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Biomedical subjects

L Rönnblom

Publications and source records attributed to L Rönnblom.

At least 19 recordsLinked to original sources
PubMed2006

Glucocorticoid resorption and influence on the hypothalamic-pituitary-adrenal axis after intra-articular treatment of the knee in resting and mobile patients.

BACKGROUND: Studies have shown that intra-articular glucocorticoid injection treatment for knee synovitis has a better outcome in resting patients than in mobile patients. One reason for this observation might be that rest retards steroid resorption, causing an enhanced local treatment effect. OBJECTIVES: To study drug resorption and the impact on hormone production in the hypothalamic-pituitary-adrenal axis after intra-articular glucocorticoid administration, with and without postinjection rest. METHODS: Twenty patients with rheumatoid arthritis and knee synovitis were randomised to either 24 hour bed rest or normal activity after intra-articular glucocorticoid treatment with 20 mg triamcinolone hexacetonide (THA). Serum levels of THA, cortisol, and adrenocorticotropic hormone (ACTH) were followed during 2 weeks. RESULTS: Short term and reversible decreases in serum cortisol and ACTH levels (p<0.001) were seen, without any significant differences between resting and mobile patients. The THA levels increased similarly in both groups, with the median serum peak seen after 8 hours. CONCLUSION: Immobilisation does not appear to retard glucocorticoid resorption after intra-articular administration. Further studies are therefore needed to clarify the mechanism behind the beneficial effects of rest after intra-articular glucocorticoid treatment for knee synovitis.

Absorption↗
PubMed2005

Changes of cartilage and bone markers after intra-articular glucocorticoid treatment with and without postinjection rest in patients with rheumatoid arthritis.

BACKGROUND: Joint immobilisation improves the therapeutic effect of intra-articular glucocorticoid injection for knee synovitis. This may be due to retarded steroid resorption by immobilisation, a procedure that also could influence cartilage and bone metabolism. OBJECTIVE: To evaluate changes in cartilage and bone turnover after intra-articular glucocorticoid treatment for knee synovitis with and without postinjection rest. METHODS: 20 patients with rheumatoid arthritis and knee synovitis were randomised to 24 hour bed rest or to normal activity after intra-articular glucocorticoid treatment. Serum and urine markers of cartilage and bone turnover were studied for two weeks. Cartilage oligomeric matrix protein (COMP) was used as a marker of cartilage turnover, osteocalcin as marker of bone formation, and deoxipyridinoline (DPD) as marker of bone resorption. RESULTS: After the glucocorticoid injection COMP levels decreased in both groups (p<0.001), but significantly more in resting patients. Serum osteocalcin levels decreased significantly (p<0.001) without any difference between the groups. DPD was unchanged in both groups. CONCLUSIONS: Intra-articular glucocorticoid treatment for knee synovitis reduced serum COMP, which suggests that such treatment may have a cartilage protective effect. The slightly larger decrease of serum COMP in the resting group may reflect a lower clearance of COMP from the joint cavity. Serum osteocalcin was temporarily reduced, indicating a reversible suppression of bone formation.

Adult↗
PubMed2003

Randomised controlled study of postinjection immobilisation after intra-articular glucocorticoid treatment for wrist synovitis.

BACKGROUND: Intra-articular glucocorticoid treatment is frequently used in arthritic disorders. Postinjection rest has been shown to improve the outcome of knee injections. OBJECTIVE: To investigate whether better treatment results might also be achieved by a similar postinjection regimen for the wrist, which is non-weightbearing. METHODS: 117 patients with rheumatoid arthritis and wrist synovitis were treated with intra-articular glucocorticoid injections. The patients were randomly allocated to 48 hour postinjection immobilisation in elastic wrist orthoses (n=58) or to normal postinjection activity (n=59). The primary end point was relapse of synovitis. In addition, joint circumference, pain, function, range of movement, and grip strength were followed up during six months. RESULTS: 24 relapses occurred in the orthoses group and 14 in the active group (p=0.056). The secondary measure showed no statistically significant differences between the groups. CONCLUSION: The use of elastic wrist orthoses as a postinjection regimen does not improve the outcome of intra-articular glucocorticoid treatment for wrist synovitis. Results achieved in studies on knees should not be generalised to other joints, and postinjection recommendations should differ depending on the joint treated.

Adult↗
PubMed2003

The heterogeneity of neuropsychiatric systemic lupus erythematosus is reflected in lack of association with cerebrospinal fluid cytokine profiles.

The objective was to study the occurrence of autoantibodies and cytokines in serum and cerebrospinal fluid (CSF) in neuropsychiatric systemic lupus erythematosus (NPSLE). In total, 28 consecutive patients with NPSLE and 16 systemic lupus erythematosus (SLE) patients without neuropsychiatric involvement (non-NPSLE) were studied. IFN-alpha, IL-6, IL-10, soluble terminal complement complex (TCC), anti-ribosomal P protein antibodies (anti-P) and anti-cardiolipin antibodies (aCL) were measured in serum and CSF by immunoassays. Analyses of white blood cell differential count, CSF-albumin/serum-albumin ratio, IgG-index in CSF and isoelectric focusing in serum and CSF were also performed. CSF specimens from 23 healthy individuals were used as controls. IFN-alpha was elevated in the CSF of 5 of 28 NPSLE patients compared to three of 14 among the non-NPSLE patients. IL-6 was elevated in CSF in three of 26 NPSLE patients. Normal concentration of IL-10 was found in CSF in all 27 NPSLE-patients analysed. IFN-alpha in serum was elevated in 18 of 28 NPSLE patients. No distinct clinical phenotype was related to elevated cytokine concentration in serum or CSF. One patient with cerebral involvement complicated by progressive multifocal leukoencephalopathy displayed a very high IFN-alpha concentration in serum. High concentration of TCC was present in CSF from only one patient with systemic vasculitis and focal cerebral symptoms. In conclusion, the results of this study suggest that the diagnostic value of serum and CSF concentrations of IFN-alpha, IL-10, IL-6 and TCC is limited in unselected neuropsychiatric SLE, probably due to the heterogeneity of NPSLE pathogenesis.

Adolescent↗
PubMed2001

Activation of natural interferon-alpha producing cells by apoptotic U937 cells combined with lupus IgG and its regulation by cytokines.

We recently demonstrated that IgG from patients with systemic lupus erythematosus (SLE) in combination with U937 cells made apoptotic by UV-irradiation, can induce interferon-alpha (IFN-alpha) production in normal peripheral blood mononuclear cells (PBMC). In the present study we show by flow cytometry that the actual IFN-alpha producing cells (IPC) among PBMC had the same phenotype (HLA-DR+, CD4+, CD11b-, CD11c-, CD14-, CD19-, CD32-, CD36+, CD40+, CD45RA+, CD68+, CD83+, CD86-, IL-3R+ and IL-10R-) and low frequency (approximately 2/10(4)PBMC) as the IPC activated by Herpes simplex virus type I. Consequently, these cells correspond to the natural IPC, also described as type 2 precursor dendritic cells. We also demonstrated that cytokines of possible importance in the pathogenesis in SLE had effects on the IFN-alpha production. Specifically, the IFN-alpha production was strongly increased by the type I IFNs, IFN-alpha and -beta, but markedly inhibited by IL-10 and also to some extent by TFN-alpha. In contrast, the cytokines IFN-gamma, IL-6, TGF-beta and GM-CSF had no clear effects. No production of IL-10 was detected in PBMC stimulated by apoptotic U937 cells and SLE IgG. These results may explain the cause of the ongoing IFN-alpha production in SLE patients and its relation to the autoimmune process.

Adolescent↗
PubMed2001

An etiopathogenic role for the type I IFN system in SLE.

The type I interferon (IFN) system plays a pivotal role in the etiopathogenesis of systemic lupus erythematosus (SLE). The initial appearance of autoantibody-producing B cells can be precipitated by infection-induced type I IFNs, but the further, significant generation of autoimmune T and B cells is caused by the prolonged production of IFN-alpha, which is maintained by a vicious circle mechanism. This involves the activation of immature dendritic cells, known as natural IFN-producing cells, by continuously formed endogenous IFN-alpha inducers. These IFN-alpha inducers consist of complexes of autoantibodies with nucleic-acid-containing autoantigens derived from apoptotic cells.

Autoimmunity↗
PubMed2001

Importance of CpG dinucleotides in activation of natural IFN-alpha-producing cells by a lupus-related oligodeoxynucleotide.

The oligodeoxyribonucleotide (ODN) 5'-TTTTCAATTCGAAGATGAAT-3' (ODN H), identified in systemic lupus erythematosus (SLE) serum, induced the production of interferon (IFN)-alpha in human peripheral blood mononuclear cells (PBMC) when combined with lipofectin. Flow cytometric analysis with staining for surface antigens and intracellular IFN-alpha, showed that the IFN-alpha-producing cells (IPC) were the natural IPC, also termed type 2 dendritic cell precursors (pDC2) or plasmacytoid monocytes. The importance of unmethylated CpG dinucleotides for the interferogenic activity of ODN was studied. Methylation of CpG impaired the activity of single-stranded (ss) ODN H, but increased that of the complementary ssODN I. Furthermore, CpG-methylated double-stranded (ds) ODN Hmet-Imet lost, but hemimethylated dsODN H-Imet retained interferogenic activity. Inversion of the CpG to GpC had no effect on the interferogenic activity of ssODN H, increased that of ssODN I, however abolished the activity of dsODN H-I. Alteration of the CpG in ODN H to ApG and in the ODN I to CpT destroyed their activity. The induction of IFN-alpha is therefore sequence-specific, but unmethylated CpGs are not always required, especially not in ssODNs. Interferogenic DNA sequences could therefore be more frequent in eukaryotic genomes than previously thought and their capacity to activate natural IPC may have implications for immune responses to microbial antigens and nuclear autoantigens.

Antigens↗
PubMed2001

Presence of cutaneous interferon-alpha producing cells in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) patients have increased levels of interferon-alfa (IFN-alpha) in the circulation but a reduced number of functionally intact natural IFN-alpha producing cells (IPC) in peripheral blood. In search for tissue localisation of activated IPC, we investigated skin biopsies from SLE patients for the occurrence of such cells. Eleven SLE patients with inflammatory skin lesions and six healthy controls were biopsied. An immunohistochemical technique (IH) and in situ hybridisation (ISH) were used to detect intracellular IFN-alpha protein and IFN-alpha mRNA, respectively. In all 11 biopsies from SLE lesions, a high number of IPC were detected by IH. In the nonlesional SLE biopsies we could also demonstrate IPC in 10/11 patients. In 6/11 SLE patients, IFN-alpha mRNA containing cells could be detected in the specimens. A low number of IPC were detected in 1/6 healthy controls by IH, but no ISH positive cells were seen. Our results demonstrate that SLE patients have active IPC in both dermal lesions and in noninflammatory skin. A recruitment of IPC from blood to peripheral tissues may explain the low number of circulating natural IPC in SLE patients. Because the type I IFN system is involved in the SLE disease process, these results are of interest for the understanding of the pathogenesis in SLE.

Adult↗
PubMed2000

The combination of apoptotic U937 cells and lupus IgG is a potent IFN-alpha inducer.

Patients with active systemic lupus erythematosus (SLE) have signs of an ongoing IFN-alpha production, that may be of pathogenic significance in the disease. We previously showed that SLE patients have an IFN-alpha-inducing factor in blood, probably consisting of complexes containing anti-DNA Abs and immunostimulatory DNA. The DNA component could be derived from apoptotic cells, because SLE patients have been reported to have both increased apoptosis and reduced clearance of apoptotic cell material. In the present study, we therefore investigated whether apoptotic cells, together with IgG from SLE patients, could act as an IFN-alpha inducer in normal PBMC in vitro. We found that apoptotic cells of the myeloid leukemia cell line U937 as well as four other cell lines (MonoMac6, H9, Jurkat, U266) could induce IFN-alpha production in PBMC when combined with IgG from SLE patients. The IFN-alpha production by PBMC was much enhanced when PBMC were costimulated by IFN-alpha2b. The ability of IgG from different SLE patients to promote IFN-alpha induction by apoptotic U937 cells was associated with the presence of anti-ribonucleoprotein Abs, but not clearly with occurrence of anti-DNA Abs. These results suggest that apoptotic cells in the presence of autoantibodies can cause production of a clearly immunostimulatory cytokine, which is IFN-alpha. This mechanism for induction of IFN-alpha production could well be operative also in vivo, explain the IFN-alpha production seen in SLE patients, and be important in the pathogenesis of SLE.

Adjuvants, Immunologic↗
PubMed2000

Ro 52kD autoantibodies are detected in a subset of ANA-negative sera.

To define Ro 52kD, Ro 60kD, and La specificities of autoantibodies within ANA-negative sera, samples from 64 ANA-negative but SSA positive patients undergoing investigation due to suspected CTD were analysed, using recombinant antigens and synthetic peptides by immunoblotting and ELISA. The sera were selected from 4025 sera submitted for routine ANA analysis. Antibodies to Ro or La were detected in 42/64 sera (65%). Anti-Ro 52kD antibodies occurred most frequently and were present in 42/64 sera (65%). This was the only specificity of autoantibody detected in 18 sera. No patient had only anti-La or anti-Ro 60 antibodies. In total 18.64 patients (28%) had Ro 60 antibodies and 14/64 had anti-La antibodies (21%). Eight patients had antibodies reacting with all three antigens. We used the same set of sera to test the antigenicity of different regions of Ro 52kD represented by deletion clones and peptides derived from the Ro 52kD sequence. Out of 30 sera reacting with a recombinant deletion clone encompassing as residues 136-227, 12 sera reacted with a peptide corresponding to a 200-239. Some sera gave a low positive OD value with a peptide of a 176-196. Based on the results of this study in which we demonstrate Ro 52kD autoantibodies in 65% of selected ANA negative sera and define an autocephitope within the Ro 52kD protein composed of the leucine zipper domain, we suggest that testing for Ro 52kD antibodies could be included in an extended investigation of ANA negative patients with suspected connective tissue disease.

Antibodies, Antinuclear↗
PubMed2000

Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies.

The objective was to investigate the relation between serum levels of interferon-alpha (IFN-alpha), the activity of an endogenous IFN-alpha inducing factor (SLE-IIF), clinical and immunological disease activity as well as serum levels of antiretroviral antibodies in SLE. Serum levels of IFN-alpha were measured in serial sera from 30 patients sampled at different stages of disease activity (SLEDAI score). The SLE-IIF activity was measured by its ability to induce IFN-alpha production in cultures of normal peripheral blood mononuclear cells. Both serum IFN-alpha and SLE-IIF increased markedly at flare in serially followed patients. The SLEDAI score, levels of anti-dsDNA antibodies and IL-10 correlated positively, and complement components Clq, C3 and leukocytes correlated inversely with serum concentrations of IFN-alpha. The extent of multiple organ involvement correlated with serum IFN-alpha. No relation between concentrations of retroviral peptide binding antibodies and IFN-alpha or SLE-IIF activity was found. The close relationship between disease activity in SLE patients and IFN-alpha serum levels suggests that activation of the type 1 IFN system might be of importance in the disease process.

Adult↗
PubMed1999

Anti-double-stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-alpha inducer in systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) have increased blood levels of IFN-alpha, which correlate to disease activity. We previously identified an IFN-alpha-inducing factor (IIF) in the blood of SLE patients that activated the natural IFN-alpha-producing cells in cultures of normal PBMC. The SLE-IIF contained DNA and IgG, possibly as small immune complexes. In our study, we demonstrated that SLE-IIF correlated to the presence of anti-dsDNA Abs in patients and contained anti-dsDNA Abs as an essential component. Purified anti-DNA Abs or SLE-IgG caused only a weak IFN-alpha production in cultures of normal PBMC in the presence of costimulatory IFN-alpha2b. However, they converted the plasmid pcDNA3, which itself induced no IFN-alpha production in PBMC, into an efficient IFN-alpha inducer. A human monoclonal anti-ss/dsDNA Ab had the same effect. This IFN-alpha-inducing activity of the plasmid was abolished by methylation, suggesting that unmethylated CpG DNA motifs were important. Like IIF in SLE serum, the combination of SLE-IgG and pcDNA3 appeared to stimulate IFN-alpha production in natural IFN-alpha-producing cells, a unique cell population resembling immature dendritic cells. The IFN-alpha production was greatly enhanced by IFN-alpha2b and IFN-beta, and for SLE-IIF it was also enhanced by GM-CSF but inhibited by IL-10. We have therefore identified a new function of DNA-anti-DNA Ab complexes, IFN-alpha induction, that might be important in the pathogenesis of SLE.

Antigen-Antibody Complex↗
PubMed1999

Patients with systemic lupus erythematosus (SLE) have a circulating inducer of interferon-alpha (IFN-alpha) production acting on leucocytes resembling immature dendritic cells.

Patients with active SLE often have an ongoing production of IFN-alpha. We therefore searched for an endogenous IFN-alpha-inducing factor (IIF) in SLE patients and found that their sera frequently induced production of IFN-alpha in cultures of peripheral blood mononuclear cells (PBMC) from healthy blood donors, especially when the PBMC were costimulated with the cytokines IFN-alpha2b and granulocyte-macrophage colony-stimulating factor (GM-CSF). The phenotype of the IFN-alpha-producing cells (IPC) as determined by flow cytometry corresponded to that of the natural IPC, resembling immature dendritic cells. The IIF activity in SLE sera was sometimes as high as that of a virus and was present especially in patients with active disease and with measurable IFN-alpha levels in serum. The IIF had an apparent molecular weight of 300-1000 kD and appeared to consist of both immunoglobulin and DNA, possibly being immune complexes. This endogenous IFN-alpha inducer may be of pathogenic significance, since a reported occasional adverse effect of IFN-alpha therapy in patients with non-autoimmune disorders is development of anti-dsDNA antibodies and SLE.

Adult↗
PubMed1998

Patients with systemic lupus erythematosus have reduced numbers of circulating natural interferon-alpha- producing cells.

Systemic lupus erythematosus (SLE) patients often have continuous production of interferon-alpha (IFN-alpha), but production of in vitro IFN-alpha by peripheral blood mononuclear cells (PBMC) may be varyingly reduced. We here report that IFN-alpha production induced by Herpes simplex virus (HSV) in PBMC resembling immature dendritic cells and designated natural IFN-alpha producing cells (NIPC), was much more affected than that induced by sendai virus (SV) in monocytes. At the cell level, the frequency of HSV-activated NIPC was reduced 70-fold, but residual NIPC produced normal amounts of IFN-alpha (1-2 U/cell). The NIPC frequency increased 10-fold in SLE-PBMC, but not in control PBMC, when co-stimulated by the combination IFN-alpha-gamma and GM- CSF. No spontaneous IFN-alpha production by PBMCs was detected in SLE patients. While no SLE serum factor inhibiting IFN-alpha production was seen, sera of four out of 11 SLE patients induced IFN-alpha production in healthy control PBMC. We propose that the number of NIPC in SLE are reduced in blood because of recruitment to tissues and activation by an endogenous IFN-alpha inducer, as well as because of lack of co-stimulatory cytokines. IFN-alpha produced in SLE could be of pathogenic significance, because autoimmune diseases develop in patients with infections or tumours during IFN-alpha therapy.

Adult↗
PubMed1998

Antibodies against double-stranded DNA and development of polymyositis during treatment with interferon.

Alpha interferons have become effective palliative treatments for patients with neuroendocrine tumours such as carcinoids and endocrine pancreatic tumours. However, several reports indicate an increased incidence of both autoantibodies and autoimmune diseases in patients treated with interferon-alpha (IFN-alpha). We studied the development of antibodies against double-stranded DNA (dsDNA) and clinical signs of autoimmune disease in 214 patients with malignant carcinoids or endocrine pancreatic tumours consecutively admitted for treatment with IFN-alpha. Seventeen patients (8%) developed antibodies against dsDNA, predominantly females (12 females and 5 males). One patient had clinical and laboratory signs of polymyositis. Among the other 16 patients, three developed hypothyroidism and in six patients the anti-dsDNA autoantibodies normalized despite continuing therapy. Although a significant number of patients developed autoantibodies against dsDNA, overt autoimmune disease related to these antibodies is a rare event and many patients spontaneously normalize these titres despite continuing IFN-alpha treatment.

Aged↗
PubMed1997

Increased phosphate content in complement component C3, fibrinogen, vitronectin, and other plasma proteins in systemic lupus erythematosus: covariation with platelet activation and possible association with thrombosis.

OBJECTIVE: To investigate whether extracellular phosphorylation of plasma proteins takes place in vivo in patients with systemic lupus erythematosus (SLE), to determine possible correlations between phosphate levels and clinical and/or laboratory parameters, and to identify individual phosphorylated plasma proteins. METHODS: Sera from SLE patients were analyzed for total amounts of protein-bound phosphate by a colorimetric technique, and for levels of beta-thromboglobulin by radioimmunoassay. In addition, the ability of these sera to activate platelets, resulting in the release of protein kinase, was tested using an assay in which platelet-rich plasma from healthy blood donors was incubated with sera or immune complexes from SLE patients. In this assay, [gamma-32P]ATP was added, and 32P-labeled C3 was quantified. Phosphate in individual proteins was detected by Western blot analysis. RESULTS: 32P-labeled, activated platelets were able to phosphorylate exogenously added proteins, without the addition of ATP or cations. Platelet-rich plasma from healthy blood donors became activated by sera or by polyethylene glycol-precipitated immune complexes from patients with SLE, which led to the extracellular phosphorylation of plasma proteins, exemplified in the C3 assay. The phosphate content in plasma proteins was increased in SLE patients with previous thrombosis. The degree of phosphorylation increased up to 3-fold in serial samples obtained from 2 SLE patients during periods of disease exacerbation. Substantial phosphate increases were seen in C3 and fibrinogen. The changes were linked to platelet activation because of the observed covariation with the levels of beta-thromboglobulin. CONCLUSION: In SLE patients, the phosphate content in plasma proteins (including C3 and fibrinogen) increases due to platelet activation.

Adolescent↗
PubMed1997

Limited Wegener's granulomatosis with central nervous system involvement and fatal outcome.

A 74-year-old woman was admitted to the medical department with vertigo and confusion, and suffered seizures three days later. Clinical, radiological and histopathological examination revealed limited Wegener's granulomatosis (WG) with central nervous system (CNS) involvement. Initially she was treated successfully with prednisolone and cyclophosphamide, but she relapsed after 25 months and died four weeks later. Autopsy showed widespread granulomas with vasculitis in the cerebrum. These findings emphasize the importance of considering WG in CNS disease of unclear origin, and demonstrate the aggressive nature of the disease.

Aged↗