Search PubMed⌕ Search

Biomedical subjects

Ingrid E Lundberg

Publications and source records attributed to Ingrid E Lundberg.

At least 19 recordsLinked to original sources
PubMed2025

Genetic Architecture of Idiopathic Inflammatory Myopathies From Meta-Analyses.

OBJECTIVE: Idiopathic inflammatory myopathies (IIMs, myositis) are rare systemic autoimmune disorders that lead to muscle inflammation, weakness, and extramuscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis data set to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes. METHODS: We performed association analyses on 14,903 individuals (3,206 patients and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine reference panel. Fine-mapping and expression quantitative trait locus colocalization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities. RESULTS: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-transfer RNA synthetase autoantibodies (anti-Jo-1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in Epstein-Barr virus (EBV)-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation. CONCLUSION: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research.

Humans↗
PubMed2006

Endothelial cell activation and neovascularization are prominent in dermatomyositis.

BACKGROUND: While vascular and immune abnormalities are common in juvenile and adult dermatomyositis (DM), the molecular changes that contribute to these abnormalities are not clear. Therefore, we investigated pathways that facilitate new blood vessel formation and dendritic cell migration in dermatomyositis. METHODS: Muscle biopsies from subjects with DM (9 children and 6 adults) and non-myositis controls (6 children and 7 adults) were investigated by immunohistochemistry using antibodies that recognize existing (anti-CD146) and newly formed blood vessels (anti-alphaVbeta3) and mature dendritic cells (anti-DC-LAMP). Blood vessel quantification was performed by digitalized image analysis. Additional muscle biopsies from subjects with adult DM and non-myositis controls were used for global gene expression profiling experiments. RESULTS: A significant increase in neovascularization was found in muscle biopsies of DM patients; neovascularization (alphaVbeta3 positive capillaries and vessels per muscle fiber) was much higher in juvenile than in adult DM patients (control vs juvenile DM: Mean +/- SE: 0.06 +/- 0.01 vs 0.6 +/- 0.05; p < 0.0001 and control vs adult DM: Mean +/- SE: 0.60 +/- 0.1 vs 0.75 +/- 0.1; p = 0.051). Gene expression analysis demonstrated that genes that participate not only in angiogenesis but also in leukocyte trafficking and the complement cascade were highly up regulated in DM muscle in comparison to age matched controls. DC-LAMP positive dendritic cells were highly enriched at perivascular inflammatory sites in juvenile and adult DM patients along with molecules that facilitate dendritic cell transmigration and reverse transmigration (CD142 and CD31). CONCLUSION: These results suggest active neovascularization and endothelial cell activation in both juvenile and adult DM. It is likely that close association of monocytes with endothelial cells initiate rapid dendritic cell maturation and an autoimmune response in DM.

Journal Article↗
PubMed2006

Functional index-2: Validity and reliability of a disease-specific measure of impairment in patients with polymyositis and dermatomyositis.

OBJECTIVE: To revise the content of the Functional Index in myositis (FI) and to evaluate measurement properties of a revised FI. METHODS: Previously performed FI (n = 287) were analyzed for internal redundancy and consistency, and ceiling and floor effects. Content was evaluated and a preliminary revised FI was developed. To evaluate the construct validity of the preliminary revised FI, it was compared with isokinetic measurements of muscular strength and endurance, the Myositis Activities Profile, disease impact on general wellbeing, and creatine phosphokinase levels. Minor adjustments were made and the revised FI was investigated for interrater reliability and intrarater reliability over a 1-week period. After this, some minor, additional adjustments were made leading to the final version, FI-2. RESULTS: Five tasks were removed from the original FI due to ceiling effects. Performance pace and number of repetitions were modified for the remaining tasks. A moderate correlation (r(s) = 0.58) was found between the shoulder flexion task of the preliminary revised FI and isokinetic measurements of shoulder flexion endurance. Intraclass correlation coefficient (ICC) for interrater reliability of the revised FI varied from 0.86-0.99 with no systematic differences. ICC for intrarater reliability varied from 0.56-0.99 with systematic differences (P < 0.05) between test and retest in 3 of the tasks. The sit-up task was excluded due to low intrarater reliability resulting in the final 7-item FI-2. There was a good correlation between tasks on the right and left side suggesting that the FI-2 could be performed unilaterally. CONCLUSION: The FI-2 is a valid and reliable outcome measure of impairment for patients with polymyositis or dermatomyositis. It is well tolerated and the unilateral FI-2 requires a maximum of 20 minutes to perform. Further evaluation of sensitivity to change and testing in healthy individuals needs to be conducted.

Activities of Daily Living↗
PubMed2005

Lipid peroxidation is enhanced in patients with systemic lupus erythematosus and is associated with arterial and renal disease manifestations.

OBJECTIVE: Cardiovascular disease with premature atherosclerosis is common in patients with systemic lupus erythematosus (SLE). We previously identified elevated levels of oxidized low-density lipoprotein (OxLDL) together with elevated levels of autoantibodies related to OxLDL as risk factors for cardiovascular disease in female patients with SLE. Autoantibodies to OxLDL are common in SLE and cross-react with anticardiolipin antibodies (aCL). We therefore hypothesized that lipid peroxidation is enhanced in patients with SLE in general. METHODS: One hundred forty-seven female patients with SLE and 60 age- and sex-matched controls were compared. A monoclonal antibody to oxidized phospholipids, EO6, was used to determine oxidation epitopes on LDL. Anti-OxLDL and autoantibodies to malondialdehyde (MDA)-modified LDL, cardiolipin, and oxidized aCL were determined by chemiluminescence technique. RESULTS: As determined by binding of EO6, patients with SLE had a higher level of oxidized phospholipids on LDL (P = 0.005) compared with controls. The level of OxLDL (e.g., oxidized phospholipid/apolipoprotein B) was associated with arterial disease (P = 0.006) and renal manifestations (P = 0.04). As reported previously, levels of aCL, autoantibodies to OxLDL, and autoantibodies to MDA-modified LDL were enhanced and were closely correlated in SLE. Anticardiolipin antibodies from these SLE patients recognized mainly oxidized forms of cardiolipin, indicating that antigenic epitopes on cardiolipin are related to lipid peroxidation in patients with SLE. CONCLUSION: In general, patients with SLE (particularly those with cardiovascular disease) had more oxidized epitopes on LDL compared with controls. Furthermore, aCL in these patients recognized epitopes generated during lipid peroxidation. Thus, "neo" self antigens on lipoproteins, generated during oxidation, are present in SLE and may be of importance for the development of premature cardiovascular disease and possibly also for other autoimmune phenomena observed in SLE.

Adult↗
PubMed2005

The prognosis of mixed connective tissue disease.

The prognosis for patients who have mixed connective tissue disease (MCTD) varies from a benign course to severe progressive disease. In approximately one third of patients the clinical symptoms go into long-term remission and the anti-U1 small nuclear ribonucleoprotein antibodies disappear. One third of patients have a severe, progressive disease course. Persistent morbidity often is attributable to arthritis, easy fatiguability, and dyspnea on exertion. The most severe clinical manifestation is pulmonary hypertension which contributes to premature death in patients who have MCTD. Pulmonary hypertension is associated with proliferative vascular abnormalities that involve small pulmonary vessels, rather than interstitial lung disease.

Autoantibodies↗
PubMed2005

The role of exercise in the rehabilitation of idiopathic inflammatory myopathies.

PURPOSE OF REVIEW: The objective of this review is to provide an update on exercise and clinical assessment in the idiopathic inflammatory myopathies. RECENT FINDINGS: Polymyositis, dermatomyositis and inclusion body myositis are rare conditions with muscle weakness as a common prominent feature. Earlier, these patients were discouraged from active exercise due to a fear of increased muscle inflammation with recommendations to rest, perform range of motion exercises and in some cases, isometric exercises. However, beginning in the 1990s, studies reported reduced disability in patients with chronic polymyositis/dermatomyositis following resistive mild/moderate to intensive muscular training and aerobic endurance training, without signs of increased muscle inflammation. Patients with active, recent onset disease seem to benefit from mild/moderate muscular exercise without signs of increased muscle inflammation. There is no evidence of increased muscle inflammation following exercise in inclusion body myositis. However the beneficial effects are unclear as one study report increased muscle strength, while the other could not achieve impairment reduction. SUMMARY: Studies evaluating active exercise in IIM support the notion of safety and benefits. However, large multi-center studies are needed to fully establish the safety and benefits of different types of exercise. Data indicate that active exercise, adapted to disease activity and disability should be included in the rehabilitation of patients in all stages of IIM. The newly developed and validated outcome measures for patients with polymyositis and dermatomyositis help assess the effects of interventions on disease activity and disability in clinical trials and in clinical practice. However, there are no sensitive and valid outcome measure for patients with inclusion body myositis.

Disability Evaluation↗
PubMed2005

Interstitial lung disease in polymyositis and dermatomyositis.

PURPOSE OF REVIEW: The purpose of this review is to discuss current concepts regarding management of interstitial lung disease in polymyositis and dermatomyositis. RECENT FINDINGS: Interstitial lung disease seems to be a more frequent manifestation in patients with polymyositis and dermatomyositis than previously reported. Modern technology, including high-resolution computerized tomography in combination with pulmonary function tests provides sensitive tools to detect early signs of interstitial lung disease. By systematic use of these investigations in newly diagnosed polymyositis and dermatomyositis, up to two thirds of patients were discovered to have signs of interstitial lung disease in a recent study. Clinical symptoms such as cough and dyspnea may not be sensitive enough to detect interstitial lung disease. Awareness of this complication in patients with myositis is important, because early diagnosis and management of interstitial lung disease may prevent development of chronic pulmonary fibrosis and thereby prolong patient survival and improve quality of life. Treatment recommendations of interstitial lung disease in polymyositis and dermatomyositis are still limited by absence of controlled trials and could only be based on experiences from small case series and case reports. At least some patients with interstitial lung disease improve with immunosuppressive treatment, but data are limited, and longitudinal studies are needed. SUMMARY: Interstitial lung disease seems to be a common manifestation in patients with polymyositis and dermatomyositis already at diagnosis of the muscle disease. When present, interstitial lung disease has a major effect on morbidity and mortality and should be looked for in these patients using high-resolution computerized tomography and pulmonary function tests early in the disease course, because immunosuppressive treatment may change the course of the lung disease.

Biopsy↗
PubMed2004

Leukocytes, cytokines, growth factors and hormones in human skeletal muscle and blood after uphill or downhill running.

Muscular adaptation to physical exercise has previously been described as a repair process following tissue damage. Recently, evidence has been published to question this hypothesis. The purpose of this study was to investigate inflammatory processes in human skeletal muscle and epimysium after acute physical exercise with large eccentric components. Three groups of subjects (n= 19) performed 45 min treadmill running at either 4 deg (n= 5) or 8 deg (n= 9) downhill or 4 deg uphill (n= 5) and one group served as control (n= 9). One biopsy was taken from each subject 48 h post exercise. Blood samples were taken up to 7 days post exercise. Compared to the control group, none of the markers of inflammation in muscle and epimysium samples was different in any exercised group. Only subjects in the Downhill groups experienced delayed onset of muscle soreness (DOMS) and increased serum creatine kinase activity (CK). The detected levels of immunohistochemical markers for T cells (CD3), granulocytes (CD11b), leukaemia inhibitory factor (LIF) and hypoxia-inducible factor 1beta (HIF-1beta) were greater in epimysium from exercised subjects with DOMS ratings >3 (0-10 scale) compared to exercised subjects without DOMS but not higher than controls. Eccentric physical exercise (downhill running) did not result in skeletal muscle inflammation 48 h post exercise, despite DOMS and increased CK. It is suggested that exercise can induce DOMS by activating inflammatory factors present in the epimysium before exercise. Repeated physical training may alter the content of inflammatory factors in the epimysium and thus reduce DOMS.

Adolescent↗
PubMed2004

Down-regulation of the aberrant expression of the inflammation mediator high mobility group box chromosomal protein 1 in muscle tissue of patients with polymyositis and dermatomyositis treated with corticosteroids.

OBJECTIVE: High mobility group box chromosomal protein 1 (HMGB-1) is an endogenous nuclear protein that can be translocated to the cytoplasm and then released extracellularly. It can induce tumor necrosis factor and interleukin-1 production in myeloid cells. Increased expression of these 2 cytokines has been observed in muscle tissue of patients with polymyositis (PM) and dermatomyositis (DM). The present study was therefore undertaken to investigate how HMGB-1 is expressed in muscle tissue of patients with myositis and, if so, whether such expression is modulated by prednisolone therapy. METHODS: Muscle biopsy specimens from 5 patients with PM and 4 patients with DM, obtained before and 3-6 months after initiation of prednisolone therapy, were assessed by conventional microscopic evaluation and computerized image analysis, and HMGB-1 expression was investigated by immunohistochemical staining. Muscle biopsy specimens from 7 healthy controls were also studied. RESULTS: Cytoplasmic HMGB-1 expression was detected in infiltrating rounded mononuclear cells, vascular endothelial cells, and muscle fibers of PM and DM patients. Extracellular staining surrounding the inflammatory cells was also observed. After treatment with high-dose prednisolone, cytoplasmic and extracellular HMGB-1 expression was significantly reduced, coinciding mainly with a decreased number of infiltrating inflammatory cells. Cytoplasmic HMGB-1 expression was still evident in endothelial cells and muscle fibers. No HMGB-1 expression was observed in muscle tissue from healthy controls. CONCLUSION: The cytoplasmic and extracellular distribution of HMGB-1 in muscle tissue may indicate an important role of this proinflammatory molecule in the pathogenesis of PM and DM. Furthermore, our findings indicate that systemically administered high-dose corticosteroids selectively down-regulate aberrant expression of HMGB-1 in mononuclear inflammatory cells in vivo.

Adult↗
PubMed2004

Corticosteroids--from an idea to clinical use.

Corticosteroids form the basis of treatment in many inflammatory rheumatic diseases, both as systemic treatment and as treatment with local injections to reduce inflammation. In 1948 the first systemic treatment of a patient with a rheumatic disease was given to a woman with severe rheumatoid arthritis (RA); the impressive effect in this patient, and in another 15 patients, was reported by Dr Hench and co-workers in 1949. Systemic corticosteroid treatment was rapidly adopted and used not only for patients with RA but also for those with other rheumatic diseases such as systemic lupus erythematosus-as well as other disorders such as asthma-with a similar positive effect. In the following year, 1950, the Nobel Prize was awarded for the discovery of the structure and biological effects of the adrenal cortex hormones. This open trial was followed by several controlled trials conducted in the UK in which the effects of cortisone were compared with the effects of aspirin in patients with RA-interestingly, without any significant clinical benefit for the cortisone-treated patients. It was not until 1959, in yet another multi-centre trial in Britain, that a significant effect on functional capacity and general well-being was reported after 2 years of treatment with prednisolone, compared to aspirin, in patients with early RA. Despite the dramatic effects that were observed in the severely ill RA patients reported by Hench and co-workers it took 10 years to demonstrate that this effect was superior to the effect of aspirin when the two compounds were compared in controlled trials. Why was this so? One explanation could be in the study designs and the different outcome measures used in the various studies. Perhaps the results in the first comparative studies would have been different if individual response criteria had been used. This is discussed in this chapter.

Adrenal Cortex Hormones↗
PubMed2003

Elevated triglycerides and low levels of high-density lipoprotein as markers of disease activity in association with up-regulation of the tumor necrosis factor alpha/tumor necrosis factor receptor system in systemic lupus erythematosus.

OBJECTIVE: To investigate how blood lipid levels are related to disease activity, clinical characteristics, and serum levels of tumor necrosis factor alpha (TNF alpha) and its soluble type 1 and 2 receptors, sTNFR1 and sTNFR2, in systemic lupus erythematosus (SLE). METHODS: Fasting blood samples were obtained from an unselected cohort of SLE patients at Karolinska Hospital (n = 208, mean +/- SD age 45.7 +/- 14.2 years). Disease activity was estimated using the SLE Disease Activity Measure (SLAM). Levels of circulating TNF alpha, sTNFR1, and sTNFR2 were determined by enzyme-linked immunosorbent assay. Blood lipid levels obtained after overnight fasting were analyzed by routine chemistry. RESULTS: Triglyceride (TG) levels were associated with the SLAM score (r = 0.48, P < 0.0001) and with the activities of TNF alpha (r = 0.29, P = 0.0001), sTNFR1 (r = 0.38, P < 0.0001), and sTNFR2 (r = 0.40, P < 0.0001). High-density lipoprotein (HDL) levels were negatively associated with the SLAM score (r = -0.27, P = 0.0003) and with the activities of TNF alpha (r = -0.15, P = 0.04) and sTNFR2 (r = -0.19, P = 0.01). High levels of TGs, total cholesterol, TNF alpha, sTNFR1, and sTNFR2 all showed close correlations with the presence of nephritis and arterial disease (P < 0.05). In multiple logistic regression models, the TNF alpha activity and TG levels were independent determinants (P = 0.003 for both) of active disease (SLAM score > or =7). CONCLUSION: Dyslipoproteinemia with high TG/low HDL levels correlates with disease activity in SLE, and enhanced activity in the TNFalpha/sTNFR system seems to be an important underlying factor. Both dyslipoproteinemia and enhanced activity of the TNF alpha system are closely related to cardiovascular and renal manifestations in SLE, and thus both may serve as markers of more severe disease.

Adult↗
PubMed2003

CBA/J mice infected with Trypanosoma cruzi: an experimental model for inflammatory myopathies.

Idiopathic inflammatory myopathies are inflammatory disorders of unknown origin, characterized by muscle weakness. The aim of our study was to establish and characterize an animal model for chronic inflammatory myopathy which would permit investigations of the role of T-cells in chronic myositis as well as of the mechanisms for muscle weakness in chronic inflammatory muscle disorders. CBA/J mice were infected with the protozoan parasite Trypanosoma cruzi. Immunohistochemistry was used to characterize the distribution and composition of inflammatory infiltrates, and demonstrated a chronic focal inflammation comprised mainly of T-cells and macrophages in infected mice. The inflammatory infiltrates were predominantly found in the endomysium and, to a lesser extent, in perivascular areas. CD8(+) T-cells were found to have invaded nonnecrotic muscle fibers. Degenerating muscle fibers were also found, as well as an increased number of central muscle nuclei. The murine model described in this article may be useful in studying certain aspects of idiopathic inflammatory myopathies such as the role of T-cells in chronic muscle inflammation and chronic myocytotoxicity.

Animals↗
PubMed2003

MICA4/HLA-DRB1*04/TNF1 haplotype is associated with mixed connective tissue disease in Swedish patients.

In order to investigate major histocompatibility complex (MHC) class I chain-related gene A (MICA), tumor necrosis factor (TNFa), -308TNFA, and human leukocyte antigen (HLA-DR/DQ) polymorphisms in mixed connective tissue disease (MCTD), we analyzed 24 patients and 229 healthy controls from Sweden. MICA and TNFa typing was performed by polymerase chain reaction (PCR) and genotyping. HLA-DR and -DQ were genotyped using PCR-sequence specific primers (PCR-SSP) and PCR-sequence-specific oligonucleotide probe (PCR-SSOP), respectively. For analysis of -308TNFA polymorphisms we performed PCR with restriction endonuclease enzymes. We found that the MICA5.1-5.1 genotype was positively associated with MCTD. Shared epitope genes (DRB1*01 and DRB1*04) were also significantly positively associated with MCTD. Polymorphism of -308TNFA was not differently distributed in MCTD patients compared with controls. Furthermore, we demonstrated that frequencies of three estimated haplotypes were increased in MCTD patients compared with controls. Interestingly, the haplotype with MICA allele 4 together with DRB1*04 and TNF1 alleles gives the most specific pattern for MCTD patients compared with controls. Our study demonstrates a clear contribution of HLA loci in susceptibility to MCTD in the Swedish population. Susceptibility to MCTD may be linked to the MICA4/HLA-DRB1*04/TNF1 haplotype and MICA 5.1-5.1 genotype. Mixed connective tissue disease was also associated with shared epitope genes, which in RA has been associated with a more severe disease. Whether these genotypes affect the clinical phenotype of MCTD needs to be determined.

Adult↗
PubMed2003

Sporadic inclusion body myositis: pilot study on the effects of a home exercise program on muscle function, histopathology and inflammatory reaction.

OBJECTIVE: To evaluate the safety and effect of a home training program on muscle function in 7 patients with sporadic inclusion body myositis. DESIGN: The patients performed exercise 5 days a week over a 12-week period. METHODS: Safety was assessed by clinical examination, repeated muscle biopsies and serum levels of creatine kinase. Muscle strength was evaluated by clinical examination, dynamic dynamometer and by a functional index in myositis. RESULTS: Strength was not significantly improved after the exercise, however none of the patients deteriorated concerning muscle function. The histopathology was unchanged and there were no signs of increased muscle inflammation or of expression of cytokines and adhesion molecules in the muscle biopsies. Creatine kinase levels were unchanged. A significant decrease was found in the areas that were positively stained for EN-4 (a marker for endothelial cells) in the muscle biopsies after training. CONCLUSION: The home exercise program was considered as not harmful to the muscles regarding muscle inflammation and function. Exercise may prevent loss of muscle strength due to disease and/or inactivity.

Aged↗