| 1. |
- Brauner, Susanna, et al.
(author)
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H1N1 vaccination in Sjogren's syndrome triggers polyclonal B cell activation and promotes autoantibody production
- 2017
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 76:10, s. 1755-1763
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Journal article (peer-reviewed)abstract
- ObjectivesVaccination of patients with rheumatic disease has been reported to result in lower antibody titres than in healthy individuals. However, studies primarily include patients on immunosuppressive therapy. Here, we investigated the immune response of treatment-naive patients diagnosed with primary Sjogren's syndrome (pSS) to an H1N1 influenza vaccine.Methods Patients with Sjogren's syndrome without immunomodulatory treatment and age-matched and gender-matched healthy controls were immunised with an H1N1 influenza vaccine and monitored for serological and cellular immune responses. Clinical symptoms were monitored with a standardised form. IgG class switch and plasma cell differentiation were induced in vitro in purified naive B cells of untreated and hydroxychloroquine-treated patients and healthy controls. Gene expression was assessed by NanoString technology.ResultsSurprisingly, treatment-naive patients with Sjogren's syndrome developed higher H1N1 IgG titres of greater avidity than healthy controls on vaccination. Notably, off-target B cells were also triggered resulting in increased anti-EBV and autoantibody titres. Endosomal toll-like receptor activation of naive B cells in vitro revealed a greater propensity of patient-derived cells to differentiate into plasmablasts and higher production of class switched IgG. The amplified plasma cell differentiation and class switch could be induced in cells from healthy donors by preincubation with type 1 interferon, but was abolished in hydroxychloroquine-treated patients and after in vitro exposure of naive B cells to chloroquine.ConclusionsThis comprehensive analysis of the immune response in autoimmune patients to exogenous stimulation identifies a mechanistic basis for the B cell hyperactivity in Sjogren's syndrome, and suggests that caution is warranted when considering vaccination in non-treated autoimmune patients.
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| 4. |
- Brauner, Susanna
(author)
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TRIM21/ Ro52 in B cell pathology
- 2013
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Doctoral thesis (other academic/artistic)abstract
- Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease affecting 0.2% of the population. Several B cell aberrances have been linked to pSS, such as autoantibody production, hypergammaglobulinemia and B cell associated genetic polymorphisms. In addition, pSS patients display a 16 fold increased risk to develop B cell lymphomas. Autoantibodies to TRIM21/ Ro52 are detected in approximately 70% of patients with pSS. The cellular role of TRIM21 was largely unknown when this thesis was initiated. However, TRIM21 had been implicated to belong to the TRIpartite Motif (TRIM) family, of which many proteins are E3 ligases, mediating ubiqiutination. The aims of this thesis were to characterize the role of B cells in primary Sjögren’s syndrome pathogenesis and to elucidate the cellular role of the autoantigen TRIM21. By using vaccination as a tool to study immune responses pSS in vivo, we detected a vigorous B cell hyperreactivity, specifically in IgG producing cells. Further, in vitro induction of IgG class switch revealed an increased response to endosomal Toll-like receptor (TLR) stimulation in B cells from patients. This phenomenon may explain the hypergammaglobulinemia observed in pSS patients, and possibly also the high autoantibody titers. In both in vivo and in vitro ubiquitination assays, we could show that TRIM21 is an E3 ligase. To better understand its role in immunity, a TRIM21-/- IRES-GFP mouse was generated. Studies revealed a hyperresponsive immune system. Mild immune activation induced Th17-dependent dermatitis and subsequently systemic autoimmunity with hypergammaglobulinemia, anti-nuclear antibodies and glomerulonephritis. We observed that TRIM21 regulates several interferon regulatory factors (IRFs), central transcription factors of pro-inflammatory responses, by ubiquitination. The loss of TRIM21 expression therefore resulted in loss of negative regulation of the transcription factors, and thereby accentuated immune responses. By using GFP as a reporter in the TRIM21-deficient-IRES-GFP mice, we observed that TRIM21 protein is almost exclusively expressed in hematopoietic cells. Further, overexpression of TRIM21 in a B cell lymphoma cell line resulted in markedly reduced proliferation and increased apoptosis. These findings prompted us to study the role of TRIM21 in lymphomagenesis. In three independent cohorts of diffuse large B cell lymphomas (DLBCL), a strong correlation between low TRIM21 expression and short overall and progression-free survival was demonstrated. In conclusion, these studies show that endosomal TLR hyperreactivity underlie hypergammaglobulinemia in primary Sjögren’s syndrome. Further, the major autoantigen TRIM21 is an E3 ligase, negatively regulating interferon and TLR responses. Loss of TRIM21 expression is associated both to aggravated immune responses and poor outcome in lymphoma development, implicating a central role for TRIM21 in the development of both systemic autoimmune diseases and lymphomas.
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| 5. |
- Creary, Lisa E., et al.
(author)
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Next-Generation Sequencing Identifies Extended HLA Class I and II Haplotypes Associated With Early-Onset and Late-Onset Myasthenia Gravis in Italian, Norwegian, and Swedish Populations
- 2021
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In: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 12
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Journal article (peer-reviewed)abstract
- Genetic susceptibility to myasthenia gravis (MG) associates with specific HLA alleles and haplotypes at the class I and II regions in various populations. Previous studies have only examined alleles at a limited number of HLA loci that defined only broad serotypes or alleles defined at the protein sequence level. Consequently, genetic variants in noncoding and untranslated HLA gene segments have not been fully explored but could also be important determinants for MG. To gain further insight into the role of HLA in MG, we applied next-generation sequencing to analyze sequence variation at eleven HLA genes in early-onset (EO) and late-onset (LO) non-thymomatous MG patients positive for the acetylcholine receptor (AChR) antibodies and ethnically matched controls from Italy, Norway, and Sweden. For all three populations, alleles and haplotype blocks present on the ancestral haplotype AH8.1 were associated with risk in AChR-EOMG patients. HLA-B*08:01:01:01 was the dominant risk allele in Italians (OR = 3.28, P = 1.83E−05), Norwegians (OR = 3.52, P = 4.41E−16), and in Swedes HLA-B*08:01 was the primary risk allele (OR = 4.24, P <2.2E-16). Protective alleles and haplotype blocks were identified on the HLA-DRB7, and HLA-DRB13.1 class II haplotypes in Italians and Norwegians, whereas in Swedes HLA-DRB7 exhibited the main protective effect. For AChR-LOMG patients, the HLA-DRB15.1 haplotype and associated alleles were significantly associated with susceptibility in all groups. The HLA-DR13–HLA-DR–HLA-DQ haplotype was associated with protection in all AChR-LOMG groups. This study has confirmed and extended previous findings that the immunogenetic predisposition profiles for EOMG and LOMG are distinct. In addition, the results are consistent with a role for non-coding HLA genetic variants in the pathogenesis of MG.
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| 6. |
- Espinosa, Alexander, et al.
(author)
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Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway
- 2009
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In: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 206:8, s. 1661-1671
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Journal article (peer-reviewed)abstract
- Ro52/Trim21 is targeted as an autoantigen in systemic lupus erythematosus and Sjögren's syndrome. Polymorphisms in the Ro52 gene have been linked to these autoimmune conditions, but the molecular mechanism by which Ro52 may promote development of systemic autoimmune diseases has not been explored. To address this issue, we generated Ro52-null mice (Ro52(-/-)), which appear phenotypically normal if left unmanipulated. However, Ro52(-/-) mice develop severe dermatitis extending from the site of tissue injury induced by ear tags. The affected mice further develop several signs of systemic lupus with hypergammaglobulinemia, autoantibodies to DNA, proteinuria, and kidney pathology. Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17). Loss of IL-23/IL-17 by genetic deletion of IL-23/p19 in the Ro52(-/-) mice conferred protection from skin disease and systemic autoimmunity. These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and systemic autoimmunity through the IL-23-Th17 pathway.
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| 8. |
- Oke, Vilija, et al.
(author)
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IFN-λ1 with Th17 axis cytokines and IFN-α define different subsets in systemic lupus erythematosus (SLE).
- 2017
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In: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 19
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Journal article (peer-reviewed)abstract
- BACKGROUND: Interferon (IFN)-α is thought to have a pivotal role in systemic lupus erythematosus (SLE), and type III IFNs (IFN-λ) were recently also associated with SLE. In this study, we measured levels of IFN-α, IFN-λ1, and related cytokines, such as IL-17A, IL-23, and interferon-γ-induced protein 10 (IP-10), in a Karolinska University Hospital cohort of patients with SLE and control subjects. The objective of the study was to investigate if cytokine measurements could identify different subsets of patients with active SLE and higher disease damage.METHODS: We included 261 patients with SLE and 261 population control subjects. All participants underwent a standardized clinical examination. Medical files were reviewed. Patients with SLE were assessed for current organ manifestations, disease activity, and damage. Routine blood parameters, complement levels, and serology were analyzed at the time of inclusion. Levels of IFN-λ1, IFN-α, IL-17A, IL-23, and IP-10 were measured by enzyme-linked immunosorbent assay.RESULTS: IFN-λ1 and IFN-α were detected in 29% and 44% of patients, respectively, but their levels did not correlate. High serum levels of IFN-λ1 were positively associated with antinucleosome antibodies and lymphopenia but negatively with musculoskeletal damage. Positive correlations between levels of IFN-λ1, IL-17A, and IL-23 were observed. Patients with high levels of these three cytokines had more disease damage, especially renal impairment. High levels of IFN-α were associated with mucocutaneous disease; leukopenia; and low complement, Ro/SSA, and La/SSB. Vascular events and antiphospholipid antibodies were uncommon. We identified two subgroups with high disease activity: one with double-high IFN-λ1 and IFN-α and another with IP-10(high). The former had more neuropsychiatric manifestations, and the latter had more arthritis. Increased levels of both types I and III IFNs were found in a proportion of population control subjects. Therefore, high IFN levels do not seem to be SLE-specific biomarkers.CONCLUSIONS: Measurements of circulating IFN-λ1 and IFN-α define subsets of patients with SLE with different characteristics. Levels of IFN-λ1 correlate with T-helper type 17 cytokines and identify a subgroup with more damage. High disease activity is associated with either simultaneous upregulation of IFN-λ1 and IFN-α or independently with IP-10. Our findings could be of major importance when tailoring therapy for patients with SLE with agents targeting IFN pathways.
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| 9. |
- Ottosson, Lars, et al.
(author)
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Structural, functional and immunologic characterization of folded subdomains in the Ro52 protein targeted in Sjögren's syndrome
- 2006
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In: Molecular Immunology. - : Elsevier BV. - 0161-5890 .- 1872-9142. ; 43:6, s. 588-598
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Journal article (peer-reviewed)abstract
- Ro52, one of the major autoantigens in the rheumatic disease Sjögren's syndrome (SS), belongs to the tripartite motif (TRIM) or RING-B-box-coiled-coil (RBCC) protein family, thus comprising an N-terminal RING, followed by a B-box and a coiled-coil region. Several different proteomic functions have been suggested for Ro52, including DNA binding, protein interactions and Zn 2+-binding. To analyze the presence and/or absence of these functions and, in particular, map those to different subregions, the modular composition of the Ro52 protein was experimentally characterized. Two structured parts of Ro52 were identified, corresponding to the RING-B-box and the coiled-coil regions, respectively. Secondary structure analysis by circular dichroism (CD) spectroscopy indicated that the two subregions are independently structured. The entire RING-B-box region displayed Zn2+-dependent stabilization against proteolysis in the presence of Zn2+, indicating functional Zn2+-binding sites in both the RING and the B-box. However, no stabilization with DNA was detected, irrespective of Zn2+, thus suggesting that the RING-B-box region does not bind DNA. Oligomerization of the coiled-coil was investigated by analytical ultracentrifugation and in a mammalian two-hybrid system. Both methods show weak homodimer affinity, in parity with other coiled-coil domains involved in regulatory interactions. The C-terminal B30.2 region was rapidly degraded both during cellular expression and refolding, indicating a less stable structure. Immunologic analysis of the stable protein regions with sera from patients with Sjögren's syndrome shows that immunodominant epitopes to a large extent are localized in the structurally stable parts of Ro52. The results form a basis for further Ro52 functional studies on the proteome level. © 2005 Elsevier Ltd. All rights reserved.
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| 10. |
- Petersson, Malin, et al.
(author)
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Patient-reported symptom severity in a nationwide myasthenia gravis cohort : cross-sectional analysis of the Swedish GEMG study
- 2021
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In: Neurology. - : Lippincott Williams & Wilkins. - 0028-3878 .- 1526-632X. ; 97:14, s. e1382-e1391
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Journal article (peer-reviewed)abstract
- Background and Objectives: To describe myasthenia gravis activities of daily living (MG-ADL) in relation to clinical characteristics in a large Swedish nationwide cohort.Methods: In a cross-sectional prevalence cohort study, the Genes and Environment in Myasthenia Gravis study, performed from November 2018 through August 2019, patients with myasthenia gravis (MG) were invited to submit an extensive 106-item life environment questionnaire, including the MG-ADL score. Patients were classified into early-onset MG (EOMG, <50 years), late-onset MG (LOMG, >= 50 years), or thymoma-associated MG (TAMG). Comparisons of disease-specific characteristics were made between subgroups, sexes, and different MG-ADL scores.Results: A total of 1,077 patients were included, yielding a 74% response rate: 505 (47%) were classified as EOMG, 520 (48%) LOMG, and 45 (4%) TAMG. Mean age at inclusion was 64.3 years (SD 15.7) and mean disease duration was 14.6 years (SD 14.0). Complete MG-ADL scores (n = 1,035) ranged from 0p to 18p, where 26% reported a score of 0p. Higher MG-ADL scores were associated with female sex, obesity, and diagnostic delay (odds ratio [OR] 1.62, 1.72, and 1.69; p(adj) = 0.017, 0.013, and 0.008) and inversely correlated with high educational attainment (OR 0.59; p(adj) = 0.02), but not with age at inclusion, disease subtype, or disease duration. Almost half of the population (47%) reported MG-ADL >= 3p, corresponding to an unsatisfactory symptom state.Discussion: In this nationwide study, comprising more than 40% of the prevalent MG population in Sweden, almost half of the patients reported current disease symptoms associated with an unsatisfactory symptom state, indicating the need for improved treatment options.
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