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L Truedsson

Publications and source records attributed to L Truedsson.

At least 19 recordsLinked to original sources
PubMed2006

No evidence of association between genetic variants of the PDCD1 ligands and SLE.

PDCD1, an immunoreceptor involved in peripheral tolerance has previously been shown to be genetically associated with systemic lupus erythematosus (SLE). PDCD1 has two ligands whose genes are located in close proximity on chromosome 9p24. Our attention was drawn to these ligands after finding suggestive linkage to a marker (gata62f03, Z=2.27) located close to their genes in a genome scan of Icelandic families multiplex for SLE. Here, we analyse Swedish trios (N=149) for 23 single nucleotide polymorphisms (SNPs) within the genes of the PDCD1 ligands. Initially, indication of association to eight SNPs was observed, and these SNPs were therefore also analysed in Mexican trios (N=90), as well as independent sets of patients and controls from Sweden (152 patients, 448 controls) and Argentina (288 patients, 288 controls). We do not find support for genetic association to SLE. This is the first genetic study of SLE and the PDCD1 ligands and the lack of association in several cohorts implies that these genes are not major risk factors for SLE.

Antigens, CD↗
PubMed2006

Antibodies against four proteins from a Streptococcus pyogenes serotype M1 strain and levels of circulating mannan-binding lectin in acute poststreptococcal glomerulonephritis.

BACKGROUND: Responses against antigens from the potentially nephritogenic Streptococcus pyogenes serotype M1 in patients with acute poststreptococcal glomerulonephritis (AGN) were studied to seek indications of expression of these antigens during the preceding infection. Also, the question was asked whether the complement protein mannan-binding lectin (MBL) is required for development of the hypocomplementemia associated with AGN. Hypothetically, the lectin pathway might trigger the alternative pathway, which is consistently activated in AGN. METHODS: Antibodies against three proteins associated with M1, M1 protein, streptococcal inhibitor of complement (SIC) and protein H, an IgG-binding protein, were determined by ELISA in 56 children and 17 adults with AGN. Antibodies against streptococcal cysteine proteinase, which is produced by all serotypes of S. pyogenes, were also examined. MBL concentrations were measured in the same 71 patients by a sandwich ELISA. RESULTS: Increased concentrations of antibodies were found against all four streptococcal proteins, albeit not uniformly distributed between different subgroups of patients. The prevalence of low MBL concentrations (<100 microg/l) including 2 patients with undetectable MBL (<10 microg/l) was similar in AGN (11%) and in controls (16%). CONCLUSIONS: Our results give evidence of exposure to SIC and protein H in conjunction with AGN. This implies that SIC and protein H and/or cross-reacting proteins may have a role in the pathogenesis of AGN or that streptococci expressing SIC or protein H are nephritogenic for other reasons. The finding of MBL-deficient individuals among the patients demonstrates that MBL is not necessary for the recruitment of complement in AGN.

Adolescent↗
PubMed2006

Complement deficiency and disease: an update.

Complement deficiencies are probably vastly under-diagnosed within clinical medicine. Judging from a Swedish study of C2 deficiency, a deficiency with an estimated prevalence of about 1/20,000 in Western countries, less than 10% of the deficiencies of the classical and alternative pathways and the late complement components are identified in Sweden. C1 inhibitor deficiency and deficiencies of MBL and MASP-2 were not included in the assessment. The introduction of new screening methods should facilitate detection of complement deficiencies in clinical practice. In our study of C2 deficiency (n=40), 57% of the patients had a history of invasive infection with encapsulated bacteria, mainly Streptococcus pneumoniae. This emphasizes the importance of the classical and/or the lectin pathway in defence against severe infection. Rheumatological disease, mainly systemic lupus erythematosus was present in 43% of the patients. In addition, a significant association was found between C2 deficiency and atherosclerosis. Complement-dependent disease mechanisms are discussed together with the potential importance of non-complement genes for disease expression in complement deficiencies. Analysis of larger patient groups is required in order to establish guidelines for investigation and treatment of patients with complement deficiency.

Atherosclerosis↗
PubMed2006

Systemic white blood and endothelial cell response after revascularization of critical limb ischemia is only influenced in case of ischemic ulcers.

AIM: The aim of this study was to study the inflammatory response to open revascularization of an ischemic leg in terms of activation of white blood cells (WBC), platelets and endothelial cells. DESIGN: prospective study. METHODS: Venous samples from 21 patients suffering critical limb ischemia (CLI) were drawn before, and 4 weeks after (20 patients) revascularization. Total WBC, differentiated WBC, and platelets were counted. Expression of CD11b/CD18 on granulocytes and monocytes and CD41 on platelets was measured by flow cytometry. Soluble endothelial markers (sICAM-1, sVCAM-1, sE-selectin and sP-selectin) were analysed with ELISA. RESULTS: WBC and granulocyte count decreased in the subgroup of patients with ulcer and gangrene but no change in activation of WBC was recorded. The endothelial marker sICAM-1 decreased while VCAM-1 increased following surgery, most evident in the subgroup with ulcers and gangrene. CONCLUSIONS: This study shows that revascularization of CLI does not significantly influence the inflammatory response in patients with rest pain only, but a limited response of down regulation was found in the ulcer/gangrene patients probably as an effect of healing ulcers.

Aged↗
PubMed2005

Influence of methotrexate, TNF blockers and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis.

OBJECTIVE: To compare antibody responses to 23-valent pneumococcal vaccine (Pneumovax) in controls and patients with established rheumatoid arthritis (RA) treated with TNF blockers, methotrexate (MTX) or a combination of both. METHODS: Patients with RA (n = 149) and healthy controls (n = 47) were vaccinated. Treatment with TNF blockers (etanercept or infliximab) and MTX was given to 50 patients, and 62 patients were treated with TNF blockers alone or with other DMARDs. MTX alone was given to 37 patients. Concentrations of immunoglobulin G (IgG) antibodies against pneumococcal capsular polysaccharides 23F and 6B were measured by enzyme-linked immunoassay before and 4-6 weeks after vaccination. An immune response was defined as a twofold or higher increase in antibody concentration following vaccination. RESULTS: Prevaccination antibody levels for both 23F and 6B were similar in the patient groups. Antibody concentrations after vaccination increased significantly in all groups. Patients treated with TNF blockers without MTX showed better immune responses than those treated with TNF blockers in combination with MTX (P = 0.037 for 23F and P = 0.004 for 6B) or MTX alone (P<0.001 for both 23F and 6B). RA patients given MTX alone had the lowest immune responses. Prednisolone treatment did not influence the responses. CONCLUSIONS: Patients treated with TNF blockers and controls showed similar responses to vaccination. In contrast, patients treated with MTX had reduced responses regardless of anti-TNF treatment. The findings do not argue against the use of pneumococcal vaccination in RA patients undergoing treatment with TNF blockers.

Adolescent↗
PubMed2005

Complement and its breakdown products in SLE.

The complement system has important protective functions in both the innate and the adaptive immune systems but can also, when inappropriately activated, cause tissue damage. Complement deficiency predisposes to infection and also to development of autoimmune disease, especially SLE, and complement is at the same time involved in the pathogenesis of this disease. In this review, various aspects of this dualism are discussed. An overview of activation pathways and activation products is given, together with a description of autoimmunity against complement and the potential of complement regulation in future therapeutics.

Autoantibodies↗
PubMed2005

Deficiency of the mannan-binding lectin pathway of complement and poor outcome in cystic fibrosis: bacterial colonization may be decisive for a relationship.

In cystic fibrosis (CF) prognosis concerning lung damage development is highly variable and difficult to predict. Mannan-binding lectin (MBL) deficiency has been reported to be associated with poor outcome in CF lung disease. MBL is a recognition molecule of the MBL pathway of the complement system and is encoded by a gene characterized by a high degree of polymorphism. Some genotypes result in low serum concentrations of MBL. MBL-associated serine protease 2 (MASP-2) is another protein belonging to the MBL pathway. A mutation resulting in low levels of MASP-2 in serum has been described recently. In the present study, 112 CF patients aged 4-54 years were investigated for MBL and MASP-2 genotypes, serum levels of MBL and MASP-2 and the MBL pathway function in serum. No correlation to reduced lung function or need for lung transplantation was seen, either for MBL deficiency, MASP-2 gene mutation or reduced MBL pathway function. However, in the 27 patients colonized with Staphylococcus aureus, MBL-deficient genotypes were associated with decreased lung function. As expected, MBL pathway function in serum was reduced both in MBL-deficient patients and in patients carrying a mutant MASP-2 allele. An unexpected finding was that CF patients had higher serum levels of MBL than healthy controls when corrected for MBL genotype. In conclusion, MBL pathway function was affected both by MBL and by MASP-2 genotypes. However, MBL or MASP-2 levels in serum did not affect the clinical outcome in the cohort of CF patients studied.

Adolescent↗
PubMed2005

Inflammatory markers and IL-6 polymorphism in peripheral arterial disease with and without diabetes mellitus.

Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis, recognized as an inflammatory disease of the vessel wall, probably accelerated by diabetes mellitus (DM). Elevated interleukin (IL)-6 levels have been associated with increased cardiovascular morbidity and a common polymorphism has been identified in the promoter region of the IL-6 gene. The aim of this prospective study was to investigate inflammatory mediators in PAD patients (+/- DM) and to investigate a possible relationship to the IL-6 gene polymorphism. Five groups of patients (DM, intermittent claudication +/- DM, critical limb ischemia (CLI) +/- DM) and a control group of 20 individuals each were included. Hemoglobin, high sensitive C-reactive protein (hsCRP), creatinine, blood lipids, white blood cells (WBC); CD11b/CD18; vascular cell adhesion molecule (sVCAM-1), intercellular adhesion molecule (sICAM-1), sE-selectin, sP-selectin; IL-6, IL-8, tumour necrosis factor (TNF)alpha, sTNFalpha-R1 and sTNFalpha-R2 were analysed. The IL-6 gene polymorphism was determined in all groups and also compared with 200 healthy controls from a larger study of blood donors. In a multiple regression analysis, adjusted for gender, smoking and age, the effect of CLI was significantly (p < 0.05) associated with elevated levels of the WBC count, hsCRP, proinflammatory cytokines (IL-6, TNFalpha-R1-2) and endothelial (sICAM, sVCAM) and WBC (CD11b gran) markers. The effect of less advanced PAD (intermittent claudication) was related to an increased concentration of sVCAM-1 and the number of monocytes and granulocytes. DM or leg ulcers were not significantly related to any of the markers. No significant difference in frequency of the various IL-6 genotypes was found between the groups or when compared with the group of 200 blood donors (p> 0.3). Activation of cytokines, endothelial cells and WBC was related to the Fontaine stage of PAD but not to the presence of DM or ulcers. No association was found between the polymorphism in the IL-6 promoter region and PAD.

Aged↗
PubMed2004

Postoperative on-line monitoring with intraperitoneal microdialysis is a sensitive clinical method for measuring increased anaerobic metabolism that correlates to the cytokine response.

BACKGROUND: Visceral ischaemia and cytokine release are early stages in the development of shock and multiorgan failure. Because of lack of methods to measure anaerobic metabolism or visceral hypoxia in the early phase, diagnosis is not usually established until shock and organ failure are evident. METHODS: Nineteen patients were studied postoperatively after major abdominal gastrointestinal surgery. A microdialysis catheter was placed intraperitoneally before closure of the abdomen. Analysis of glucose, pyruvate and lactate was performed every second hour and the ratio between lactate and pyruvate was calculated. Peritoneal fluid was collected from a peritoneal drainage for analysis of tumour necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10). RESULTS: Sixteen of the patients had a normal postoperative course; the lactate/pyruvate ratio started at the level of 20 immediately postoperatively and decreased significantly during the first 45 postoperative hours (P = 0.007). A similar pattern was recorded for peritoneal TNF-alpha, which decreased correspondingly (P = 0.003). A correlation coefficient of 0.303 (P < 0.001 ) between lactate/pyruvate ratio and TNF-alpha was found. After an initial short increase, IL-10 decreased over time (P < 0.001). Three of the patients had abnormalities in the microdialysis results, cytokines and clinical outcome. These patients are presented separately. CONCLUSIONS: A normal postoperative course results in a decrease in the intraperitoneal lactate/pyruvate ratio, TNF-alpha and IL-10. A correlation between the intraperitoneal lactate/pyruvate ratio and TNF-alpha was found which suggests that intraperitoneal microdialysis is a sensitive, indirect method in analysing the postoperative intraperitoneal inflammatory response. A complicated postoperative course was preceded by increase of the peritoneal lactate/pyruvate ratio interpreted as splanchnic hypoxia and also an increased TNF-alpha level.

Adult↗
PubMed2004

Induction of apoptosis in monocytes and lymphocytes by serum from patients with systemic lupus erythematosus - an additional mechanism to increased autoantigen load?

The most likely source of autoantigens in systemic lupus erythematosus (SLE) is apoptotic material. Because increased levels of circulating apoptotic cells are found in SLE we wanted to investigate the capacity of serum from patients with SLE or other autoimmune or infectious diseases and normal healthy donors (NHD) to induce apoptosis in normal monocytes, lymphocytes and corresponding cell lines, in relation to clinical and immunological data. Monocytes and lymphocytes from healthy donors were incubated with sera from 37 SLE patients, 37 sex- and age-matched NHD and sera from patients with rheumatoid arthritis, vasculitis, sepsis and mononucleosis. Sera from SLE patients were sampled at both active and inactive disease. The apoptosis-inducing effect (AIE) of these sera was monitored with flow cytometry using annexin V and propidium iodide (PI) binding. The AIE in monocytes and lymphocytes was significantly higher in sera from SLE patients than in other patient groups and NHD (P < 0.001) and was also higher when cell lines were used. Level of C5a in cell culture supernatant correlated with AIE in monocytes (r = 0.451, P = 0.005), suggesting involvement of complement. Heat-inactivation of sera did not affect the AIE, nor did depletion of IgG by protein G absorption of serum. Kinetic analyses showed a peak in apoptosis induction at 12-16 h, with a delayed PI positivity. AIE was equally high using sera from active and inactive SLE cases, and did not correlate with the SLE Disease Activity Index (SLEDAI). Thus, SLE serum has a strong and apparently disease-specific apoptosis-inducing capacity, which could contribute to a high load of potential autoantigen.

Adolescent↗
PubMed2004

Transcriptional down-regulation of the platelet ADP receptor P2Y(12) and clusterin in patients with systemic lupus erythematosus.

Cardiovascular complications are common in systemic lupus erythematosus (SLE) and myocardial infarctions are the leading cause of increased mortality. The ADP receptor P2Y(12) plays a central role in platelet activation and the P2Y(12) blocker clopidogrel reduces the incidence of cardiovascular events. Clusterin, a complement inhibitory protein suggested to be involved in the pathogenesis of SLE, has been found recently in a microarray study to be expressed at very high levels in platelets. Using a new protocol for mRNA quantification in platelets we set out to study if gene expression is altered in SLE patients compared with a healthy control group. Quantitative assay based on real-time PCR was used to measure mRNA expression, Western blot for P2 receptor protein expression and PFA-100 for platelet aggregation. The P2Y(12) receptor expression was decreased in SLE compared to the controls (P < 0.05), while expression of P2Y(1) and P2X(1) were unaltered. These findings were consistent at the protein level. The clusterin mRNA expression was very high. However, SLE patients had significantly lower levels than controls (P < 0.05). Platelet aggregation was similar in both groups. It may be suggested that a decreased level of P2Y(12) receptors could represent a protective response in SLE against thrombotic complications. Lowered clusterin levels could be involved in the pathogenesis of SLE due to decreased protective effects. These findings could help to achieve a better understanding of the platelet function in SLE and serve as a guide for further research and drug use.

Adolescent↗
PubMed2004

White blood cell and endothelial cell response to endovascular procedures in the leg.

AIM: The longterm patency of endovascular procedures is partly depending on restenosis by intimal hyperplasia, a process depending on inflammatory mechanisms resembling the mechanisms of normal repair and the process of atherosclerosis. The aim of this study was to characterize the inflammatory response of white blood cells (WBC) and endothelial cells following endovascular procedures in the leg. METHODS: Venous blood samples were drawn from a cubital vein before and 2 hours after intervention in 19 patients suffering from peripheral arterial occlusive disease (PAOD). Flow cytometry was used to identify and determine the concentrations of WBC and platelets and to measure CD11b/CD18 on WBC and CD41 on platelets. Soluble endothelial markers (sICAM-1, sE-selectin, sP-selectin and sVCAM-1) were measured by ELISA technique. RESULTS: WBC were downregulated following endovascular procedures. The endothelial cell response was limited and only downregulation of sP-selectin reached significant levels. The results were more evident in the group of patients with critical limb ischemia (CLI) compared to patients with intermittent claudication (IC). CONCLUSION: Endovascular procedures in the leg evoke only a limited response which is depending on the degree of ischemia and the magnitude of the interventional procedure.

Aged↗
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↗
PubMed2002

Early treatment with lexipafant, a platelet-activating factor-receptor antagonist, is not sufficient to prevent pulmonary endothelial damage after intestinal ischaemia and reperfusion in rats.

BACKGROUND: Intestinal ischaemia-reperfusion can lead to pulmonary injury characterised by increased macromolecular leakage and leukocyte sequestration. Important mediators of ischaemia-reperfusion-associated injury include polymorphonuclear granulocytes and platelet-activating factor. AIM: To investigate the potential therapeutic inhibition of platelet-activating factor in intestinal ischaemia-reperfusion associated pulmonary injury, by use of a potent platelet-activating factor-receptor antagonist, lexipafant. METHODS: Rats were subjected to 30 minutes of intestinal ischaemia followed by 3 or 12 hours reperfusion. Lexipafant or saline was given intraperitoneally after 30 minutes reperfusion. RESULTS: Increased leakage of radiolabelled human serum albumin was found in the lungs after intestinal ischaemia followed by 3 or 12 hours reperfusion. Administration of lexipafant did not significantly prevent the increased leakage. Pulmonary myeloperoxidase content increased after intestinal ischaemia-reperfusion, indicating polymorphonuclear granulocyte sequestration through the pulmonary endothelium. The increase in interleukin-1beta seen after 3 hours reperfusion was partly reversed by lexipafant. CONCLUSIONS: Pulmonary injury occurred following intestinal ischaemia-reperfusion, characterised by increased leakage of radiolabelled albumin over the endothelial barrier; correlating with increased pulmonary myeloperoxidase-content, implying involvement of polymorphonuclear granulocytes in the pathogenesis of remote organ injury after intestinal ischaemia-reperfusion. Lexipafant did not significantly decrease severity of pulmonary damage.

Animals↗
PubMed2001

Increased level of soluble HLA class I antigens in systemic lupus erythematosus: correlation with anti-DNA antibodies and leukopenia.

The concentration of soluble HLA class I (sHLA-I) was measured by ELISA in serum samples from 30 well-characterised SLE patients at high and low disease activity states and from 100 healthy controls. HLA-A allotypes in the patients were analysed by a PCR-based typing technique. A higher level of sHLA-I was found in SLE patient sera both at high and low disease activity than in controls (P< 0.001). The sHLA-I level was further increased during active disease (P< 0.01). Concentrations of sHLA-I correlated with anti-dsDNA antibodies at high disease activity, but not with disease activity as analysed by a modified SLEDAI. Numbers of leukocytes and lymphocytes, as well as levels of C1q and C3 correlated inversely with sHLA-I concentration. In five serial samples from ten patients the sHLA-I level co-varied with disease activity. Presence of HLA allotype A9 was associated with higher sHLA-I levels in both patients (P< 0.001) and controls (P< 0.001). We conclude that the increased sHLA-I concentration in SLE patients was related to several laboratory parameters reflecting disease activity suggesting that sHLA-I molecules are connected with the disease process. Increased sHLA-I level due to HLA-A allotype was not a disease susceptibility factor for SLE.

Adult↗
PubMed2001

Group A streptococcal phagocytosis resistance is independent of complement factor H and factor H-like protein 1 binding.

Factor H (FH) and factor H-like protein 1 (FHL-1) regulate complement activation through the alternative pathway. Several extracellular bacterial pathogens, prime targets for the complement system, bind FH and FHL-1, thereby acquiring a potential mechanism for minimizing complement deposition on their surface. For group A streptococci (GAS), surface-bound antiphagocytic M proteins mediate the interaction. To study the role of the FH-FHL-1 interaction for complement deposition and opsonophagocytosis of GAS, we first constructed a set of truncated M5 protein variants and expressed them on the surface of a homologous M-negative GAS strain. Binding experiments with the resulting strains demonstrated that the major FH-FHL-1 binding is located in a 42-amino-acid region within the N-terminal third of M5. Measurement of bacteria-bound complement factor C3 after incubation in plasma showed that the presence of this region had little impact upon complement deposition through the alternative pathway. Moreover, streptococci expressing M5 proteins lacking the major FH and FHL-1 binding sequence resisted phagocytosis in human blood as efficiently as bacteria expressing the wild-type protein. Consequently, the data suggest that the binding of the regulators of the alternative pathway is of limited importance for GAS phagocytosis resistance.

Antigens, Bacterial↗
PubMed2001

The inflammatory response and its consequence for the clinical outcome following aortic aneurysm repair.

OBJECTIVE: to review published studies on the outcome of the inflammatory response after abdominal aortic aneurysm (AAA) repair. METHODS: a literature search on PubMed was performed. All studies that determined the inflammatory response (cytokine release) after AAA repair were included. The results of the studies and differences between open and endoluminal repair were compared and evaluated. RESULTS: seventeen studies were identified. In most studies the investigated cytokines were TNF-alpha and IL-6. Determination of IL-1 beta, IL-8, TNFsr1 and TNFsr2 were less often performed. TNF-alpha may reflect, but not strictly predict, the clinical outcome in patients with ruptured AAA. IL-6 levels correlate well with the surgical trauma per se. Variations in recorded cytokine release during endovascular AAA repair may depend on the times of blood sampling. CONCLUSION: both open and endovascular AAA repair provoke a cytokine response. This response is greater during open repair than during endovascular aortic aneurysm exclusion.

Aortic Aneurysm, Abdominal↗