosus. In: George C. Tsokos (Ed.), Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects (pp. 153-158). Academic Press
Open this publication in new window or tab >>The Interferon System in Lupus Erythematosus
2016 (English)In: Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects / [ed] George C. Tsokos, Academic Press, 2016, p. 153-158Chapter in book (Refereed)
Abstract [en]

The interferons (IFNs) are a large group of proteins classified into three types (I-III) that induce viral resistance in cells and also act as immune adjuvants and stimulate the adaptive immune system. Increased levels of mainly type I IFN are seen in patients with systemic lupus erythematosus (SLE), which is due to the presence of self-derived inducers of type I IFN production acting on plasmacytoid dendritic cells. Such inducers consist of autoantigens containing nucleic acid that stimulate endosomal Toll-like receptors, which trigger the ongoing IFN synthesis that leads to an increased transcription of type I IFN-regulated genes in target cells (an interferon signature). The type I IFN production contributes to the autoimmune process and several therapies aiming to inhibit the production, or action, of type I IFN have been developed. Preliminary results indicate that this therapeutic strategy may be successful in a subset of patients with SLE.

Place, publisher, year, edition, pages
Academic Press, 2016
Keywords
Interferon, Interferon signature, Plasmacytoid dendritic cell, Systemic lupus erythematosus, Toll-like receptor
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-310266 (URN)10.1016/B978-0-12-801917-7.00019-X (DOI)2-s2.0-84967225658 (Scopus ID)9780128020098 (ISBN)9780128019177 (ISBN)
Available from: 2017-01-02 Created: 2016-12-13 Last updated: 2017-01-02Bibliographically approved
Hagberg, N., Theorell, J., Hjorton, K., Spee, P., Eloranta, M.-L., Bryceson, Y. T. & Rönnblom, L. (2015). Functional Anti-CD94/NKG2A and Anti-CD94/NKG2C Autoantibodies in Patients With Systemic Lupus Erythematosus. ARTHRITIS & RHEUMATOLOGY, 67(4), 1000-1011
Open this publication in new window or tab >>Functional Anti-CD94/NKG2A and Anti-CD94/NKG2C Autoantibodies in Patients With Systemic Lupus Erythematosus
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2015 (English)In: ARTHRITIS & RHEUMATOLOGY, ISSN 2326-5191, Vol. 67, no 4, p. 1000-1011Article in journal (Refereed) Published
Abstract [en]

Objective. Recently we serendipitously identified a patient with systemic lupus erythematosus (SLE) who was positive for autoantibodies to CD94/natural killer receptor group 2A (NKG2A). The present study was undertaken to investigate the occurrence and function of autoantibodies targeting lectin-like NK cell receptors in SLE. Methods. Sera from 203 SLE patients and 90 healthy individuals were analyzed, by flow cytometry, for Ig binding to Ba/F3 cells transfected with CD94/NKG2A, CD94/NKG2C, or NKG2D. Autoantibodies identified were characterized with regard to interference with HLA-E binding, effect on NK cell activation in response to HLA-E-transfected K562 cells, and capacity to facilitate antibody-dependent cell-mediated cytotoxicity (ADCC). Levels of autoantibodies were determined in longitudinally sampled sera, and correlations with disease activity (SLE Disease Activity Index 2000) and severity (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) were investigated. Results. Anti-CD94/NKG2A autoantibodies were identified in 7 SLE patients. The autoantibodies from 6 patients inhibited binding of HLA-E to CD94/NKG2A, whereas those from the seventh patient augmented this binding. Autoantibodies from 2 patients also reacted with the activating receptor CD94/NKG2C, with inhibition of the binding of HLA-E to CD94/NKG2C observed in 1 case and enhancement of this binding in the other. None of the sera contained anti-NKG2D autoantibodies. The levels of anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies correlated with disease activity and with a more severe SLE phenotype. Mechanistically, anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies both interfered with HLA-E-mediated regulation of NK cell activation and facilitated the elimination of target cells expressing CD94/NKG2A or CD94/NKG2C through ADCC. Conclusion. Anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies occur in a subset of patients with clinically active SLE. Given their capacity to deplete certain NK cell subsets and interfere with particular NK cell function, such autoantibodies may promote the pathogenesis of SLE.

National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-251974 (URN)10.1002/art.38999 (DOI)000351841800019 ()25510434 (PubMedID)
Available from: 2015-05-05 Created: 2015-04-28 Last updated: 2016-08-08Bibliographically approved
Hagberg, N. & Rönnblom, L. (2015). Systemic lupus erythematosus: a disease with a dysregulated type I interferon system. Scandinavian Journal of Immunology, 82(3), 199-207
Open this publication in new window or tab >>Systemic lupus erythematosus: a disease with a dysregulated type I interferon system
2015 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 82, no 3, p. 199-207Article, review/survey (Refereed) Published
Abstract [en]

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by the loss of tolerance to nuclear antigens, immune complex formation and inflammation in multiple organs. The disease is very heterogeneous and most clinicians consider SLE as a group of diseases with similar features where the pathogenesis is driven by a combination of genetic and environmental factors. One of the most prominent features, shared by the majority of SLE patients, is a continuous activation of the type I interferon (IFN) system, which manifests as increased serum levels of IFNα and/or an increased expression of type I IFN induced genes, a so called type I IFN-signature. The mechanisms behind this IFN-signature have partly been clarified during recent years, although the exact function of the IFN regulated genes in the disease process is unclear. In this review we will describe the type I IFN system and its regulation and summarize the numerous findings implicating an important ethiopathogenic role of a dysregulated type I IFN system in SLE. Furthermore, strategies to therapeutically target the type I IFN system that are currently evaluated preclinically and in clinical trials will be mentioned.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-259463 (URN)10.1111/sji.12330 (DOI)000360044100006 ()26099519 (PubMedID)
Available from: 2015-08-04 Created: 2015-08-04 Last updated: 2017-12-04Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-2064-2716

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