| 1. |
- Hagberg, Niklas, et al.
(författare)
-
IFN-α Production by Plasmacytoid Dendritic Cells Stimulated with RNA-Containing Immune Complexes Is Promoted by NK Cells via MIP-1β and LFA-1
- 2011
-
Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 186:9, s. 5085-5094
-
Tidskriftsartikel (refereegranskat)abstract
- Several systemic autoimmune diseases display a prominent IFN signature. This is caused by a continuous IFN-α production by plasmacytoid dendritic cells (pDCs), which are activated by immune complexes (ICs) containing nucleic acid. The IFN-α production by pDCs stimulated with RNA-containing IC (RNA-IC) consisting of anti-RNP autoantibodies and U1 small nuclear ribonucleoprotein particles was recently shown to be inhibited by monocytes, but enhanced by NK cells. The inhibitory effect of monocytes was mediated by TNF-α, PGE2, and reactive oxygen species, but the mechanisms for the NK cell-mediated increase in IFN-α production remained unclear. In this study, we investigated the mechanisms whereby NK cells increase the RNA-IC–induced IFN-α production by pDCs. Furthermore, NK cells from patients with systemic lupus erythematosus (SLE) were evaluated for their capacity to promote IFN-α production. We found that CD56dim NK cells could increase IFN-α production >1000-fold after RNA-IC activation, whereas CD56bright NK cells required costimulation by IL-12 and IL-18 to promote IFN-α production. NK cells produced MIP-1α, MIP-1β, RANTES, IFN-γ, and TNF-α via RNA-IC–mediated FcγRIIIA activation. The IFN-α production in pDCs was promoted by NK cells via MIP-1β secretion and LFA-mediated cell–cell contact. Moreover, NK cells from SLE patients displayed a reduced capacity to promote the RNA-IC–induced IFN-α production, which could be restored by exogenous IL-12 and IL-18. Thus, different molecular mechanisms can mediate the NK cell-dependent increase in IFN-α production by RNA-IC–stimulated pDCs, and our study suggests that the possibility to therapeutically target the NK–pDC axis in IFN-α–driven autoimmune diseases such as SLE should be investigated.
|
|
| 2. |
- Eriksson, D, et al.
(författare)
-
Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease
- 2016
-
Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 286:6, s. 595-608
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology.METHODS: To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls.RESULTS: We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10(-15) , MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex.CONCLUSION: Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.
|
|
| 3. |
- Eloranta, Maija-Leena, et al.
(författare)
-
Type I interferon system activation and association with disease manifestations in systemic sclerosis
- 2010
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 69:7, s. 1396-1402
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To study the presence of interferogenic autoantibodies in systemic sclerosis (SSc) and their correlation with clinical manifestations, serum levels of interferon alpha (IFNalpha) and chemokines of importance in the disease process. METHODS: Peripheral blood mononuclear cells (PBMCs) or purified plasmacytoid dendritic cells (pDCs) from healthy donors were stimulated with sera from patients with SSc (n=70) or healthy individuals (n=30), together with necrotic or apoptotic cell material. The IFNalpha produced and serum levels of IFNalpha, IFN-inducible protein-10 (IP-10)/chemokine (C-X-C motif) ligand 10, monocyte chemoattractant protein-1 (MCP-1)/(C-C motif) ligand-2 (CCL-2), macrophage inflammatory protein-1alpha (MIP-1alpha)/CCL-3 and RANTES/CCL-5 were measured and correlated with the presence of autoantibodies and clinical manifestations in the patients with SSc. RESULTS: Sera from both diffuse SSc and limited SSc contained interferogenic antibodies, which correlated with the presence of anti-ribonucleoprotein and anti-Sjögren syndrome antigen autoantibodies. The pDCs were responsible for the IFNalpha production which required interaction with FcgammaRII and endocytosis. Increased serum levels of IP-10 were associated with vascular manifestations such as cardiac involvement (p=0.027) and pulmonary arterial hypertension (p=0.036). Increased MCP-1 or IFNalpha serum levels were associated with lung fibrosis (p=0.019 and 0.048, respectively). Digital ulcers including digital loss were associated with increased serum levels of IFNalpha (p=0.029). CONCLUSION: An activated type I IFN system previously seen in several other systemic autoimmune diseases is also present in SSc and may contribute to the vascular pathology and affect the profibrotic process.
|
|
| 4. |
- Feng, Di, et al.
(författare)
-
Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus
- 2010
-
Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 62:2, s. 562-573
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Genetic variants of the interferon (IFN) regulatory factor 5 gene (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). The contribution of these variants to IRF-5 expression in primary blood cells of SLE patients has not been addressed, nor has the role of type I IFNs. The aim of this study was to determine the association between increased IRF-5 expression and the IRF5 risk haplotype in SLE patients. METHODS: IRF-5 transcript and protein levels in 44 Swedish patients with SLE and 16 healthy controls were measured by quantitative real-time polymerase chain reaction, minigene assay, and flow cytometry. Single-nucleotide polymorphisms rs2004640, rs10954213, and rs10488631 and the CGGGG insertion/deletion were genotyped in these patients. Genotypes of these polymorphisms defined both a common risk haplotype and a common protective haplotype. RESULTS: IRF-5 expression and alternative splicing were significantly up-regulated in SLE patients compared with healthy donors. Enhanced transcript and protein levels were associated with the risk haplotype of IRF5; rs10488631 displayed the only significant independent association that correlated with increased transcription from the noncoding first exon 1C. Minigene experiments demonstrated an important role for rs2004640 and the CGGGG insertion/deletion, along with type I IFNs, in regulating IRF5 expression. CONCLUSION: This study provides the first formal proof that IRF-5 expression and alternative splicing are significantly up-regulated in primary blood cells of patients with SLE. Furthermore, the risk haplotype is associated with enhanced IRF-5 transcript and protein expression in patients with SLE.
|
|
| 5. |
- Lood, Christian, et al.
(författare)
-
C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells : a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis
- 2009
-
Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:10, s. 3081-3090
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: C1q deficiency is the strongest risk factor known for the development of systemic lupus erythematosus (SLE), since almost all humans with a genetic deficiency of C1q develop this disease. Low C1q serum concentration is also a typical finding in SLE during flares, emphasizing the involvement of C1q in SLE pathogenesis. Recent studies have revealed that C1q has a regulatory effect on Toll-like receptor-induced cytokine production. Therefore, we undertook this study to investigate whether C1q could regulate production of interferon-alpha (IFNalpha). METHODS: Peripheral blood mononuclear cells (PBMCs) and plasmacytoid dendritic cells (PDCs) were stimulated with 3 known interferogenic stimuli and cultured with physiologic concentrations of C1q. IFNalpha production was determined by an immunoassay. RESULTS: C1q significantly inhibited PBMC IFNalpha production induced by RNA-containing immune complexes (ICs), herpes simplex virus (HSV), and CpG DNA. C1q also inhibited PDC IFNalpha production induced by ICs and CpG DNA but increased PDC IFNalpha production induced by HSV. The regulatory role of C1q was not specific for IFNalpha but was also seen for interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha. We demonstrated binding of C1q to PDCs both by surface plasmon resonance interaction analysis and by flow cytometry, and we also demonstrated intracellular detection of 2 C1q binding proteins. CONCLUSION: Our findings contribute to the understanding of why C1q deficiency is such a strong risk factor for SLE and suggest an explanation for the up-regulation of the type I IFN system seen in SLE patients.
|
|
| 6. |
- Peura, Sari, et al.
(författare)
-
Normal values for calprotectin in stool samples of infants from the population-based longitudinal born into life study
- 2018
-
Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - Stockholm : Taylor & Francis Group. - 0036-5513 .- 1502-7686. ; 78:1-2, s. 120-124
-
Tidskriftsartikel (refereegranskat)abstract
- Faecal calprotectin is a protein used as a diagnostic marker for inflammatory bowel diseases. We determined upper limits for normal calprotectin values for neonatal, 6, 12 and 24 months old children using a turbidimetric immunoassay in a cohort of Swedish children. The advantage of the method is that opposite to previously used enzyme-linked immunosorbent assay (ELISA) method, it enables measuring single samples, and thus, shortens the analysis time significantly. There were 72 samples (41.7% female) collected neonatally, 63 samples (34.9% female) at 6 months, 60 samples (40.0% female) at 12 months and 51 samples (43.1% female) at 24 months. The upper limits for normal values were 233, 615, 136 and 57 µg mg-1 for infants aged 0, 6, 12 and 24 months, respectively.
|
|
| 7. |
- Berntson, Lillemor, 1957-, et al.
(författare)
-
A Pilot Study Investigating Faecal Microbiota After Two Dietary Interventions in Children with Juvenile Idiopathic Arthritis
- 2022
-
Ingår i: Current Microbiology. - : Springer Science and Business Media LLC. - 0343-8651 .- 1432-0991. ; 79:7
-
Tidskriftsartikel (refereegranskat)abstract
- There is evidence for an impact of the gut microbiota on the immune system, which has consequences for inflammatory diseases. Exclusive enteral nutrition (EEN) and the specific carbohydrate diet (SCD) have been demonstrated as effective anti-inflammatory treatments for children with Crohn’s disease. We have previously shown an anti-inflammatory effect from these nutritional treatments in children with juvenile idiopathic arthritis (JIA). The aim of this study was to investigate if improved clinical symptoms after EEN or SCD treatment in children with JIA could be linked to changes in faecal microbiota. We included sixteen patients with JIA (age 7–17 years), six for treatment with EEN and ten with SCD. EEN was given for 3–5 weeks and SCD for 4–5 weeks, with clinical and laboratory status assessed before and after treatment. Faecal samples were analysed for microbiota diversity and composition using 16S rRNA gene sequencing. Analyses of the faecal microbiota showed an effect on the overall composition with both interventions; the most striking result was a decreased relative abundance of the genus Faecalibacterium from EEN and of Bifidobacterium from SCD. The α-diversity decreased significantly from SCD (P = 0.04), but not from EEN (P = 0.22). Despite the study cohorts being small, both EEN and SCD were shown to impact the faecal microbiota. Future larger studies with a focus on metagenomics or metabolomics could possibly reveal a link and clarify the clinical effects of those nutritional regimens.
|
|
| 8. |
- Skiöldebrand, Eva, et al.
(författare)
-
Serotonin-evoked cytosolic Ca2+ release and opioid receptor expression are upregulated in articular cartilage chondrocytes from osteoarthritic joints in horses
- 2019
-
Ingår i: Veterinary and Animal Science. - : Elsevier BV. - 2451-943X. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Osteoarthritis is a pain-associated progressive disease and pain mediators, such as opioid receptors, expressed in articular cartilage could represent novel therapeutic targets. Acute and chronic stages of OA indicate different metabolic abilities of the chondrocytes depending on inflammatory state. This study aimed to investigate the response of healthy and osteoarthritic chondrocytes and their expression and release of pain mediators in response to acute inflammation. Interleukin-1 beta (IL-1β) and lipopolysaccharide (LPS) were used to induce an acute inflammatory response in cultured equine chondrocytes harvested from healthy joints (HC) and osteoarthritic joints (OAC), the latter representing acute exacerbation of a chronic inflammatory state. Intracellular Ca2+ release was determined after exposure to serotonin (5-hydroxytryptamine (5-HT), glutamate or ATP. Protein expression levels of F- and G-actin, representing actin rearrangement, and opioid receptors were investigated. Glutamate concentrations in culture media were measured. Cartilage was immunohistochemically stained for µ (MOR), κ (KOR), and δ (DOR) opioid receptors. Upon exposure to acute inflammatory stimuli, OAC showed increased intracellular Ca2+ release after 5-HT stimulation and increased expression of MOR and KOR. When cells were stimulated by inflammatory mediators, glutamate release was increased in both HC and OAC. Immunostaining for MOR was strong in OA cartilage, whereas KOR was less strongly expressed. DOR was not expressed by cultured HC and OAC and immunostaining of OA cartilage equivocal. We show that chondrocytes in different inflammatory stages react differently to the neurotransmitter 5-HT with respect to intracellular Ca2+ release and expression of peripheral pain mediators. Our findings suggest that opioids and neurotransmitters are important in the progression of equine OA. The inflammatory stage of OA (acute versus chronic) should be taken into consideration when therapeutic strategies are being developed. © 2019 The Author(s)
|
|
| 9. |
- Hansson, Elisabeth, 1955, et al.
(författare)
-
Anti-inflammatory effects induced by pharmaceutical substances on inflammatory active brain astrocytes-promising treatment of neuroinflammation
- 2018
-
Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 15:1
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pharmaceutical treatment with probable anti-inflammatory substances that attack cells in various ways including receptors, ion channels, or transporter systems may slow down the progression of inflammatory conditions. Astrocytes and microglia are the most prominent target cells for inflammation in the central nervous system. Their responses upon inflammatory stimuli work through the NO/cyclic GMP/protein kinase G systems that can downregulate the ATP-induced Ca2+ signaling, as well as G protein activities which alter Na+ transporters including Na+/K+-ATPase pump activity, Toll-like receptor 4 (TLR4), glutamate-induced Ca2+ signaling, and release of pro-inflammatory cytokines. The rationale for this project was to investigate a combination of pharmaceutical substances influencing the NO and the Gi/Gs activations of inflammatory reactive cells in order to make the cells return into a more physiological state. The ATP-evoked Ca2+ signaling is important maybe due to increased ATP release and subsequent activation of purinergic receptors. A balance between intercellular Ca2+ signaling through gap junctions and extracellular signaling mediated by extracellular ATP may be important for physiological function. METHODS: Astrocytes in primary cultures were incubated with lipopolysaccharide in a physiological glucose concentration for 24 h to induce inflammatory reactivity. The probable anti-inflammatory substances sildenafil and 1α,25-Dihydroxyvitamin D3 together with endomorphin-1, naloxone, and levetiracetam, were used in the presence of high glucose concentration in the medium to restore the cells. Glutamate-, 5-HT-, and ATP-evoked intracellular Ca2+ release, Na+/K+-ATPase expression, expression of inflammatory receptors, and release of tumor necrosis factor alpha were measured. RESULTS: Sildenafil in ultralow concentration together with 1α,25-Dihydroxyvitamin D3 showed most prominent effects on the ATP-evoked intracellular Ca2+ release. The μ-opioid agonist endomorphin-1, the μ-opioid antagonist naloxone in ultralow concentration, and the antiepileptic agent levetiracetam downregulated the glutamate-evoked intracellular Ca2+ release and TLR4. The combination of the pharmaceutical substances in high glucose concentration downregulated the glutamate- and ATP-evoked Ca2+ signaling and the TLR4 expression and upregulated the Na+/K+-ATPase pump. CONCLUSION: Pharmaceutical treatment with the combination of substances that have potential anti-inflammatory effects, which attack different biochemical mechanisms in the cells may exert decisive effects to downregulate neuroinflammation in the nervous system.
|
|
| 10. |
- Madsen, Rasmus Kirkegaard, 1979-, et al.
(författare)
-
Diagnostic properties of metabolic perturbations in rheumatoid arthritis
- 2011
-
Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 13:1, s. R19-
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The aim of the study was to assess the feasibility of diagnosing early rheumatoid arthritis (RA) by measuring selected metabolic biomarkers. METHODS: We compared the metabolic profile of patients with RA with those of healthy controls and patients with psoriatic arthritis (PsoA). The metabolites were measured using two different chromatography-mass spectrometry platforms, thereby giving a broad overview of serum metabolites. The metabolic profiles of patient and control groups were compared using multivariate statistical analysis. The findings were validated in a follow-up study of RA patients and healthy volunteers. RESULTS: RA patients were diagnosed with a sensitivity of 93 % and a specificity of 70 % in a validation study using detection of 52 metabolites. Patients with RA or PsoA could be distinguished with a sensitivity of 90 % and a specificity of 94 %. Glyceric acid, D-ribofuranoise and hypoxanthine were increased in RA patients, whereas histidine, threonic acid, methionine, cholesterol, asparagine and threonine were all decreased when compared with healthy controls. CONCLUSIONS: Metabolite profiling (metabolomics) is a potentially useful technique for diagnosing RA. The predictive value was irrespective of the presence of antibodies against cyclic citrullinated peptides (ACPA).
|
|
