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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↗
PubMed2007

Restricted T cell receptor BV gene usage in the lungs and muscles of patients with idiopathic inflammatory myopathies.

OBJECTIVE: To investigate T cell receptor (TCR) expression in 3 different compartments that could be involved in patients with myositis: muscle, lung, and peripheral blood. METHODS: Nine patients with polymyositis (PM), dermatomyositis, or inclusion body myositis underwent bronchoscopy and bronchoalveolar lavage (BAL) as well as muscle biopsy and blood sampling. A panel of 19 monoclonal antibodies specific for TCR V(beta) (BV) and V(alpha) (AV) were used to characterize the TCR profile in CD4(+) and CD8(+) T cell populations in BAL fluid and peripheral blood by flow cytometry. Muscle biopsy tissues were analyzed by immunohistochemistry. Patients were also typed for HLA-DRB1 and DRB3 alleles. RESULTS: A total of 17 T cell expansions were detected in BAL fluid, 6 in the CD4(+) T cell population and 11 in the CD8(+) T cell population. Four T cell expansions were detected in peripheral blood. A selective TCR V usage was found in muscle. Two PM patients, both of whom had BAL fluid BV3(+) T cell expansions in the CD4 population and in whom BV3 was also a prominent TCR V segment in muscle tissue, shared the HLA-DRB1*03 allele. These 2 patients were the only ones who were positive for anti-Jo-1 antibody. CONCLUSION: We found a restricted accumulation of T lymphocytes expressing selected TCR V-gene segments in the target organ compartments (i.e., lung and muscle). The occurrence of shared TCR gene segment usage in muscle and lungs could suggest common target antigens in these organs.

Adult↗
PubMed2006

Genetically determined imbalance between serum levels of tumour necrosis factor (TNF) and interleukin (IL)-10 is associated with anti-Jo-1 and anti-Ro52 autoantibodies in patients with poly- and dermatomyositis.

Our aim was to investigate presence of tumour necrosis factor (TNF) and interleukin (IL)-10 in serum and their relation to different genotypes as well as to clinical and laboratory phenotypes in patients with polymyositis and dermatomyositis. In 65 patients with poly- or dermatomyositis the inflammatory cytokine balance was evaluated by the assessing absolute levels as well as the ratio between TNF and IL-10 in serum. These levels were correlated to the G-308A TNFA, G-1087A IL10 and G915C TGFB1 gene polymorphisms and haplotype frequencies, gender, autoantibody profiles and clinical manifestations. Increased serum levels of TNF and IL-10 were observed in patients compared to controls. A significantly higher TNF:IL-10 ratio was detected in female poly- and dermatomyositis patients carrying the TNF2 allele compared to female patients with the TNF1/TNF1 genotype (median+/-IQR 1.513+/-0.0.679 vs. 0.950+/-1.173, p=0.021). This ratio was also significantly higher in patients with the extended MICA5.1/TNF2/TNFa2/DRB1*03 haplotype compared to patients lacking this haplotype. A significantly higher TNF:IL-10 ratio was recorded in sera of patients with anti-Ro52 (1.513+/-1.275 and 1.276+/-0.671, positive vs. negative, p=0.010) antibodies and in women with anti-Jo-1 (1.919+/-0.918 and 1.281+/-0.790, positive vs. negative, p=0.041). Our data suggest that a genetically programmed cytokine imbalance exists in patients with poly- or dermatomyositis and that this imbalance is related to the presence of disease-associated autoantibodies.

Adult↗
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↗
PubMed2006

Pathogenesis of idiopathic inflammatory myopathies.

The idiopathic inflammatory myopathies, myositis, are characterized by a chronic course with decreased muscle endurance and by infiltrates of T lymphocytes and macrophages in muscle tissue. Treatment with immunosuppressives rarely leads to recovery of muscle function, despite abolishment of inflammatory cell infiltrates in muscle tissue. Therefore, other mechanisms than immune-mediated muscle fiber damage are likely to contribute to the pathogenesis. One such non-immune-mediated muscle dysfunction could be caused by a disturbed microcirculation due to capillary loss or to phenotypically changed endothelial cells in the capillaries. These aberrations may affect the micro-environment of muscle tissue and lead to local tissue hypoxia with development of a secondary metabolic myopathy. Another possible non-immune-mediated mechanism leading to muscle dysfunction is the newly identified endoplasmatic reticulum (ER) stress response in myositis. The ER stress response is thought to be a consequence of the up-regulation of major histocompatibility complex class I in muscle fibers. These newly identified molecular pathways could play a major role in the pathogenesis of myositis and could be important targets in the development of new therapies.

Humans↗
PubMed2006

Cytokines in idiopathic inflammatory myopathies.

Recent findings suggest cytokines as important key molecules in the pathogenic mechanisms of idiopathic inflammatory myopathies, myositis. In this review, we focus on cytokines with a potential role in disease mechanisms in myositis and present some general information on individual cytokines and an updated summary from the literature concerning cytokines in these disorders. The idiopathic inflammatory myopathies is a heterogeneous group of disorders clinically characterized by symmetric proximal muscle weakness and by certain defined histolopathological findings, including inflammatory infiltrates in muscle tissue. Other prominent findings in the target tissue of these patients are defined molecular changes of blood vessels and muscle fibers, including reformation to high endothelial venule (HEV)-like blood vessels and intensive MHC class I expression in muscle fibers. The predominant clinical symptoms of muscle weakness and decreased muscle endurance are shared by all subsets of inflammatory myopathies and indicate that some pathogenic mechanisms related to muscle function may be shared by the different disease groups. Studies on cytokine gene, RNA and protein expression in muscle tissue from patients with various forms of the disease also indicate similar profiles, despite different phenotypes of the inflammatory cells present in muscle tissue from the different subsets of myositis. There is a pronounced expression of various cytokines in muscle tissue, among which the proinflammatory cytokines TNF-alpha and IL-1 are most widely explored in the inflammatory myopathies, which has made them into potential therapeutic targets. The use of targeted cytokine therapy has been successful in several other chronic inflammatory diseases and although the exact role of cytokines in chronic idiopathic inflammatory myopathies remains to be delineated their potential role as targets for new therapies in this disorder will be discussed in this review.

Animals↗
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↗