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- Ambrosi, Aurelie, et al.
(författare)
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Development of heart block in children of SSA/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern
- 2012
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Ingår i: Annals of the Rheumatic Diseases. - London : BMJ Publishing Group. - 0003-4967 .- 1468-2060. ; 71:3, s. 334-340
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Tidskriftsartikel (refereegranskat)abstract
- Objective Congenital heart block may develop in the fetuses of Ro/SSA-positive and La/SSB-positive mothers. Recurrence rates of only 10-20% despite persisting maternal antibodies indicate that additional factors are critical for the establishment of heart block. The authors investigated the influence of other maternal and fetal factors on heart block development in a Swedish population-based cohort. less thanbrgreater than less thanbrgreater thanMethods The influence of fetal gender, maternal age, parity and time of birth on heart block development was analysed in 145 families, including Ro/La-positive (n=190) and Ro/La-negative (n=165) pregnancies. less thanbrgreater than less thanbrgreater thanResults There was a recurrence rate of 12.1% in Ro/La-positive women, and no recurrence in Ro/La-negative women. Fetal gender and parity did not influence the development of heart block in either group. Maternal age in Ro/La-positive pregnancies with a child affected by heart block was, however, significantly higher than in pregnancies resulting in babies without heart block (pandlt;0.05). Seasonal timing of pregnancy influenced the outcome. Gestational susceptibility weeks 18-24 occurring during January-March correlated with a higher proportion of children with heart block and lower vitamin D levels during the same period in a representative sample of Swedish women and a corresponding higher proportion of children with heart block born in the summer (pandlt;0.02). Maternal age or seasonal timing of pregnancy did not affect the outcome in Ro/La-negative pregnancies. less thanbrgreater than less thanbrgreater thanConclusion This study identifies maternal age and seasonal timing of pregnancy as novel risk factors for heart block development in children of Ro/La-positive women. These observations may be useful for counselling when pregnancy is considered.
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- Ambrosi, Aurélie
(författare)
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The TRIM21/Ro52 E3 ligase and its antibodies in autoimmune disease
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with the systemic autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS) often have autoantibodies against Ro/SSA (composed of the TRIM21/Ro52 and Ro60 antigens) and La/SSB. The biological function of the TRIM21/Ro52 protein itself has remained unknown until its recent description as a tripartite-motif (TRIM) family member and an E3 ligase involved in ubiquitination. Congenital heart block (CHB) is a passively acquired autoimmune condition that may develop in fetuses of anti-Ro/La positive women following transfer of maternal autoantibodies across the placenta and disruption of the fetal atrioventricular (AV) conduction system. Although anti-Ro, and especially anti-TRIM21/Ro52 antibodies, have been associated with development of CHB, the risk for CHB in an anti-Ro positive pregnancy is only 1-2%. In addition, a recurrence rate of 12-20% despite persistence of maternal antibodies indicates that additional factors are required for the establishment of heart block. The aims of this thesis were 1) to contribute to the elucidation of the biological function of the TRIM21/Ro52 protein, especially regarding its role in autoimmunity, and 2) to characterize the involvement of anti-TRIM21/Ro52 antibodies in CHB pathogenesis and identify risk factors other than maternal autoantibodies for the development of heart block. Using in vitro and in vivo studies, TRIM21/Ro52 was shown to be an IFN-inducible protein expressed in immune cells, mainly localized in the cell cytoplasm but able to translocate into the nucleus upon inflammatory stimuli such as IFNα. Ubiquitination assays demonstrated that TRIM21/Ro52 is a RING-dependent E3 ligase that can interact with different E2s both in the cytoplasm and in the nucleus, and that its E3 enzymatic activity is inhibited by anti-RING antibodies present in serum of patients with SLE or SS. Importantly, TRIM21/Ro52 was shown to ubiquitinate several interferon regulatory factors (IRFs), which are transcription factors activated downstream of TLR/IFN signaling, and disruption of the Trim21 locus in vivo led to increased production of pro-inflammatory cytokines and development of systemic autoimmunity following tissue injury/infection. Anti-TRIM21/Ro52 antibodies recognizing the p200 part (amino-acids 200-239) of the protein were specifically implicated in the pathogenesis of CHB by demonstrating that they induced AV block in rodents following transfer during gestation, while antibodies targeting other domains of TRIM21/Ro52 did not. Using a rat immunization model of heart block, maternal MHC genes were shown to regulate the generation of pathogenic anti-TRIM21/Ro52 antibodies, while a different MHC haplotype was linked to susceptibility to disease in the offspring. In addition, maternal age and seasonal timing of pregnancy were identified as risk factors for the development of CHB in anti-Ro/La antibody positive pregnancies in a Swedish cohort of families with individuals affected with CHB. In summary, the TRIM21/Ro52 autoantigen is a negative regulator of IFN/TLR responses via ubiquitination of several IRFs and as such may play an important role in the pathogenesis of SLE and SS. Anti-TRIM21/Ro52 p200 antibodies can initiate development of fetal heart block and factors such as fetal genetic susceptibility, maternal age and seasonal timing of pregnancy may promote the establishment of CHB.
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| 7. |
- Brauner, Susanna, et al.
(författare)
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H1N1 vaccination in Sjogren's syndrome triggers polyclonal B cell activation and promotes autoantibody production
- 2017
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 76:10, s. 1755-1763
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Tidskriftsartikel (refereegranskat)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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- Espinosa, Alexander, et al.
(författare)
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Anti-Ro52 Autoantibodies from Patients with Sjögren's Syndrome Inhibit the Ro52 E3 Ligase Activity by Blocking the E3/E2 Interface
- 2011
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Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 286:42, s. 36478-36491
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Tidskriftsartikel (refereegranskat)abstract
- Ro52 (TRIM21) is an E3 ligase of the tripartite motif family that negatively regulates proinflammatory cytokine production by ubiquitinating transcription factors of the interferon regulatory factor family. Autoantibodies to Ro52 are present in patients with lupus and Sjögren's syndrome, but it is not known if these autoantibodies affect the function of Ro52. To address this question, the requirements for Ro52 E3 ligase activity were first analyzed in detail. Scanning a panel of E2 ubiquitin-conjugating enzymes, we found that UBE2D1–4 and UBE2E1–2 supported the E3 ligase activity of Ro52 and that the E3 ligase activity of Ro52 was dependent on its RING domain. We also found that the N-terminal extensions in the class III E2 enzymes affected their interaction with Ro52. Although the N-terminal extension in UBE2E3 made this E2 enzyme unable to function together with Ro52, the N-terminal extensions in UBE2E1 and UBE2E2 allowed for a functional interaction with Ro52. Anti-Ro52-positive patient sera and affinity-purified anti-RING domain autoantibodies inhibited the E3 activity of Ro52 in ubiquitination assays. Using NMR, limited proteolysis, ELISA, and Ro52 mutants, we mapped the interactions between Ro52, UBE2E1, and anti-Ro52 autoantibodies. We found that anti-Ro52 autoantibodies inhibited the E3 ligase activity of Ro52 by sterically blocking the E2/E3 interaction between Ro52 and UBE2E1. Our data suggest that anti-Ro52 autoantibodies binding the RING domain of Ro52 may be actively involved in the pathogenesis of rheumatic autoimmune disease by inhibiting Ro52-mediated ubiquitination.
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- Espinosa, Alexander, et al.
(författare)
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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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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 206:8, s. 1661-1671
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Tidskriftsartikel (refereegranskat)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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| 11. |
- Strandberg, Linn, et al.
(författare)
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Interferon-alpha induces up-regulation and nuclear translocation of the Ro52 autoantigen as detected by a panel of novel Ro52-specific monoclonal antibodies
- 2008
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Ingår i: Journal of Clinical Immunology. - : Springer Science and Business Media LLC. - 0271-9142 .- 1573-2592. ; 28:3, s. 220-31
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Tidskriftsartikel (refereegranskat)abstract
- Interferon-alpha (IFN-alpha) has been implicated in the pathogenesis of Sjögren's syndrome and systemic lupus erythematosus. Ro52, which was recently identified as an E3 ligase with anti-proliferative and pro-apoptotic properties, is a major autoantigen targeted in both these conditions. Microarray analyses have indicated up-regulation of Ro52 by IFN-alpha, and the objective of the present study was to address the potential link between IFN-alpha and Ro52. To investigate the influence of IFN-alpha on Ro52 protein levels and cellular localization, we generated a panel of monoclonal antibodies to different domains of Ro52. These novel monoclonal antibodies were characterized by immunoprecipitation, Western blot, and enzyme-linked immunosorbent assay using cell lysates, recombinant Ro52 protein, and synthetic peptides. Ro52 was up-regulated in HeLa cells and human B cells at the messenger RNA and protein levels in response to IFN-alpha stimulation as detected by reverse transcriptase polymerase chain reaction and Western blot. After up-regulation, Ro52 translocated from the cytoplasm to the nucleus. The nuclear translocation of Ro52 was observed after staining with generated monoclonal antibodies specific for both the RING, coiled-coil, and B30.2 domains of Ro52 and the nuclear translocation of Ro52 preceded IFN-alpha-induced apoptotic cell death detected by caspase-3 and TUNEL staining in the treated cultures. In conclusion, our data show that IFN-alpha first induces up-regulation of Ro52 protein and then prompts translocation of the up-regulated Ro52 protein in to the nucleus. The translocation precedes apoptosis of the IFN-alpha exposed cells, suggesting a role for Ro52 in mediating the anti-proliferative or pro-apoptotic effects of the autoimmune-related cytokine IFN-alpha.
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- Tingström, Joanna, et al.
(författare)
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Anti-Ro/SSA autoantibody-positive women's experience of information given on the risk of congenital heart block.
- 2016
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Ingår i: Lupus. - : Sage Publications. - 0961-2033 .- 1477-0962. ; 25:5, s. 536-542
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Congenital heart block (CHB) may develop in fetuses of women with anti-Ro/SSA autoantibodies, and carries substantial morbidity and mortality. The aim was to evaluate how information on CHB is imparted and identify areas of improvement.METHODS: A questionnaire was distributed to anti-Ro/SSA antibody-positive women who had either participated in a surveillance programme but whose expected child did not develop CHB (n = 100, denoted Doppler-Assessed Pregnancies (DAP) group) or given birth to a child with CHB (n = 88, denoted CHB-Affected Pregnancies (CAP) group).RESULTS: The response rate was 83% (157/188). Most women received the information on CHB when they were already pregnant (DAP group 60%, CAP group 83%). However, a majority of them would have wanted the information before pregnancy (DAP group 52%, CAP group 56%), and most stated that it would not have influenced their decision to have a child (DAP group 77%, CAP group 58%). The ability to both understand the information and to perceive the information as sufficient were significantly higher when someone trained in paediatric cardiology gave the information.CONCLUSIONS: Our findings indicate that information on CHB should be given to women before pregnancy. The data further highlight the importance of having specific knowledge for giving relevant and understandable, yet sufficient information.
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