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| 32. |
- Berggren, Olof, et al.
(författare)
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Activation of plasmacytoid dendritic cells and B cells with two structurally different Toll-like receptor 7 agonists
- 2020
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 91:6
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Tidskriftsartikel (refereegranskat)abstract
- Synthetic Toll-like receptor (TLR) 7 agonists have been suggested as immune modulators in a range of conditions. In contrast, self-derived TLR7 activators, such as RNA-containing immune complexes (RNA-IC), can contribute to autoimmune diseases due to endogenous immune activation. The exact difference in immune cell response between synthetic and endogenous TLR7 triggers is only partly known. An understanding of these differences could aid in the development of new therapeutic agents and provide insights into autoimmune disease mechanisms. We therefore compared the stimulatory capacity of two TLR7 agonists, RNA-IC and a synthetic small molecule DSR-6434, on blood leucocytes, plasmacytoid dendritic cells (pDCs) and B cells from healthy individuals. IFN-α, IL-6, IL-8 and TNF levels were measured by immunoassays, and gene expression in pDCs was analysed by an expression array. DSR-6434 triggered 20-fold lower levels of IFN-α by pDCs, but higher production of IL-6, IL-8 and TNF, compared to RNA-IC. Furthermore, IFN-α and TNF production were increased with exogenous IFN-α2b priming, whereas IL-8 synthesis by B cells was reduced for both stimuli. Cocultivation of pDCs and B cells increased the RNA-IC-stimulated IFN-α and TNF levels, while only IL-6 production was enhanced in the DSR-6434-stimulated cocultures. When comparing pDCs stimulated with RNA-IC and DSR-6434, twelve genes were differentially expressed (log2 fold change >2, adjusted P-value <.05). In conclusion, RNA-IC, which mimics an endogenous TLR7 stimulator, and the synthetic TLR7 agonist DSR-6434 trigger distinct inflammatory profiles in immune cells. This demonstrates the importance of using relevant stimuli when targeting the TLR7 pathway for therapeutic purposes.
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| 33. |
- Berggren, Olof, et al.
(författare)
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B lymphocytes enhance the interferon-α production by plasmacytoid dendritic cells
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 64:10, s. 3409-3419
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:Type I interferon (IFN) system and B cells are activated in many autoimmune diseases, e.g. systemic lupus erythematosus (SLE). IFNα produced by plasmacytoid dendritic cells (pDC) stimulate several B cell functions, including autoantibody production. However, not much is known how B cells influence the pDC function. We therefore investigated the regulatory effect of B cells on IFNα production by pDC.METHODS:PDC and B cells from healthy blood donor PBMC were stimulated with RNA-containing immune complexes (RNA-IC) consisting of U1 snRNP and IgG from SLE patients, herpes simplex virus (HSV) or oligonucleotide ODN2216, alone or in co-cultures. IFNα, several other cytokines and pDC or B cell-associated surface molecules were analyzed by immunoassays or flow cytometry.RESULTS:B cells enhanced the IFNα production by pDC up to 47-fold, and the effect was most pronounced for pDC stimulated with RNA-IC. Anti-CD31 antibody reduced the RNA-IC-induced IFNα production by 80%, but not when ODN2216 was used as IFN-inducer. Supernatants from ODN2216-stimulated B cells promoted IFNα production by pDC, while supernatants from RNA-IC-stimulated B cells did not.CONCLUSION: Our results reveal a novel B cell function, enhancing the type I IFN production by pDC. Since B cells are activated by type I IFN, this pDC-B cell cross-talk might be of fundamental importance in the etiopathogenesis of SLE, and contribute to a chronic immune activation in SLE and other systemic rheumatic diseases.
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| 34. |
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| 35. |
- Berggren, Olof, et al.
(författare)
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IFN-α production by plasmacytoid dendritic cell associations with polymorphisms in gene loci related to autoimmune and inflammatory diseases
- 2015
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:12, s. 3571-3581
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Tidskriftsartikel (refereegranskat)abstract
- The type I interferon (IFN) system is persistently activated in systemic lupus erythematosus (SLE) and many other systemic autoimmune diseases. Studies have shown an association between SLE and several gene variants within the type I IFN system. We investigated whether single nucleotide polymorphisms (SNPs) associated with SLE and other autoimmune diseases affect the IFN-α production in healthy individuals. Plasmacytoid dendritic cells (pDCs), B and NK cells were isolated from peripheral blood of healthy individuals and stimulated with RNA-containing immune complexes (IC), herpes simplex virus (HSV) or the oligonucleotide ODN2216. IFN-α production by pDCs alone or in cocultures with B or NK cells was measured by an immunoassay. All donors were genotyped with the 200K ImmunoChip and a 5bp CGGGG length polymorphism in the IFN regulatory factor 5 gene (IRF5) was genotyped by PCR. We found associations between IFN-α production and 18-86 SNPs (p ≤ 0.001), depending on the combination of the stimulated cell types. However, only three of these associated SNPs were shared between the cell type combinations. Several SNPs showed novel associations to the type I IFN system among all the associated SNPs, while some loci have been described earlier for their association with SLE. Furthermore, we found that the SLE-risk variant of the IRF5 CGGGG-indel was associated with lower IFN-α production. We conclude that the genetic variants affecting the IFN-α production highlight the intricate regulation of the type I IFN system and the importance of understanding the mechanisms behind the dysregulated type I IFN system in SLE.
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| 36. |
- Berggren, Olof, et al.
(författare)
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Plasmacytoid dendritic cells and RNA-containing immune complexes drive expansion of peripheral B cell subsets with an SLE-like phenotype
- 2017
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:8
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 37. |
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| 38. |
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| 39. |
- Bianchi, Matteo, et al.
(författare)
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Contribution of rare genetic variation to disease susceptibility in a large Scandinavian myositis cohort
- 2022
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Ingår i: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 74:2, s. 342-352
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Tidskriftsartikel (refereegranskat)abstract
- Objective Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs.Methods Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune-related genes in a Scandinavian case–control cohort of 454 IIM patients and 1,024 healthy controls. Gene-based aggregate testing, together with rare variant– and gene-level enrichment analyses, was implemented to explore genotype–phenotype relations.Results Gene-based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle–specific gene PTGES3L, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants.Conclusion Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.
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| 40. |
- Blomberg, Stina, et al.
(författare)
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Anti-SSA/Ro antibody determination by enzyme-linked immunosorbent a supplement to standard immunofluorescence in antinuclear antibody screening
- 2000
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 51:6, s. 612-7
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate the frequency and possible clinical relevance of SSA/Ro antibodies, as determined by enzyme-linked immunosorbent assay (ELISA), in patient sera not exhibiting a concomitant positive reaction by the standard immunofluorescence (IF) test using HEP-2 cells as substrate. SSA/Ro reactivity, as shown by ELISA, was found in 285 (7%) of 4025 serum samples consecutively remitted for antinuclear antibody (ANA) screening. Seventy-five of these serum samples (26%), derived from 64 patients, were negative by the IF-ANA screening test. Serum samples from all 64 patients exhibiting SSA/Ro reactivity by ELISA without concomitant positivity by IF-ANA were further investigated by IF using transfected HEP-2 cells hyperexpressing the 60,000 MW SSA/Ro antigen (HEP-2000(R)) and by immunodiffusion (ID) and Western blot. In 55 of these 64 patients, SSA/Ro reactivity could be verified by one or more of the other techniques investigated. Twelve of these patients fulfilled four or more American College of Rheumatology (ACR) criteria for systemic lupus erythematosus (SLE) and another five patients exhibited a histologically confirmed cutaneous lupus erythematosus (LE). In four of the 12 IF-ANA-negative patients with a diagnosis of SLE, the SSA/Ro reactivity was only detectable by ELISA and Western blot. In conclusion, the use of a sensitive ELISA assay could provide a clinically important supplement to the routine ANA screening by IF, which does not detect certain anti-SSA/Ro-containing sera among patients with relevant autoimmune diagnoses. Detection of anti-SSA/Ro antibodies, however, does not alone signify cutaneous LE or SLE but adds weight to these diagnoses that should rely heavily on other clinical information.
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