ABSTRACT Background The IFN signature has been described to be present in many autoimmune disease... more ABSTRACT Background The IFN signature has been described to be present in many autoimmune diseases, including myositis. The extent of this signature appears to be related to disease activity, however, the underlying mechanism resulting in such a signature has not been revealed yet. Detailed insight into such a mechanism would increase the understanding of role of the IFN systems in myositis and autoimmunity. Objectives In this study we investigated the association between (the extent of) the IFN signature and autoantibody profiles in myositis. Methods RNA samples, obtained from whole blood from 94 patients with polymyositis, dermatomyositis, and inclusion body myositis recruited from the Karolinska University Hospital and Prague University, were assessed for expression levels of 9 IFN related genes using BioMarkTM Dynamic Arrays. IFN score was determined as the average gene expression level of these genes. Median IFN score (4.38) was used to define patients as IFNhigh or IFNlow. ANA positivity was determined by indirect immunofluorescence test and myositis specific autoantibodies against Jo-1 and SRP, and myositis associated autoantibodies PM-Scl, Ro52, Ro60 (SSA), La and U1RNP were detected by a line blot and in-house immunoblot assay. Results IFN signature in peripheral blood was present in a subgroup of patients with myositis. In order to determine the relevance of the differential expression of IFN type I activity in myositis we studied the association between IFN score and the presence of ANA or specific autoantibodies. No significant difference in the extent of the IFN score was observed between ANA negative (n=44) and ANA positive (n=50) nor in the number of IFNhigh or IFNlow patients. Comparison of IFN score in patients positive for myositis associated or specific autoantibodies revealed that the highest IFN score was found in U1RNP positive patients (mean IFN score = 23.66, 7/9 were IFNhigh), followed by La positive patients (mean IFN score = 11.94, all were IFNhigh n=4). In addition, a majority of Jo-1 (16 out of 23), Ro-52 (15 out of 22), Ro-60 (8 out of 10) positive patients were characterized by an IFNhigh expression profile. Detailed analysis revealed that IFNhigh patients were characterized by multi-autoantibody specificity, i.e. 17 out of 23 patients positive for 2 or more autoantibodies were IFNhigh (70%) versus 30 out of 71 of the patients positive for 1 or none of the specific autoantibodies (45%) (Pearson Chi square p=0.008). Conclusions An IFN score in myositis patients is associated with the presence of myositis specific or associated autoantibodies Jo-1, U1RNP, Ro-52, Ro-60 or La and the association was stronger when 2 or more autoantibodies were present. Based on these data and on previous studies we hypothesize that these autoantibodies could act as an endogenous trigger of the type I IFN pathway and contribute to the chronicity of these diseases. Disclosure of Interest None Declared
Interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) are important multifunctional c... more Interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) are important multifunctional cytokines involved in tumour growth and metastasis. In this study, we have measured serial levels of serum IL-6 and TNF-alpha in prostate cancer patients. A total of 80 patients with carcinoma of the prostate and 38 controls were studied. Three patient groups, with small bulk localised, large volume localised and metastatic prostate cancer, were assessed. Serum IL-6 and TNF-alpha levels were measured and correlated with clinicopathological variables and patient survival. Serial changes in these cytokines were also assessed and related to disease progression in 40 patients with recurrent prostate cancer. Serum IL-6 levels in patients with metastatic disease (9.3+/-7.8 pg x ml(-1)) were higher than those in patients with localised disease (1.3+/-0.8 pg x ml(-1), P<0.001). Significantly elevated levels of TNF-alpha were found in metastatic disease (6.3+/-3.6 pg x ml(-1)) compared with loc...
Journal of immunology (Baltimore, Md. : 1950), 1999
Treatment with a chimeric mAb to TNF-alpha has been shown to suppress inflammation and improve pa... more Treatment with a chimeric mAb to TNF-alpha has been shown to suppress inflammation and improve patient well-being in rheumatoid arthritis (RA), but the mechanisms of action of such treatment have not been fully explored. Here we show that in vivo administration of anti-TNF-alpha Ab, using a longitudinal analysis, results in the rapid down-regulation of a spectrum of cytokines, cytokine inhibitors, and acute-phase proteins. Marked diurnal variation in the serum levels of some of these were detected. These results were consistent with the concept of a cytokine-dependent cytokine cascade, and the degree of clinical benefit noted after anti-TNF-alpha therapy is probably due to the reduction in many proinflammatory mediators apart from TNF-alpha, such as IL-6, which reached normal levels within 24 h. Serum levels of cytokine inhibitors such as soluble p75 and p55 TNFR were reduced as was IL-1 receptor antagonist. Reductions in acute-phase proteins occurred after serum IL-6 fell and inclu...
Antibodies to nRNP, Sm and La were detected and characterised by immunoblot analysis. A compariso... more Antibodies to nRNP, Sm and La were detected and characterised by immunoblot analysis. A comparison was made between IgG and IgM autoantibodies in 77 patients with systemic lupus erythematosus (SLE) and 50 normal subjects. No antibodies were detected in the normal subjects. In all 3 antigen specificity groups, a heterogeneity of antibody class was observed between patients. Antibodies to the 2 nRNP-specific polypeptides (33 and 67 kD) were approximately equally frequent. Although IgG antibodies to the 67 kD polypeptide were detected in 88% of patients with antibodies to this polypeptide, IgG antibodies to the 33 kD polypeptide were only detected in 43% of patients with antibodies to this polypeptide. This suggested either that anti-33 kD antibody is produced by a B cell which cannot mature to an IgG-secretor, or that anti-33 kD antibody production succeeds an initial immune response producing anti-67 kD. Reactivity with the 29 kD, Sm-specific polypeptide appeared to be the most frequ...
The aromatase inhibitor (AI)-associated musculoskeletal syndrome (AIMSS) occurs in approximately ... more The aromatase inhibitor (AI)-associated musculoskeletal syndrome (AIMSS) occurs in approximately 50% of AI-treated patients. Inflammatory mediators are associated with oestrogen signalling and may change with oestrogen depletion. We hypothesised that AIMSS may be associated with changes in circulating inflammatory markers. Patients with breast cancer were enrolled in a trial of adjuvant AI therapy. Changes in pain and function during therapy were assessed prospectively. We selected 30 cases with AIMSS and 22 controls without AIMSS, matched for demographics and prior therapy. Serum samples collected at baseline and during treatment were assayed for multiple inflammatory cytokines and lipid mediators using multiplex assays. Before AI therapy, mean serum concentrations of 6 of 36 assayed factors were statistically significantly lower in cases than controls (all P<0.003). No statistically significant changes during AI therapy relative to pre-treatment were observed between cases and ...
ABSTRACT Background The IFN signature has been described to be present in many autoimmune disease... more ABSTRACT Background The IFN signature has been described to be present in many autoimmune diseases, including myositis. The extent of this signature appears to be related to disease activity, however, the underlying mechanism resulting in such a signature has not been revealed yet. Detailed insight into such a mechanism would increase the understanding of role of the IFN systems in myositis and autoimmunity. Objectives In this study we investigated the association between (the extent of) the IFN signature and autoantibody profiles in myositis. Methods RNA samples, obtained from whole blood from 94 patients with polymyositis, dermatomyositis, and inclusion body myositis recruited from the Karolinska University Hospital and Prague University, were assessed for expression levels of 9 IFN related genes using BioMarkTM Dynamic Arrays. IFN score was determined as the average gene expression level of these genes. Median IFN score (4.38) was used to define patients as IFNhigh or IFNlow. ANA positivity was determined by indirect immunofluorescence test and myositis specific autoantibodies against Jo-1 and SRP, and myositis associated autoantibodies PM-Scl, Ro52, Ro60 (SSA), La and U1RNP were detected by a line blot and in-house immunoblot assay. Results IFN signature in peripheral blood was present in a subgroup of patients with myositis. In order to determine the relevance of the differential expression of IFN type I activity in myositis we studied the association between IFN score and the presence of ANA or specific autoantibodies. No significant difference in the extent of the IFN score was observed between ANA negative (n=44) and ANA positive (n=50) nor in the number of IFNhigh or IFNlow patients. Comparison of IFN score in patients positive for myositis associated or specific autoantibodies revealed that the highest IFN score was found in U1RNP positive patients (mean IFN score = 23.66, 7/9 were IFNhigh), followed by La positive patients (mean IFN score = 11.94, all were IFNhigh n=4). In addition, a majority of Jo-1 (16 out of 23), Ro-52 (15 out of 22), Ro-60 (8 out of 10) positive patients were characterized by an IFNhigh expression profile. Detailed analysis revealed that IFNhigh patients were characterized by multi-autoantibody specificity, i.e. 17 out of 23 patients positive for 2 or more autoantibodies were IFNhigh (70%) versus 30 out of 71 of the patients positive for 1 or none of the specific autoantibodies (45%) (Pearson Chi square p=0.008). Conclusions An IFN score in myositis patients is associated with the presence of myositis specific or associated autoantibodies Jo-1, U1RNP, Ro-52, Ro-60 or La and the association was stronger when 2 or more autoantibodies were present. Based on these data and on previous studies we hypothesize that these autoantibodies could act as an endogenous trigger of the type I IFN pathway and contribute to the chronicity of these diseases. Disclosure of Interest None Declared
Interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) are important multifunctional c... more Interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) are important multifunctional cytokines involved in tumour growth and metastasis. In this study, we have measured serial levels of serum IL-6 and TNF-alpha in prostate cancer patients. A total of 80 patients with carcinoma of the prostate and 38 controls were studied. Three patient groups, with small bulk localised, large volume localised and metastatic prostate cancer, were assessed. Serum IL-6 and TNF-alpha levels were measured and correlated with clinicopathological variables and patient survival. Serial changes in these cytokines were also assessed and related to disease progression in 40 patients with recurrent prostate cancer. Serum IL-6 levels in patients with metastatic disease (9.3+/-7.8 pg x ml(-1)) were higher than those in patients with localised disease (1.3+/-0.8 pg x ml(-1), P<0.001). Significantly elevated levels of TNF-alpha were found in metastatic disease (6.3+/-3.6 pg x ml(-1)) compared with loc...
Journal of immunology (Baltimore, Md. : 1950), 1999
Treatment with a chimeric mAb to TNF-alpha has been shown to suppress inflammation and improve pa... more Treatment with a chimeric mAb to TNF-alpha has been shown to suppress inflammation and improve patient well-being in rheumatoid arthritis (RA), but the mechanisms of action of such treatment have not been fully explored. Here we show that in vivo administration of anti-TNF-alpha Ab, using a longitudinal analysis, results in the rapid down-regulation of a spectrum of cytokines, cytokine inhibitors, and acute-phase proteins. Marked diurnal variation in the serum levels of some of these were detected. These results were consistent with the concept of a cytokine-dependent cytokine cascade, and the degree of clinical benefit noted after anti-TNF-alpha therapy is probably due to the reduction in many proinflammatory mediators apart from TNF-alpha, such as IL-6, which reached normal levels within 24 h. Serum levels of cytokine inhibitors such as soluble p75 and p55 TNFR were reduced as was IL-1 receptor antagonist. Reductions in acute-phase proteins occurred after serum IL-6 fell and inclu...
Antibodies to nRNP, Sm and La were detected and characterised by immunoblot analysis. A compariso... more Antibodies to nRNP, Sm and La were detected and characterised by immunoblot analysis. A comparison was made between IgG and IgM autoantibodies in 77 patients with systemic lupus erythematosus (SLE) and 50 normal subjects. No antibodies were detected in the normal subjects. In all 3 antigen specificity groups, a heterogeneity of antibody class was observed between patients. Antibodies to the 2 nRNP-specific polypeptides (33 and 67 kD) were approximately equally frequent. Although IgG antibodies to the 67 kD polypeptide were detected in 88% of patients with antibodies to this polypeptide, IgG antibodies to the 33 kD polypeptide were only detected in 43% of patients with antibodies to this polypeptide. This suggested either that anti-33 kD antibody is produced by a B cell which cannot mature to an IgG-secretor, or that anti-33 kD antibody production succeeds an initial immune response producing anti-67 kD. Reactivity with the 29 kD, Sm-specific polypeptide appeared to be the most frequ...
The aromatase inhibitor (AI)-associated musculoskeletal syndrome (AIMSS) occurs in approximately ... more The aromatase inhibitor (AI)-associated musculoskeletal syndrome (AIMSS) occurs in approximately 50% of AI-treated patients. Inflammatory mediators are associated with oestrogen signalling and may change with oestrogen depletion. We hypothesised that AIMSS may be associated with changes in circulating inflammatory markers. Patients with breast cancer were enrolled in a trial of adjuvant AI therapy. Changes in pain and function during therapy were assessed prospectively. We selected 30 cases with AIMSS and 22 controls without AIMSS, matched for demographics and prior therapy. Serum samples collected at baseline and during treatment were assayed for multiple inflammatory cytokines and lipid mediators using multiplex assays. Before AI therapy, mean serum concentrations of 6 of 36 assayed factors were statistically significantly lower in cases than controls (all P<0.003). No statistically significant changes during AI therapy relative to pre-treatment were observed between cases and ...
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Papers by peter charles