| 1. |
|
|
| 2. |
- Compagno, Michele, et al.
(författare)
-
Low diagnostic and predictive value of anti-dsDNA antibodies in unselected patients with recent onset of rheumatic symptoms: results from a long-term follow-up Scandinavian multicentre study.
- 2013
-
Ingår i: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 1502-7732 .- 0300-9742. ; 42:4, s. 311-316
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: To verify the diagnostic accuracy of anti-double-stranded DNA (anti-dsDNA) antibodies detected by the Crithidia luciliae immunofluorescence test (CLIFT) in a cohort of unselected patients, referred to a rheumatologist due to recent onset of rheumatic symptoms. Method: A total of 1073 consecutive patients were screened for anti-nuclear antibodies (ANAs). Serum samples from 292 ANA-positive and 292 matching ANA-negative patients were tested three times for anti-dsDNA antibodies, using two different CLIFT kits (ImmunoConcepts(®) and Euroimmun(®)). An initial clinical diagnosis was made by rheumatologists unaware of the results. The diagnoses were updated after a median follow-up of 4.8 years. Results: CLIFT was positive at least once in 60 patients but only 23 patients were CLIFT positive in all of the assays. Diagnosis of systemic lupus erythematosus (SLE) was made initially in 65 patients, of whom 24 (37%) were CLIFT positive. Many other diagnoses were observed among the CLIFT-positive patients. Overall, 16 (5.5%) ANA-negative patients were CLIFT positive. After approximately 5 years, the diagnosis of SLE remained unchanged in 63 patients (23 CLIFT positive) and altered in only two (one CLIFT positive). Among the 36 CLIFT-positive patients who were not diagnosed with SLE at study entry, only one developed SLE during the follow-up period. Conclusions: CLIFT was not reliable as a diagnostic tool in unselected patients with rheumatic symptoms. ANAs were of little value as a screening test before the CLIFT analysis. CLIFT had surprisingly low positive predictive value (PPV) for the diagnosis of SLE despite its high specificity. For non-SLE patients, being CLIFT positive poses little risk of developing SLE within 5 years.
|
|
| 3. |
- Enocsson, Helena, 1982-
(författare)
-
Biomarkers and mediators in systemic lupus erythematosus : IFNα versus the CRP response, and evaluation of suPAR and anti-dsDNA antibody assays
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease which may affect multiple organ systems. Interferon alpha (IFNα) and autoantibodies that form immune complexes with nuclear antigens (ANA) are hallmarks believed to drive the disease into a vicious circle of inflammation, tissue damage, autoantigen exposure and autoantibody production.In SLE, the disease course is characterized by episodes of exacerbations alternating with remissions. In order to best treat the patient it is important to closely monitor symptoms and signs of disease activity. Because of the disease heterogeneity, no single biomarker has yet been found to reflect SLE disease activity in general, although antidouble stranded DNA (anti-dsDNA) antibodies sometimes indicate activity, primarily with renal involvement, and constitutes an item of the SLE disease activity score SLEDAI-2K. However, the method of anti-dsDNA measurement is not standardized and therefore varies between different laboratories. In many other inflammatory conditions, such as rheumatoid arthritis and during bacterial infections, the C-reactive protein (CRP) level is a good indicator of ongoing inflammation, but in SLE and during viral infections, CRP commonly fails to reflect the degree of inflammation. Both viral infections and SLE are characterized by IFNα, and we thus aimed to elucidate whether IFNα can inhibit CRP production. Further, four assays for anti-dsDNA antibody measurements were evaluated with regard to SLE disease specificity and activity, and a new potential biomarker of inflammation, the soluble urokinase plasminogen activator receptor (suPAR), was assessed in relation to disease activity and organ damage.An in vitro inhibitory effect of IFNα on CRP transcription and production was found in hepatocytes, and this was consolidated by in vivo studies of CRP and IFNα in sera from well-characterized SLE patients (KLURING; Kliniskt lupusregister i nordöstra Götaland). Here, CRP and disease activity were associated among patients without IFNα and without a CRP lowering gene variant (SNP rs1205). The poor disease activity compliance of CRP could therefore be explained, at least in part, by polymorphisms in the CRP gene and increased levels of IFNα. Critical differences between the methods measuring anti-dsDNA were found regarding disease specificity and ability to reflect disease activity and the results suggests the Crithidia luciliae immunofluorescence test (CLIFT) for diagnostic purposes and a bead-based multiplex assay (FIDIS) for monitoring of disease activity. Evaluation of suPAR in SLE revealed no association of suPAR with disease activity, but interestingly instead with accumulated organ damage. suPAR could therefore possibly be used to advert patients at high risk of organ damage.A detailed biological and clinical characterization of established and emerging SLE biomarkers is of importance since it may improve the clinical management as well as increase the knowledge about disease mechanisms.
|
|
| 4. |
- Gullstrand, Birgitta, et al.
(författare)
-
Combination of Autoantibodies Against Different Histone Proteins Influences Complement-dependent Phagocytosis of Necrotic Cell Material by Polymorphonuclear Leukocytes in Systemic Lupus Erythematosus.
- 2012
-
Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 39:8, s. 1619-1627
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Polymorphonuclear leukocytes (PMN) with autoantibody-coated engulfed necrotic cell material (NC) are frequently seen in systemic lupus erythematosus (SLE). We evaluated the roles of complement, different antihistone antibodies (anti-H ab), and oxidative burst in the phagocytosis of NC by PMN, as well as association to disease activity and clinical phenotype in SLE. METHODS: ELISA and immunoblot were used to measure antibodies to different histone proteins in sera from patients with SLE and complement-deficient individuals. Phagocytosis of NC by PMN and oxidative burst activity was assessed by flow cytometry. RESULTS: A clearly increased phagocytosis of NC was seen in patients with active SLE, which was associated with high levels of anti-H ab concentrations and oxidative burst activity. The complement system contributed to efficient phagocytosis of NC by PMN through activation of the classical pathway, and the phagocytosis was mediated by FcγRIIA, FcγRIIIB, and CR1 in combination. A pattern of high phagocytosis, consumption of classical pathway components, and a broad anti-H ab repertoire was seen particularly in patients with nephritis and serositis. The combination of antibodies to several different histone proteins, often with anti-DNA antibodies, promoted an efficient uptake of NC, whereas antibodies against only histone H1 or a few histones seemed to be of less importance. CONCLUSION: The distributions of specificities among anti-H ab are of great importance in the complement-dependent phagocytosis of debris from NC in SLE. Measurement of anti-H ab could be useful in monitoring of this disease and contribute to improved understanding of the autoimmune process.
|
|
| 5. |
- Leonard, Dag, 1975-
(författare)
-
Cardiovascular Disease and Immune Mechanisms in Systemic Lupus Erythematosus
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune, inflammatory disease characterized by autoantibody production and an activated type I interferon system. Cardiovascular disease (CVD) is as a major cause of morbidity and mortality. The aim of this thesis was to identify genetic risk factors for CVD in SLE. The role of T cells in regulation of the interferon-α (IFNα) production by plasmacytoid dendritic cells (pDCs) was also investigated. In paper I, a thicker intima, thinner media and increased intima/media ratio was found in young premenopausal women with SLE compared to healthy controls indicating increased cardiovascular risk. As traditional ultrasound assessment of the common carotid intima-media thickness (CCA-IMT) in SLE has given conflicting results separate measurement of the intima and media can be a useful tool to identify SLE patients at increased risk of CVD. In paper II, an association was demonstrated in SLE between a STAT4 risk allele and ischemic cerebrovascular disease and presence of anti-phospholipid antibodies (aPL). The association remained after adjustment for traditional CVD risk factors. A possible mechanism for this association is that the risk allele leads to increased production of aPL, which promotes thromboembolism. In paper III, a genetic locus in IRF8 was identified to be associated to coronary heart disease (CHD) in SLE. The association remained after adjustment of other CHD risk factors. Patients with the IRF8 risk variant had increased CCA-IMT, more carotid plaques and reduced frequency of circulating B cells. Weaker binding of nuclear protein to the risk allele was demonstrated, suggesting a regulatory function of the IRF8 risk variant. In paper IV, activated T cells were found to strongly enhance the IFNα production by pDC stimulated with RNA-containing immune complexes via GM-CSF and IL-3. Activated SLE T cells enhanced the IFNα production to the same extent as T cells from healthy controls. This finding together with previous observations in SLE of increased levels of GM-CSF and IL-3 suggests that T cells contribute to the activated type I interferon system in SLE. In conclusion, this thesis demonstrates that genetic predisposition is important for CVD in SLE and describes a new role for T cells in the pathogenesis of SLE.
|
|
| 6. |
- Nielsen, Christoffer T, et al.
(författare)
-
Increased IgG on cell-derived plasma microparticles in systemic lupus erythematosus is associated with autoantibodies and complement activation.
- 2012
-
Ingår i: Arthritis and Rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 64:4, s. 1227-1236
-
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.
|
|
| 7. |
|
|
