| 1. |
- C Kapetanovic, Meliha, et al.
(författare)
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Antibody response is reduced following vaccination with 7-valent conjugate pneumococcal vaccine in adult methotrexate-treated patients with established arthritis, but not those treated with tumor necrosis factor inhibitors
- 2011
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 63:12, s. 3723-3732
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Tidskriftsartikel (refereegranskat)abstract
- Objective To study the influence of antiinflammatory treatments, including methotrexate (MTX) and tumor necrosis factor (TNF) inhibitors, on antibody response following vaccination using a 7-valent conjugate pneumococcal vaccine in adult patients with established arthritis. Methods. Patients with rheumatoid arthritis (RA) or spondylarthropathy (SpA) (including psoriatic arthritis) were vaccinated (n = 505). All patients were stratified into 6 prespecified groups based on diagnosis and treatment (RA patients receiving MTX, RA patients receiving anti-TNF agents and MTX, RA patients receiving TNF inhibitors as monotherapy, SpA patients receiving anti-TNF agents and MTX, SpA patients receiving TNF inhibitors as monotherapy, and SpA patients receiving nonsteroidal antiinflammatory drugs [NSAIDs] and/or analgesics). SpA patients receiving only NSAIDs/analgesics served as a control group. All patients received 1 dose (0.5 ml) of vaccine intramuscu-larly. Levels of IgG antibodies against 23F and 6B serotypes were measured at vaccination and at 4-6 weeks following vaccination, using standardized enzyme-linked immunosorbent assays. Results. Positive antibody response was defined as an antibody response ratio (ARR) (i. e., ratio of post-to prevaccination antibody levels) of > 2. The ARR differed significantly between the groups. A better ARR was seen among patients in the control group compared to those in groups treated with MTX or MTX in combination with TNF inhibitors. Among patients treated with TNF inhibitors as monotherapy, ARRs for both serotypes were lower numerically, but were not significantly different, compared to those in controls. Ongoing MTX treatment was predictive of reduced response (odds ratio 0.41 [95% confidence interval 0.24-0.68], P = 0.001). Higher age was associated with impaired positive antibody response. Concomitant prednisolone treatment elicited better positive antibody response in patients with RA. Conclusion. Treatment with MTX and higher age were predictive of an impaired antibody response to the 7-valent conjugate pneumococcal vaccine in this cohort of patients with chronic arthritis. TNF inhibitors did not significantly affect antibody responses.
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| 2. |
- Lood, Christian, et al.
(författare)
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C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells : a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:10, s. 3081-3090
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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.
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| 3. |
- Lood, Christian, et al.
(författare)
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IgG glycan hydrolysis by endoglycosidase S diminishes the proinflammatory properties of immune complexes from patients with systemic lupus erythematosus: A possible new treatment?
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 64:8, s. 2698-2706
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Tidskriftsartikel (refereegranskat)abstract
- Objective Systemic lupus erythematosus (SLE) is an autoimmune disease with chronic or episodic inflammation in several organ systems, related to the presence of circulating and tissue-deposited immune complexes (ICs) that stimulate leukocytes through Fc? receptors (Fc?R) with subsequent inflammation. Treatment with endoglycosidase S (EndoS), an IgG glycanhydrolyzing bacterial enzyme from Streptococcus pyogenes, has shown beneficial effects in several experimental animal models of chronic inflammatory disease. This study was undertaken to investigate whether EndoS affects the proinflammatory properties of ICs and has the potential to be developed as a therapy for SLE. Methods ICs purified from SLE patients or RNA-containing ICs formed in vitro were treated with EndoS and used in several assays reflecting different important features of SLE pathogenesis, such as phagocytosis by polymorphonuclear cells (PMNs) and plasmacytoid dendritic cells (PDCs), complement activation, and interferon-a (IFNa) production by PDCs. Results EndoS treatment abolished all proinflammatory properties of the ICs investigated. This included Fc?R-mediated phagocytosis by PDCs (P = 0.001) and subsequent production of IFNa (P = 0.002), IC-induced classical pathway of complement activation (P = 0.008), chemotaxis, and oxidative burst activity of PMNs (P = 0.002). EndoS treatment also had a direct effect on the molecular structure of ICs, causing decreased IC size and glycosylation. Conclusion Our findings indicate that EndoS treatment has prominent effects on several pathogenetically important IC-mediated events, and suggest that EndoS has the potential to be developed as a novel therapy for SLE.
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| 4. |
- Lood, Christian, et al.
(författare)
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IgG glycan hydrolysis by EndoS diminishes the pro-inflammatory properties of immune complexes from patients with SLE : a possible new treatment?
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 64:8, s. 2698-2706
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVESystemic lupus erythematosus (SLE) is an autoimmune disease with chronic or episodic inflammation in several organ systems, related to the presence of circulating and tissue-deposited immune complexes (ICs) which stimulate leukocytes through FcγRs with subsequent inflammation. Treatment with EndoS, an IgG glycan hydrolyzing bacterial enzyme from Streptococcus pyogenes, has shown beneficial effects in several experimental animal models of chronic inflammatory disease. In the present study we asked if EndoS could affect pro-inflammatory properties of ICs and have the potential to be developed as a therapy in SLE.METHODSICs, purified from SLE patients or RNA-containing ICs formed in vitro, were treated with EndoS and used in several assays reflecting different important parts of SLE pathogenesis such as phagocytosis by polymorphonuclear neutrophils (PMNs) and plasmacytoid dendritic cells (pDCs), complement activation and IFNα production by pDCs.RESULTSOur results demonstrate that EndoS treatment could abolish all pro-inflammatory properties of ICs investigated. This includes FcγR-mediated phagocytosis by pDCs (p<0.0001) and subsequent production of IFNα (p<0.0001), IC-induced classical complement pathway activation (p<0.0001), chemotaxis and oxidative burst activity of PMNs (p=0.002). We could also demonstrate direct effects on the molecular structure of ICs after EndoS treatment with decreased size and glycosylation patterns.CONCLUSIONSProminent effects of EndoS treatment were seen in several pathogenetically important IC-mediated events and our data suggest that EndoS have the potential to be developed as a novel therapy in SLE.
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| 5. |
- Löfgren, Sara E., et al.
(författare)
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A 3 '-Untranslated Region Variant Is Associated With Impaired Expression of CD226 in T and Natural Killer T Cells and Is Associated With Susceptibility to Systemic Lupus Erythematosus
- 2010
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 62:11, s. 3404-3414
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Costimulatory receptor CD226 plays an important role in T cell activation, differentiation, and cytotoxicity. This study was undertaken to investigate the genetic association of CD226 with susceptibility to systemic lupus erythematosus (SLE) and to assess the functional implications of this association. Methods. Twelve tag single-nucleotide polymorphisms (SNPs) in CD226 were typed in 1,163 SLE patients and 1,482 healthy control subjects from Europe or of European ancestry. Analyses of association were performed by single-marker Cochran-Mantel-Haenszel meta-analysis, followed by haplotype analysis. Gene expression was analyzed by quantitative real-time polymerase chain reaction analyses of RNA from peripheral blood mononuclear cells, and by fluorescence-activated cell sorter analysis. To study the functional impact of the associated variants, luciferase reporter constructs containing different portions of the 3'-untranslated region (3'-UTR) of the gene were prepared and used in transfection experiments. Results. A 3-variant haplotype, rs763361; rs34794968; rs727088 (ATC), in the last exon of CD226 was associated with SLE (P = 1.3 x 10(-4), odds ratio 1.24, 95% confidence interval 1.11-1.38). This risk haplotype correlated with low CD226 transcript expression and low CD226 protein levels on the surface of CD4+ and CD8+ T cells and natural killer T (NKT) cells. NK cells expressed high levels of CD226, but this expression was independent of the haplotype. Reporter assays with deletion constructs indicated that only the presence of rs727088 could account for the differences in the levels of luciferase transcripts. Conclusion. This study identified an association of CD226 with SLE in individuals of European ancestry. These data support the importance of the 3'-UTR SNP rs727088 in the regulation of CD226 transcription both in T cells and in NKT cells.
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| 6. |
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| 7. |
- Nielsen, Christoffer T, et al.
(författare)
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Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation.
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 64:4, s. 1227-1236
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE.: To quantify immunoglobulin and C1q on circulating cell-derived microparticles (MPs) in systemic lupus erythematosus (SLE) and to correlate this with clinical and serological parameters. METHODS.: Sixty-eight clinically well-characterized SLE patients, 38 healthy controls (HC), 6 systemic sclerosis (SSc), and 6 rheumatoid arthritis (RA) patients were included. The numbers of annexin V-binding MPs displaying IgG, IgM or C1q were enumerated by flow cytometry. MP protein levels were determined by mass spectrometry in clinically defined subsets of SLE patients and controls. The MP-IgG load was determined by flow cytometry of all SLE and HC samples. RESULTS.: SLE patients had significantly increased total and relative numbers of IgG-positive MPs (p = 0.0004) with a much higher average IgG-load/MP (p < 0.0001) than HCs. Quantitative mass spectrometry of purified MPs verified significantly increased IgG, IgM, and C1q in SLE. In RA and SSc the average IgG/MP was significantly lower than in SLE (p = 0.006 and 0.05, respectively). Also, IgM/MP and C1q/MP were higher in SLE than in controls (p < 0.05) except for IgM in the RA-group. IgG-positive MPs were significantly associated with the presence of anti-dsDNA, anti-ENA, and anti-histone antibodies, with total IgG, and with decreased leukocyte counts. Average IgG/MP was associated with lower concentrations of MPs, the presence of anti-C1q antibodies, and with complement consumption. CONCLUSIONS.: Circulating cell-derived MPs in SLE carry increased loads of IgG, IgM, and C1q and IgG-MPs are associated with autoantibodies and complement activation. The findings link immunological reactions on MPs with the etiopathology of SLE. © 2012 American College of Rheumatology.
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| 8. |
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| 9. |
- Sánchez, Elena, et al.
(författare)
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Association of a CD24 Gene Polymorphism with Susceptibility to Systemic Lupus Erythematosus
- 2007
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 56:9, s. 3080-3086
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To determine the potential role of the CD24 A57V gene polymorphism in systemic lupus erythematosus (SLE). Methods. We studied 3 cohorts of Caucasian patients and controls. The Spanish cohort included 696 SLE patients and 539 controls, the German cohort included 257 SLE patients and 317 controls, and the Swedish cohort included 310 SLE patients and 247 controls. The CD24 A57V polymorphism was genotyped by polymerase chain reaction, using a predeveloped TaqMan allele discrimination assay. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Results. In the Spanish cohort there was a statistically significant difference in the distribution of the CD24 V allele between SLE patients and controls (OR 3.6 [95% CI 2.13-6.16], P < 0.0001). In addition, frequency of the CD24 V/V genotype was increased in SLE patients compared with controls (OR 3.7 [95% CI 2.16-6.34], P < 0.00001). We sought to replicate this association with SLE in a German population and a Swedish population. A similar trend was found in the German group. The CD24 V/V genotype and the CD24 V allele were more frequent in SLE patients than in controls, although this difference was not statistically significant. No differences were observed in the Swedish group. A meta-analysis of the Spanish and German cohorts demonstrated that the CD24 V allele has a risk effect in SLE patients (pooled OR 1.25 [95% Cl 1.08-1.46], P = 0.003). In addition, homozygosity for the CD24 V risk allele significantly increased the effect (pooled OR 2.1,9 [95% Cl 1.50-3.22], P = 0.00007). Conclusion. These findings suggest that the CD24 A57V polymorphism plays a role in susceptibility to SLE in a Spanish population.
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