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Hjorton, Karin
Publications (8 of 8) Show all publications
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
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
Hellbacher, E., Hjorton, K., Sundström, C., Baecklund, E. & Knight, A. (2017). Malignant Lymphoma In Granulomatosis With Polyangiitis. Rheumatology, 56
Open this publication in new window or tab >>Malignant Lymphoma In Granulomatosis With Polyangiitis
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2017 (English)In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 56Article in journal (Refereed) Published
Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2017
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-320970 (URN)000397054900398 ()
Available from: 2017-04-27 Created: 2017-04-27 Last updated: 2017-04-27Bibliographically 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., 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
Knight, A., Hjorton, K., Sundström, C., Höglund, M., Backlin, C., Smedby, K. E., . . . Baecklund, E. (2015). Leukemia and Myelodysplastic Syndrome in Granulomatosis with Polyangiitis: Subtypes, Clinical Characteristics, and Outcome. Journal of Rheumatology, 42(4), 690-694
Open this publication in new window or tab >>Leukemia and Myelodysplastic Syndrome in Granulomatosis with Polyangiitis: Subtypes, Clinical Characteristics, and Outcome
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2015 (English)In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 42, no 4, p. 690-694Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Previous studies have shown that patients with granulomatosis with polyangiitis (GPA) have an increased risk of hematological malignancies, especially leukemia. Our aim was to assess clinical characteristics and treatment of patients with GPA complicated by hematological malignancies with focus on leukemia and to describe these malignancies in more detail.

METHODS: From the Swedish population-based patient register, all individuals with a diagnosis of GPA from 1964-2012 were identified (n = 3224). Through linkage with the Swedish Cancer Register, we searched for all cases of leukemia [International Classification of Diseases (ICD) 7: 204-207 and corresponding codes ICD 8-10] registered after the first discharge listing GPA. The GPA diagnosis was evaluated using the European Medical Association classification algorithm. To confirm the hematological malignancy, all diagnostic bone marrow samples were reclassified. Clinical data of both the GPA and hematological malignancy were collected from medical files.

RESULTS: Twenty-one cases were identified, all of myeloid origin, including 9 with myelodysplastic syndrome developing to acute myeloid leukemia (MDS-AML), 7 AML, 3 MDS, and 2 chronic myeloid leukemia. The median time from GPA diagnosis to hematological malignancy was 8 years (range 5-21). All patients had severe generalized GPA and had received high doses of cyclophosphamide (CYC; median cumulative dose 96.5 g). Cytopenia occurred in 76% of the patients prior to the hematological malignancy.

CONCLUSION: The findings emphasize the longterm risk of leukemia and MDS in CYC-treated, severely ill patients with GPA. Cytopenia during the course of GPA may be a warning sign and warrants a liberal attitude toward bone marrow examination.

National Category
Immunology in the medical area Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-244990 (URN)10.3899/jrheum.141104 (DOI)000353775400019 ()25641890 (PubMedID)
Available from: 2015-02-24 Created: 2015-02-23 Last updated: 2019-04-02Bibliographically approved
Hjorton, K., Hellbacher, E., Sundstrom, C., Baecklund, E. & Knight, A. (2015). Lymphoma in Patients with Granulomatosis with Polyangiitis. Arthritis & Rheumatology, 67(Suppl 10), Article ID 869.
Open this publication in new window or tab >>Lymphoma in Patients with Granulomatosis with Polyangiitis
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2015 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, no Suppl 10, article id 869Article in journal, Meeting abstract (Other academic) Published
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-285945 (URN)10.1002/art.39448 (DOI)000370860202135 ()
Available from: 2016-04-21 Created: 2016-04-20 Last updated: 2017-11-30Bibliographically approved
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