| 1. |
- Blomberg, Stina, et al.
(författare)
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Expression of the markers BDCA-2 and BDCA-4 and production of interferon-alpha by plasmacytoid dendritic cells in systemic lupus erythematosus
- 2003
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 48:9, s. 2524-32
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To study the expression of blood dendritic cell antigen 2 (BDCA-2) and BDCA-4 molecules by plasmacytoid dendritic cells (PDCs) in the blood of patients with systemic lupus erythematosus (SLE), and to study PDC production of interferon-alpha (IFN alpha) and its inhibition by anti-BDCA-2 and anti-BDCA-4 antibodies. METHODS: Peripheral blood mononuclear cells (PBMCs) from SLE patients (SLE PBMCs) and from healthy controls were induced to produce IFN alpha in vitro by SLE serum containing an endogenous IFN alpha-inducing factor (SLE-IIF) or by herpes simplex virus type 1 (HSV-1). The frequencies and numbers of BDCA-2-, BDCA-3-, and BDCA-4-expressing cells were analyzed by flow cytometry, and the effects of anti-BDCA-2 and anti-BDCA-4 monoclonal antibodies (mAb) on IFN alpha production were investigated. RESULTS: IFN alpha production by SLE PBMCs induced by SLE-IIF or HSV-1 was decreased compared with that of healthy control PBMCs (P = 0.002 and P = 0.0007, respectively). The proportions of BDCA-2- and BDCA-3-expressing cells in SLE PBMCs were reduced compared with those in PBMCs from healthy controls (P = 0.01 and P = 0.004, respectively). IFN alpha producers in culture, especially among SLE PBMCs, displayed reduced BDCA-2 expression and constituted only a minority of the BDCA-2-positive cells, at least in healthy control PBMCs (median 18%). IFN alpha production by both SLE and healthy control PBMCs stimulated by SLE-IIF or HSV-1 was markedly reduced by anti-BDCA-2 mAb (median 81-98% inhibition). Anti-BDCA-4 mAb only partially inhibited SLE-IIF-induced IFN alpha production. CONCLUSION: SLE patients had a reduced number of BDCA-2-expressing PDCs, also termed natural IFN alpha-producing cells, and their IFN alpha production could be inhibited by anti-BDCA-2/4 mAb. Such mAb may be a therapeutic option for inhibiting the ongoing IFN alpha production in SLE patients.
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| 2. |
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| 3. |
- Båve, Ullvi, et al.
(författare)
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Activation of the type I interferon system in primary Sjögren's syndrome : a possible etiopathogenic mechanism
- 2005
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 52:4, s. 1185-1195
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Tidskriftsartikel (refereegranskat)abstract
- Objective The etiopathogenesis of primary Sjögren's syndrome (SS) is largely unknown. In other autoimmune diseases, type I interferon (IFN) may play a pivotal role by triggering and sustaining the disease process. We therefore aimed to determine whether patients with primary SS had an activated type I IFN system. Methods Salivary gland biopsy specimens and sera from patients with primary SS were investigated for the occurrence of IFNα-producing cells and measurable IFNα levels, respectively. The ability of primary SS sera together with apoptotic or necrotic cells to induce IFNα production in normal peripheral blood mononuclear cells was examined. The IFNα inducer was characterized, and IFNα-producing cells were identified. Clinical data were correlated with the IFNα-inducing capacity of primary SS sera. Results Numerous IFNα-producing cells were detected in salivary gland biopsy specimens, despite low serum IFNα levels. Autoantibodies to RNA-binding proteins, combined with material released by necrotic or late apoptotic cells, were potent inducers of IFNα production in plasmacytoid dendritic cells (PDCs). This appeared to be attributable to RNA-containing immune complexes triggering PDCs by means of RNA and interaction with Fcγ receptor IIa. The IFNα-inducing capacity of sera was associated with positive results of a labial salivary gland biopsy (focus score ≥1) and with dermatologic, hematologic, and pulmonary manifestations. Conclusion Patients with primary SS have an activated type I IFN system. Although virus may initiate the production of IFN, the continued IFNα synthesis is caused by RNA-containing immune complexes that activate PDCs to prolong IFNα production at the tissue level. This IFNα promotes the autoimmune process by a vicious circle–like mechanism, with increased autoantibody production and formation of more endogenous IFNα inducers.
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| 4. |
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| 5. |
- Båve, Ullvi, et al.
(författare)
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Fc gamma RIIa is expressed on natural IFN-alpha-producing cells (plasmacytoid dendritic cells) and is required for the IFN-alpha production induced by apoptotic cells combined with lupus IgG
- 2003
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Ingår i: Journal of Immunology. - : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 171:6, s. 3296-302
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Tidskriftsartikel (refereegranskat)abstract
- An ongoing production of IFN-alpha may be of etiopathogenic significance in systemic lupus erythematosus (SLE). It may be due to the natural IFN-producing cells (NIPC), also termed plasmacytoid dendritic cells (PDC), activated by immune complexes that contain nucleic acids derived from apoptotic cells. We here examined the role of FcgammaR in the IFN-alpha production in vitro by PBMC induced by the combination of apoptotic U937 cells and autoantibody-containing IgG from SLE patients (SLE-IgG). The Fc portion of the SLE-IgG was essential to induce IFN-alpha production, because Fab fragments or F(ab')(2) were ineffective. Normal, especially heat-aggregated, IgG inhibited the IFN-alpha production, suggesting a role for FcgammaR on PBMC. Using blocking anti-FcgammaR Abs, the FcgammaRIIa,c (CD32) but not FcgammaRI or FcgammaRIII were shown to be involved in the IFN-alpha induction by apoptotic cells combined with SLE-IgG, but not by HSV or CpG DNA. In contrast, the action of all of these inducers was inhibited by the anti-FcgammaRIIa,b,c mAb AT10 or heat-aggregated IgG. Flow cytometric analysis revealed that approximately 50% of the BDCA-2-positive PBMC, i.e., NIPC/PDC, expressed low but significant levels of FcgammaRII, as did most of the actual IFN-alpha producers activated by HSV. RT-PCR applied to NIPC/PDC purified by FACS demonstrated expression of FcgammaRIIa, but not of FcgammaRIIb or FcgammaRIIc. We conclude that FcgammaRIIa on NIPC/PDC is involved in the activation of IFN-alpha production by interferogenic immune complexes, but may also mediate inhibitory signals. The FcgammaRIIa could therefore have a key function in NIPC/PDC and be a potential therapeutic target in SLE.
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| 6. |
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| 7. |
- Båve, Ullvi
(författare)
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Mechanisms of Interferon-α Induction in Systemic Lupus Erythematosus
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Patients with systemic lupus erythematosus (SLE) have an activated type I interferon (IFN) system with an ongoing IFN-α synthesis. This may be caused by circulating immune complexes, consisting of anti-DNA antibodies (Abs) and DNA, with IFN-α inducing capacity. Produced IFN-α may be crucial in the pathogenesis, because this cytokine can break tolerance and promote autoimmunity.In the present thesis, possible mechanisms of the IFN-α production in SLE were studied. To investigate whether IFN-α inducing material could be derived from apoptotic cells, IgG from SLE patients (SLE-IgG) were combined with apoptotic cells. This combination induced high IFN-α production in normal peripheral blood mononuclear cells (PBMC). The IFN-α induction was associated to presence of anti-RNP Abs, but not to anti-dsDNA Abs, indicating that two inducers could be active in SLE, one containing DNA and the other RNA.Apoptotic cells and SLE-IgG exclusively activated the natural interferon producing cells (NIPC) and the IFN-α response was enhanced by type I IFN and inhibited by IL-10 and TNF-α. The IFN-α induction was dependent on FcγRII, because blocking this receptor reduced IFN-α production and NIPC were found to express FcγRIIa.To further elucidate the role of different autoantibodies in the IFN-α induction, sera from patients with Sjögren´s syndrome (SS), containing autoantibodies to RNA binding proteins (SSA, SSB, RNP and/or Sm) were investigated. The combination of SS or SLE sera and apoptotic or necrotic cell material induced high IFN-α production in PBMC. RNA, but not DNA, was required for IFN-α induction, indicating that RNA and Abs to RNA-binding proteins form potent IFN-α inducing complexes.The findings in this thesis can explain central mechanisms for the activation of NIPC in SLE, and perhaps also other autoimmune diseases. This activation is mediated by interferogenic immune complexes, and modulating the NIPC activation may be a novel therapeutic approach in SLE.
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| 9. |
- Eloranta, Maija-Leena, et al.
(författare)
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A possible mechanism for endogenous activation of the type I interferon system in myositis patients with anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies
- 2007
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 56:9, s. 3112-3124
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate type I interferon (IFN) system activation and its correlation with autoantibodies and organ manifestations in polymyositis (PM), dermatomyositis (DM), and inclusion body myositis. METHODS: Sera from 30 patients and 16 healthy controls, or purified IgG, were combined with material released from necrotized cells to stimulate IFNalpha production by peripheral blood mononuclear cells (PBMCs) from healthy blood donors. Muscle biopsy specimens from 25 patients and 7 healthy controls were investigated for blood dendritic cell antigen 2 (BDCA-2)-positive plasmacytoid dendritic cells (PDCs) and IFNalpha/beta-inducible myxovirus resistance 1 (MX-1) protein. RESULTS: Sera from 13 patients who were positive for anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies induced IFNalpha production in PBMCs when combined with necrotic cell material. In addition, IgG prepared from anti-Jo-1-positive PM sera induced IFNalpha with necrotic material, but not when the latter was treated with RNase. BDCA-2 expression in PDCs in muscle tissue was increased in PM patients with anti-Jo-1 autoantibodies, while MX-1 staining in capillaries was increased in DM patients, compared with healthy individuals. IFNalpha-inducing capacity correlated with interstitial lung disease, while MX-1 expression in the capillaries correlated with DM. CONCLUSION: Immune complexes containing anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies and RNA may act as endogenous IFNalpha inducers that activate IFNalpha production in PDCs. These PDCs could be of importance for inducing myositis, whereas in DM patients without autoantibodies the presence of MX-1 protein in capillaries suggests another cellular IFNalpha source and induction mechanism. Consequently, the type I IFN system may be of importance in both PM and DM, but via different pathways.
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| 10. |
- Lövgren, Tanja, et al.
(författare)
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Induction of interferon-α by immune complexes or liposomes containing systemic lupus erythematosus autoantigen- and Sjögren's syndrome autoantigen-associated RNA
- 2006
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 54:6, s. 1917-1927
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Tidskriftsartikel (refereegranskat)abstract
- Objective To investigate the ability of systemic lupus erythematosus (SLE) autoantigen– and Sjögren's syndrome (SS) autoantigen–associated U1 small nuclear RNA (U1 snRNA) and hY1RNA to induce interferon-α (IFNα) production. Methods In vitro–transcribed U1 snRNA or hY1RNA and lipofectin were added to peripheral blood mononuclear cell (PBMC) cultures. Purified U1 snRNP particles and IgG from SLE patients (SLE-IgG) were added to cultures of PBMCs, enriched monocytes, or natural interferon–producing cells (NIPCs); the latter are also known as plasmacytoid dendritic cells (pDC). Cells were double-stained for IFNα and either blood dendritic cell antigen 2 (NIPCs/pDC) or CD14 (monocytes) and then analyzed by flow cytometry. In some experiments, RNase or inhibitors of Fcγ receptor IIa (FcγRIIa) (specific antibodies), endocytosis (chloroquine, bafilomycin A), or Toll-like receptors (TLRs; oligodeoxynucleotide 2088) were used. The produced IFNα was measured by immunoassay. Results Lipofected U1 snRNA and hY1RNA both induced IFNα production in monocytes, but not in NIPC/pDC. In contrast, U1 snRNP combined with SLE-IgG induced IFNα production only in NIPCs/pDC, and this response was decreased by RNase treatment or inhibition of the FcγRIIa, the endocytosis pathways, or the TLRs. Conclusion Our finding that U1 snRNA and hY1RNA have IFNα-inducing capacity indicates that immune complexes containing such RNA, for example U1 snRNP particles, can be at least partly responsible for the ongoing IFNα production seen in SLE and SS. These results may help to explain the molecular mechanisms behind the pathogenesis of these and other autoimmune diseases in which autoantibodies to RNA- binding proteins occur.
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