| 1. |
- Edvardsson, Maria, et al.
(författare)
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Classification of ≥80-year-old individuals into healthy, moderately healthy, and frail based on different frailty scores affects the interpretation of laboratory results
- 2022
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Ingår i: Asian Journal of Medical Sciences. - : Nepal Journals Online (NepJOL). - 2467-9100 .- 2091-0576. ; 13:9, s. 63-71
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Tidskriftsartikel (refereegranskat)abstract
- Background: Interpretation laboratory analyses are crucial when assessing the patient’s condition. Reference intervals from apparently healthy and disease-free individuals may cause problems when outcomes from elderly patients with chronic diseases and on medications are being interpreted. Elderly individuals are a heterogeneous group ranging from individuals managing their daily life independently to individuals with diseases and impairment, in need of nursing care around the clock, that is, frail; a term widely used although there is no consensus on the definition.Aims and Objectives: The aim of the study was to study the effect of classification of elderly into healthy, moderately healthy, and frail, based on activities of daily living (ADL) and Mini-Mental State Examination (MMSE) or frailty index (FI), on the interpretation of outcomes regarding: Albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and gamma-glutamyltransferase (γ-GT) levels.Materials and Methods: Individuals ≥80 years (n=568) were classified either on ADL and MMSE or number of deficits, (FI).Results: Individuals classified as frail based on FI had lower mean levels for ALT, creatinine and γ-GT than individuals classified based on ADL and MMSE (P<0.05).Conclusion: The model to define health status to some extent affected laboratory analyte levels in ≥80 years old, classified as healthy, moderately healthy, and frail based on ADL and MMSE versus FI.
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| 2. |
- Eriksson, Per, 1958-, et al.
(författare)
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Relationship between serum levels of IL-18 and IgG1 in patients with primary Sjögren's syndrome, rheumatoid arthritis and healthy controls
- 2004
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 137:3, s. 617-620
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Tidskriftsartikel (refereegranskat)abstract
- Primary Sjögren's syndrome (SS) is characterized by inflammation in salivary and lachrymal glands, with a local predominance of Th1-like cytokines, as well as the pleiotropic cytokine interleukin (IL) 18. High serum levels of polyclonal IgG are common, with a subclass imbalance in which IgG1 is increased and IgG2 is normal or low. IL-18 is also of pathogenetic importance in rheumatoid arthritis. In the present study we looked for any relationship between serum IL-18 as well as transforming growth factor (TGF) β1 versus IgA, IgM, and IgG subclass levels in SS (n = 16), rheumatoid arthritis (RA) (n = 15), and healthy controls (n = 15). SS was defined by the revised American-European classification criteria. IL-18 and TGF-β1 were analyzed with enzyme immunoassays (EIA), and IgG1, IgG2 and IgG3 by single radial immunodiffusion. In the composite group of RA, SS and normal controls, IgG1 and IL-18 were related (R = 0.52, P = 0.0005). No relation was found neither between IL-18 versus IgG2, IgG3 or IgA, nor between serum TGF-β1 versus any of the immunoglobulins. Since serum levels of IL-18 are related to serum IgG1, IL-18 may be of importance for IgG1 switch and/or release.
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| 3. |
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| 4. |
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| 5. |
- Hellberg, Sandra, 1986-
(författare)
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Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple sclerosis (MS) is characterized by a dysregulated immune system leading to chronic inflammation in the central nervous system. Despite increasing number of treatments, many patients continue to deteriorate. A better understanding of the underlying disease mechanisms involved in driving disease is a pre-requisite for finding new biomarkers and new treatment targets. The improvement of MS during pregnancy, comparable to the beneficial effects of the most effective treatment, suggests that the transient and physiological immune tolerance established during pregnancy could serve as a model for successful immune regulation. Most likely the immune-endocrine alterations that take place during pregnancy to accommodate the presence of the semi-allogenic fetus contribute to the observed disease improvement.The aim of this thesis was to characterize the dysregulated immune system in MS and define potential factors and mechanisms established during pregnancy that could be involved in the pregnancy-induced effects in MS, focusing on CD4+ T cells as one of the main drivers in immunity and in the MS pathogenesis. Using a network-based modular approach based on gene expression profiling, we could show that CD4+ T cells from patients with MS displayed an altered dynamic gene response to activation, in line with a dysregulated immune system in MS. The resulting gene module disclosed cell activation and chemotaxis as central components in the deviating response, results that form a basis for further studies on its modulation during pregnancy. Moreover, a combination of secreted proteins (OPN+CXCL1-3+CXCL10-CCL2), identified from the module, could be used to separate patients and controls, predict disease activity after 2 years and discriminate between high and low responders to treatment, highlighting their potential use as biomarkers for predicting disease activity and response to treatment.The pregnancy hormone progesterone (P4), a potential factor involved in the pregnancy-induced amelioration of MS, was found to significantly dampen CD4+ T cell activation. Further detailed transcriptomic profiling revealed that P4 almost exclusively down-regulated immune-related pathways in activated T cells, several related to or downstream of T cell activation such as JAKSTAT signaling, T cell receptor signaling and cytokine-cytokine receptor interaction. In particular, P4 significantly affected genes of relevance to diseases known to be modulated during pregnancy, where genes associated to MS were most significantly affected, supporting a role for P4 in the pregnancy-induced immunomodulation. By using another approach, the role of thymus in T cell regulation during pregnancy was assessed. Two established measures of thymic output, CD31 expression and TREC content, were used and showed that thymic output of T cells is maintained during human pregnancy, or even possibly increased in terms of regulatory T cells.This thesis further supports a pivotal role for CD4+ T cells and T cell activation in the MS pathogenesis and adds to the knowledge of how they could be involved in driving disease. We identified a novel strategy for capturing central aspects of the deviating response to T cell activation that could be translated into potentially clinically relevant biomarkers. Further, P4 is emerging as a promising candidate for the pregnancy-induced immunomodulation that could be of importance as a future treatment option. Lastly, maintained thymic output of T cells during human pregnancy challenges the rodent-based dogma of an inactive thymus during pregnancy. Thymic dysfunction has been reported not only in MS but also in rheumatoid arthritis, another inflammatory disease that improves during pregnancy, which highlights a potential role for thymus in immune regulation that could be involved in the pregnancy-induced amelioration.
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| 6. |
- Håkansson, Irene, 1976-
(författare)
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Biomarkers and Disease Activity in Multiple Sclerosis : A cohort study on patients with clinically isolated syndrome and relapsing remitting multiple sclerosis
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on disease activity in clinically isolated syndrome (CIS) and newly diagnosed relapsing remitting multiple sclerosis (RRMS). The papers are based on data from 41 patients in a prospective longitudinal cohort study. All patients were untreated at baseline. Age- and sex-matched healthy controls (n=22) for blood and cerebrospinal fluid (CSF) samples were recruited from blood donors.Paper I evaluated the prognostic value of baseline levels of CXCL1, CXCL8, CXCL10, CXCL13, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase-3-like-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9) and osteopontin in CSF in relation to disease activity during the first two years of follow-up. Disease activity was defined as clinical relapses, new T2 lesions in brain magnetic resonance imaging (MRI) and/or sustained Expanded Disability Status Scale (EDSS) progression. Absence of these three signs of disease activity was called no evidence of disease activity (NEDA-3). Logistic regression analysis showed that NFL in CSF was the best predictive marker of disease activity and correctly classified 93% of the patients with evidence of disease activity during two years of follow-up and 67% of those without.Paper II presented four year follow-up data from the cohort and also included brain volume data as well as serum levels of NFL. The correlation between NFL in CSF and serum was fairly strong (r=0.74, p<0.001). NFL in CSF was associated with new T2 lesions as well as with brain volume loss, whereas CHI3L1 in CSF was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22 and MMP-9 in CSF were mainly associated with new T2 lesions. Taken together, paper I and II confirm and extend the knowledge of NFL as a useful biomarker in CIS and RRMS and suggests that NFL, rather than total brain volume loss, could be included in an expanded NEDA concept and used in clinical monitoring of disease activity/treatment effect. Although serum levels of NFL were correlated with the corresponding CSF levels, CSF-NFL showed a stronger association to subsequent disease activity (NEDA-3).Paper III addressed the patients´ self-reported Modified Fatigue Impact Scale (MFIS) scores in relation to other cohort study data. MFIS scores correlated with other self-assessment questionnaire data (Hospital Anxiety and Depression scale (HAD), Multiple Sclerosis Impact Scale 29 (MSIS-29) and Short Form 36 (SF-36) scores (Spearman´s rho 0.45-0.78, all p≤0.01)) but not with EDSS ratings, number of T2 lesions, total brain volume or NFL levels, indicating that subjective fatigue scores are not well reflected by some commonly used and objectively measurable disease parameters.Paper IV focused on the complement factors C1q, C3, C3a and sC5b-9 in CSF and plasma. CSFC1q was significantly higher in patients than in controls at baseline. The subgroup of patients with ongoing relapse at baseline also had higher levels of CSF-C3a than controls. Baseline levels of CSF-C1q and CSF-C3a correlated significantly with several pro-inflammatory chemokines as well as with MMP-9, CHI3L1 and NFL in CSF. Baseline CSF-C3a also correlated significantly with the number of T2 lesions and Gadolinium enhancing lesions in brain MRI at baseline, as well as with the number of new T2 lesions during follow-up. This study indicates that the complement system is involved already at early stages of MS. It also suggests that especially CSF-C1q and CSF-C3a levels are associated with other neuroinflammatory and neurodegenerative markers and that CSF-C3a levels may carry some prognostic information.
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| 7. |
- Lindvall, Björn, 1952-, et al.
(författare)
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Subclinical myositis is common in primary Sjögren's syndrome and is not related to muscle pain
- 2002
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Ingår i: Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 29:4, s. 717-725
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Although muscle pain is common in primary Sjögren's syndrome (SS), the underlying mechanisms are mainly unknown. We studied all patients with SS at our rheumatology unit with respect to muscle pain in general and to fibromyalgia (FM), and correlated clinical data to muscle biopsy findings.METHODS: We investigated 48 patients with SS according to the modified European diagnostic criteria. The ACR criteria for FM were used to subgroup the patients. Muscle biopsy was performed in 36 patients. Light microscope morphology and immunohistochemical expression of MHC class I, MHC class II, and membrane attack complex (MAC) were studied.RESULTS: We found 44% of patients complained of muscle pain; 27% fulfilled the ACR criteria for FM, whereas 17% had other forms of myalgia. Muscle pain could not be related to histopathological findings. Signs of inflammation were found in 26 of 36 biopsies (72%), and inflammation combined with degeneration/regeneration (i.e., histological signs of polymyositis) in 17 biopsies (47%). However, only 5 patients (14%) had clinical as well as histological signs of polymyositis. Eight muscle biopsies (22%) showed histological features of inclusion body myositis (IBM). However, no patient had clinical symptoms suggestive of this disease. Abnormal expression of MHC class I, MHC class II, and MAC was found in 18 (50%), 16 (44%), and 27 (75%) patients, respectively.CONCLUSION: Muscle pain, especially FM, is common in SS. Histopathological signs of myositis are very common in SS. However, muscle symptoms are not related to histological signs of muscle inflammation. IBM-like findings may represent vacuolar myopathic degeneration due to previous subclinical muscle inflammation rather than a specific clinical entity.
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| 8. |
- Lindvall, Björn, 1952-, et al.
(författare)
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The expression of adhesion molecules in muscle biopsies : the LFA-1/VLA-4 ratio in polymyositis
- 2003
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 107:2, s. 134-141
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Tidskriftsartikel (refereegranskat)abstract
- Objectives– The expression of three pairs of adhesion receptors and ligands was examined in 22 consecutive muscle biopsies showing morphological signs of inflammation.Material and methods– The following groups were studied: patients with polymyositis (PM) (n=7), patients with myositis that did not fulfil criteria for PM, i.e. suspected PM (n=5), patients with other diseases, with no clinical signs of inflammatory myopathy (n=6), and a small group of non-PM inflammatory myopathies (n=4). The endothelial expression of ICAM-1, VCAM-1 and E-selectin was evaluated, as was the cellular expression of LFA-1, VLA-4 and SLex. In addition, the expression of MHC class I and II was studied.Results– The ratio between the number of cells expressing LFA-1 and VLA-4 showed significant differences between the groups, with the lowest values in PM.Conclusion– The LFA-1/VLA-4 ratio should be suitable for diagnostic purposes. Our findings also indicate that the VLA-4/VCAM-1 system is important for chronic T cell inflammation in muscle, in line with findings in other “hidden” organs like joints and the central nervous system.
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| 9. |
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| 10. |
- Nilsson, Bengt-Olof, 1954-, et al.
(författare)
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Antinuclear antibodies in the oldest-old women and men
- 2006
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Ingår i: Journal of Autoimmun. - : Elsevier. ; 27:4, s. 281-288
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to compare the prevalence of antinuclear antibodies (ANA) in very old individuals (>/=86years of age) with healthy younger (18-68years) blood donors (n=200) regarding gender, health status, ratio of circulating CD4/CD8 cells and cytomegalovirus (CMV) serology. Frozen plasma was used for ANA detection in two study groups, i.e. 'OCTO' (97 persons aged 86-92years, 65% women) and 'NONA' (136 persons aged 86-95years, 70% women). OCTO participants were recruited on the basis that they were healthy or moderately healthy according to a selection protocol. No exclusion criteria regarding health status were applied in the NONA sample. The prevalence of ANA was significantly higher in the oldest-old samples compared to blood donors. There was no association between health status and the presence of ANA in the oldest-old. The difference across age was most pro-nounced in men, with low levels at younger age, whereas the prevalence among the oldest-old men reached similar levels as in women. There were no associations between the presence of ANA and CD4/CD8 ratio or with CMV status in the oldest-old. Our findings confirm an in-creased prevalence of ANA in the oldest-old, and emphasize the importance of taking gender and age into consideration when evaluating ANA.
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| 11. |
- Reckner Olsson, Åsa, 1965-, et al.
(författare)
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Allergic manifestations in patients with rheumatoid arthritis
- 2003
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Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - : Wiley. - 0903-4641 .- 1600-0463. ; 111:10, s. 940-944
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Tidskriftsartikel (refereegranskat)abstract
- A functional dichotomy between Th1- and Th2-type immune responses has been suggested. This study was performed to investigate whether rheumatoid arthritis (RA), a disease with indications of Th1-deviated immune activation, is inversly related to atopic conditions which are Th2-mediated. Two hundred and sixty-three adult cases of RA, fulfilling the American Rheumatism Association (ARA) 1987 Revised Classification Criteria for RA, were identified in 1995 and compared with 541 randomly selected population referents. The presence of atopic manifestations was established through a postal questionnaire and by demonstrating circulating IgE antibodies to common allergens. RA was inversely associated with certain manifestations of rhinitis, which were regarded as the most reliable indicators of atopic disease in the present study. However, no negative association was seen between RA and asthma and eczema, respectively. The main results give some support for an inverse relationship between RA and rhinitis. The prevalence of circulating IgE antibodies was however similar in cases and controls, suggesting that the T-cell commitment mainly occurs in the affected organs.
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| 12. |
- Wikby, Anders, et al.
(författare)
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An immune risk phenotype, cognitive impairment, and survival in very late life : Impact of allostatic load in Swedish octogenarian and nonagenarian humans
- 2005
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Ingår i: The journals of gerontology. Series A, Biological sciences and medical sciences. - 1079-5006 .- 1758-535X. ; 60:5, s. 556-565
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Tidskriftsartikel (refereegranskat)abstract
- In the previous OCTO longitudinal study, we identified an immune risk phenotype (IRP) of high CD8 and low CD4 numbers and poor proliferative response. We also demonstrated that cognitive impairment constitutes a major predictor of nonsurvival. In the present NONA longitudinal study, we simultaneously examine in a model of allostatic load IRP and compromised cognition in 4-year survival in a population-based sample (n = 138, 86-94 years). Immune system measurements consisted of determinations of T-cell subsets, plasma interleukin 6 and cytomegalovirus and Epstein-Barr virus serology. Interleukin 2 responsiveness to concanavalin A, using data from the previous OCTO (octogenarians) immune study, hereafter OCTO immune, was also examined. Cognitive status was rated using a battery of neuropsychological tests. Logistic regression indicated that the IRP and cognitive impairment together predicted 58% of observed deaths. IRP was associated with late differentiated CD8+CD28-CD27 - cells (p < .001), decreased interleukin 2 responsiveness (p < .05) and persistent viral infection (p < .01). Cognitive impairment was associated with increased plasma interleukin 6 (p < .001). IRP individuals with cognitive impairment were all deceased at the follow-up, indicating an allostatic overload. Copyright 2005 by The Gerontological Society of America.
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| 13. |
- Aniansson Zdolsek, Helena, 1961-, et al.
(författare)
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Expression of the T–cell markers CD3, CD4 and CD8 in healthy and atopic Children during the first 18 months of life
- 1999
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Ingår i: International Archives of Allergy and Immunology. - : S. Karger AG. - 1018-2438 .- 1423-0097. ; 119:1, s. 6-12
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is little information available about the development of T–cell immunity in healthy and atopic children. We have studied prospectively the mean fluorescence intensity of the T–cell receptor complex–associated CD3, CD4 and CD8 in relation to atopic family history (AFH) and the development of atopic disease.Methods: Children with a defined AFH (n = 172) were followed from birth to 18 months and the cumulative history of atopic disease was recorded. Blood samples were obtained at birth and at 18 months, and in a subgroup of 78 children also at 3, 6 and 12 months. Multicolour flow cytometry was used to analyse pan T–cells (CD3+CD45+CD14–), T–helper–(CD3+CD4+) and T–cytotoxic–(CD3+CD8+) cells.Results: At 18 months, 31 children were atopic and 118 non–atopic. Children who developed atopic disease had a higher CD4 expression (mean fluorescence intensity, MFI) on CD4+CD3+ lymphocytes at birth and at 3 months, particularly as compared with non–atopic children without AFH. Furthermore, the CD3 expression on CD3+CD45+CD14– lymphocytes increased more slowly with age in children with double atopic heredity, as compared with children with no or only one atopic family member.Conclusions: The higher expression of the CD4 receptor in early infancy in children who developed atopic disease compared with non–atopics suggests a delayed expression in T–helper cells. Children with a strong AFH had a slower increase in the expression of CD3, indicating a delayed T–cell maturation.
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| 14. |
- Appelgren, Daniel, 1985-, et al.
(författare)
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Regulatory B cells are reduced in the blood in patients with granulomatosis with polyangiitis, and fail to regulate T-cell IFN-γproduction
- 2023
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press. - 0009-9104 .- 1365-2249. ; 213:2, s. 190-201
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Tidskriftsartikel (refereegranskat)abstract
- Regulatory B (Breg) cells can dampen inflammation, autoreactivity, and transplant rejection. We investigated the frequencies, phenotypes, and function of Breg cells in granulomatosis with polyangiitis (GPA) to gain further knowledge as to whether there are numerical alterations or limitations of their ability to regulate T-cell function. Frequencies and phenotypes of CD24hiCD27+ and CD24hiCD38hi B-cells in the blood were determined with flow cytometry in 37 GPA patients (22 in remission and 15 with active disease) and 31 healthy controls (HC). A co-culture model was used to study the capacity of Breg cells to regulate T-cell activation and proliferation in cells from 10 GPA patients in remission and 12 HC. T-cell cytokine production in vitro and levels in plasma were determined with enzyme-linked immunosorbent assay. Frequencies of CD24hiCD27+ B-cells were reduced both during active disease and remission compared with HC (P = 0.005 and P = 0.010, respectively), whereas CD24hiCD38hi B-cells did not differ. Patient CD24hiCD27+ B-cells exhibited decreased expression of CD25 but increased expression of PD-L1 and PD-L2 during remission. B-cells from GPA patients regulated T-cell proliferation but failed to regulate interferon (IFN)-γproduction (median T-cells alone 222 ng/ml vs. T-cells + B-cells 207 ng/ml, P = 0.426). IFN-γwas also elevated in patient plasma samples (P = 0.016). In conclusion, GPA patients exhibit altered numbers and phenotypes of CD24hiCD27+ B-cells. This is accompanied by a disability to control T-cell production of Th1-type cytokines during remission, which might be of fundamental importance for the granulomatous inflammation that characterizes the chronic phase of this disease. © 2023 The Author(s). Published by Oxford University Press on behalf of the British Society for Immunology.
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| 15. |
- Backteman, K, et al.
(författare)
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A rapid and reliable flow cytometric routine method for counting leucocytes in leucocyte-depleted platelet concentrates
- 2002
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Ingår i: Vox Sanguinis. - : Wiley. - 0042-9007 .- 1423-0410. ; 83:1, s. 29-34
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives: To ensure a proper quality control it is important to use a reliable method to count low numbers of leucocytes in leucocyte-reduced platelet concentrates (PCs). Materials and Methods: A modified flow cytometric method for counting low numbers of leucocytes, based on a reference population contained in tubes with an exact number of fluorescent beads and staining with propidium iodide was used. To increase the number of events, the original sample volume was increased. Results: There was a good correlation in the number of leucocytes (r = 0.99) between the modified flow cytometric method and microscopy of samples from unfiltered and expected numbers from serially diluted PCs. Samples from leucocyte-reduced PCs obtained by apheresis or filtered buffy coats showed no correlation between results from the modified flow cytometric method and microscopy (Nageotte). Conclusion: Counting by microscopy gave a lower number of leucocytes than the modified flow cytometric method when counting a low number of cells. However, analysis of the serially diluted PCs proved that the modified flow cytometric method was reliable and rapid, making it suitable for clinical routine use.
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| 16. |
- Backteman, Karin, 1960-, et al.
(författare)
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Biological and methodological variation of lymphocyte subsets in blood of human adults
- 2007
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Ingår i: JIM - Journal of Immunological Methods. - : Elsevier BV. - 0022-1759 .- 1872-7905. ; 322:1-2, s. 20-27
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Tidskriftsartikel (refereegranskat)abstract
- Although lymphocyte populations are often monitored over time, information about the biological variation over time is limited. Three-colour-flow cytometry was used to investigate the biological and methodological variation of lymphocyte populations in blood. Fifteen healthy individuals (11 females and 4 males) were longitudinally monitored for 2-8 years. Blood samples were drawn monthly when possible. In total, 493 observations were included. Absolute counts and proportions were determined for T-cells (CD3+), T-helper cells (CD3+ CD4+), cytolytic T-cells (CD3+ CD8+), B-cells (CD3- CD19+) and NK-cells (CD3- CD16+/56+). As to variation over the year, ANOVA testing showed only a minor monthly variation for absolute counts of the CD8+ population (p < 0.05) for October compared with June and July, whereas no significant differences were found for the other populations or in the proportions of lymphocyte subsets. Although lower than the longitudinal variation, the methodological variation, expressed as coefficient of variation (CV %), was in a similar range as the variation over time, indicating that the normal biological variation should not be overestimated, while the methodological inter-assay should be taken into consideration in longitudinal studies or monitoring of patients. © 2007 Elsevier B.V. All rights reserved.
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| 17. |
- Blomgran, Parmis, 1985-, et al.
(författare)
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Cox-2 inhibition and the composition of inflammatory cell populations during early and mid-time tendon healing
- 2017
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Ingår i: Muscles, ligaments and Tendons journal. - Rome, Italy : CIC Edizioni Internazionali. - 2240-4554. ; 7:2, s. 223-229
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Tidskriftsartikel (refereegranskat)abstract
- Background: During early tendon healing, the cells within the regenerating tissue are, to a large part, inflammatory leukocytes (CD45+). In a rat Achilles tendon healing model, the inflammation resolves between 5 and 10 days. In the same model, Cox inhibitors (NSAIDs) impair healing when given during the first 5 days, but have a positive effect if given later. We tested the hypothesis that a Cox inhibitor would exert these effects by influencing inflammation, and thereby the composition of the inflammatory cell subpopulations.Methods: Achilles tendon transection was performed in 44 animals. Animals were randomized to either parecoxib or saline injections. Healing was evaluated by mechanical testing day 7 after surgery and by flow cytometry day 3 and 10.Results: Cross-sectional area, peak force and stiffness were reduced by parecoxib 31, 33, and 25% respectively (p=0.005, p=0.002, and p=0.005). By flow cytometry, there was a strong effect of time (p<0.001) on virtually all inflammatory cell subpopulations (CD45, CD11b, CD68, CCR7, CD163, CD206, CD3, CD4), but no significant effect of parecoxib at any time point.Conclusion: The results suggest that the negative effects of Cox inhibitors on tendon healing might be exerted mainly via mechanisms not directly related to inflammatory cells.
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| 18. |
- Blomgran, Parmis, 1985-
(författare)
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Inflammation and tendon healing
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tendons heal through three different overlapping phases; the inflammatory, proliferative and remodeling phase. Many studies have investigated what factors influence healing of tendons. However, little was known about inflammation and the immune cells present during Achilles tendon healing by the time this thesis started. We developed a flow cytometry method for our rat model of tendon healing, which enabled us to study different leukocyte subpopulations during Achilles tendon healing.The general aim of this thesis was to understand more about inflammation and the immune cell populations present during tendon healing and how the immune cell composition changes during normal tendon healing. Moreover, we investigated how different factors that are known to influence tendon healing affected the composition of the immune cell population.First, we described the immune cells during the time course of tendon healing focusing on different subpopulations of macrophages and T cells. Then, we studied how these cells were influenced by reduced mechanical loading. Mechanical loading prolonged the presence of M1 macrophages and delayed the switch to regulatory T cells and M2 macrophages compared to reduced mechanical loading. Next, the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the leukocyte composition revealed that, even though NSAIDs influence the mechanical properties of healing tendon, this effect was not mediated via changes in the leukocyte sub-populations during early and mid-time tendon healing. Further, the effect of corticosteroids during the inflammatory and remodeling phases of tendon healing was an improved healing of tendons and a reduction of CD8a T cells when corticosteroid was administered after the inflammatory phase. Lastly, we investigated if impairment of tendon healing by NSAIDs was related to mechanotransduction or microdamage during mechanical loading and showed that NSAIDs impair tendon healing by reducing the response to microdamage.In conclusion, these studies show that inflammation plays an important role during Achilles tendon healing, and factors that influence healing can also alter the presence or polarization of immune cell populations.
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| 19. |
- Boij, Roland, 1952-
(författare)
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Aspects of inflammation, angiogenesis and coagulation in preeclampsia
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Preeclampsia is a major challenge to obstetricians, due to its impact on maternal and fetal morbidity and mortality and the lack of preventive and treatment strategies. The overall aim of this thesis is to increase the knowledge of the pathogenesis of preeclampsia including the role of inflammation, angiogenesis and coagulation, both locally at the fetomaternal interface and in the maternal circulation. Uncompensated maternal endothelial inflammatory responses to factors from stressed trophoblasts seem to be a major contributor to the syndrome, together with an imbalance in angiogenesis and an activated coagulation system. An increasing amount of data indicates an involvement of the immune system with defect tolerance to the conceptus as an integral part of the pathogenesis, at least in early-onset preeclampsia (EOP).We showed that a single administration of human preeclampsia serum in pregnant IL-10−/− mice induced the full spectrum of preeclampsia-like symptoms including hypoxic injury in uteroplacental tissues and endotheliosis in maternal kidneys. Importantly, preeclampsia serum, as early as 12 to 14 weeks of gestation, disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity (Tube formation test). These results indicate that preeclamptic sera can be used to better understand the pathophysiology and to predict the disorder. Preeclampsia has been associated with increased inflammation, aberrant angiogenesis and activated coagulation, but their correlation and relative contribution are unknown. We found that markers for all these mechanisms were independently associated with preeclampsia. Cytokines, chemokines, and complement factors seem all to be part of a Th1-associated inflammatory reaction in preeclampsia, more pronounced in EOP than in late-onset preeclampsia (LOP), in line with a more homogeneous pathogenesis in EOP as based on placental pathology. In women with intrauterine growth restriction (IUGR), with an anticipated pathologic placentation, only differences in levels for sFlt-1 and PlGF were found in comparison with mothers without IUGR. Thus, sFlt-1 and PlGF seem to be indicators of placental pathology, while other biomarkers might also reflect maternal endothelial pathology. Chemokines, in contrast to cytokines, may prove to be useful markers in preeclampsia.A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. Utilizing recent advances in flow cytometry phenotyping, we found no major alterations in circulating Treg numbers in preeclamptic women compared with normal pregnant and non-pregnant women. However, preeclampsia was associated with increased fractions of CTLA-4+ and CCR4+ cells within Treg subpopulations, which is in line with a migratory defect of Treg cells, and potentially associated with a reduced number of suppressive Treg cells at the fetomaternal interface. As we found that corticosteroid treatment affected the results, it should be accounted for in studies of EOP. Chemokines are supposed to be part of the immune adaptation in pregnancy. We found a decreased expression of CCL18 (Th2/Tregassociated), in trophoblasts from preeclamptic compared to normal pregnant women, indicating a local regulatory defect in preeclampsia, in line with our finding of a possible migratory defect of circulating Treg cells. Due to increased expression of CCL20 (Th17) and CCL22 (Th2) in first trimester placenta and increased circulating levels of CXCL10 (Th1) and CCL20 (Th17) in third trimester preeclamptic women, we suggest that CCL20 and CCL22 may be important for implantation and early placentation while in third trimester of a preeclamptic pregnancy CXCL10 and CCL20 mainly mirror maternal increased endothelial inflammation and aberrant angiogenesis. In summary, we found that preeclampsia is associated with increased inflammation, aberrant angiogenesis and activated coagulation, caused by placental factors in maternal peripheral circulation, more pronounced in the early-onset form of preeclampsia. It also appears that there is a defective modulation of the immune system in preeclamptic pregnancies. The results provide a better understanding of the pathogenesis of preeclampsia and have given suggestions to predictive markers for preeclampsia in the future.
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| 20. |
- Bruno, Valentina, 1986-
(författare)
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Clinical and immunological aspects on recurrent pregnancy loss
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Paper I. Effects of low molecular weight heparin on the polarization and cytokine profile of macrophages and T helper cells in vitro. Sci Rep 2018. In paper I low molecular weight heparin (LMWH) in vitro effects on activation and polarization of central regulatory immune cells, such as Th cells and macrophages, were assessed, since LMWH has been widely used as an empiric treatment in recurrent pregnancy loss (RPL) and its immunological effects are not fully known. Isolated blood monocytes and T helper (Th) cells under different activation and polarizing conditions were cultured without or with LMWH at different concentrations. LMWH exposure induced an activated phenotype of macrophages, with high expression of HLA-DR and CD206 assessed by flow cytometry, associated with increased secretion of Th17-associated CCL20, and decreased secretion of CCL2 (M2-associated) and CCL22 (Th2), as measured by multiplex bead array. In accordance, LMWH exposure to Th cells reduced the proportion of CD25highFoxp3+ regulatory Tcells, and intensified IFN-γ secretion. Collectively, a mainly pro-inflammatory effect was noted on two essential tolerance-promoting cells, suggesting that potential immunological effects of LMWH may be effective mainly at an earlier gestational age to provide an appropriate implantation process in women with recurrent miscarriage. Paper II. Low-molecular-weight-heparin increases Th1- and Th17-associated chemokine levels during pregnancy in women with unexplained recurrent pregnancy loss: a randomized controlled trial. Sci Rep 2019.In paper II we investigated whether LMWH could modulate immune responses in vivo during pregnancy of women with unexplained RPL. A Swedish open multi-centre randomized controlled trial included 45 women treated with tinzaparin and 42 untreated women. Longitudinally collected plasma samples were obtained at gestational weeks (gw) 6, 18, 28 and 34 and analyzed by multiplex bead technology for levels of 11 cytokines and chemokines, chosen to represent inflammation and T-helper subset-associated immunity. LMWH-treated and untreated women showed differences during pregnancy of the Th1-associated chemokines CXCL10 (p = 0.01), CXCL11 (p < 0.001) and the Th17- associated chemokine CCL20 (p = 0.04), while CCL2, CCL17, CCL22, CXCL1, CXCL8, CXCL12, CXCL13 and IL-6 did not differ. Significantly higher plasma levels of CXCL10 and CXCL11 in treated women were detected at gw 28 and 34, compared to the untreated ones. Thus, a potential proinflammatory effect, linked mainly to Th1 immunity, was shown, suggesting an unfavorable effect of LMWH treatment, since Th1 responsea are responsible for breaking the fetal-maternal immune tolerance. Paper III. First-trimester trophoblasts obtained by chorionic villus sampling maintain tolerogenic and proteomic features in successful pregnancies despite a history of unexplained recurrent pregnancy loss. Am J Reprod Immunol. 2020.In paper III we investigate the “local” immune changes in women with RPL, since they potentially could reveal important mechanisms in RPL. Supernatants from superfluous chorionic villus sampling material culture was used in an ex vivo model, to determinate the immune proteomics profile and to perform functional assays for M2 like macrophages and regulatory T cells polarization, assessed by flow cytometry technique. Chorionic villi, human fetally derived placental tissue, were shown to induce an M2 like-phenotype and an expansion of Treg cells in an ex vivo model, and these immunological properties were maintained despite a history of RPL. Accordingly, no differences in the inflammation proteomic profile were found in RPL, compared to controls. Trophoblasts in an ex vivo model thus maintain tolerogenic and proteomic profile features in successful pregnancies, despite a history of RPL.
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| 21. |
- Edvardsson, Maria, 1972-
(författare)
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Circulating levels and assessment of clinical laboratory analytes, in >80-year-old, apparently healthy, moderately healthy, and frail individuals
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Blood samples are often used to investigate the possible presence of disease and to make treatment decisions. In the interpretation of the results, comparison either with previous values from the same individual or with a set of appropriate group-based reference intervals are used. Current reference intervals for common laboratory analytes are often based on measurements from apparently healthy persons aged 18–65 years. Age is accompanied by a general decline in organ functions and it is difficult to determine whether a change in levels of laboratory analytes in an elderly individual can be attributed to age alone, independent of environmental or disease processes. Frailty can be seen as a consequence of age-related multifactorial deterioration – physical, cognitive and sensory – resulting in vulnerability and lack of adaptability to internal stressors such as infection or new medication and/or external stressors such as fall at home. Consensus about the definition of “frail” and “frailty” is missing, both nationally and internationally, the question arises whether different definitions of “frailty” affect the interpretation of analytes when comparing different groups of elderly.The overarching aim of the thesis was to interpret and assess circulating levels of some clinical laboratory analytes in relation to conventional reference values in ≥80-year-old, “apparently healthy”, “moderately healthy”, and “frail” individuals. Data originated from other studies, in which blood samples were collected from individuals ≥80-year-old. Comparisons in Paper I of levels of some laboratory analytes, from 138 nursing home residents (NHRs), was made with blood from reference populations, both blood donor and the NORIP study. The results indicated differences for some immunological (complement factor 3 and 4, immunoglobulin G and M) and chemical analytes (alanine aminotransferase (ALT), phosphate, albumin, sodium, creatinine and urea), but no differences in levels occurred for aspartate aminotransferase (AST), gamma-glutamyltransferase (γ-GT) or lactate dehydrogenase (LDH). It was unclear whether the differences were due to differences in age between the elderly and the reference populations or whether the elderly individuals had chronic diseases and were on medication. In Paper II, 569 individuals elderly individuals ≥80 years old were classified as “healthy”, “moderately healthy”, and “frail”, based on diseases, medications and physical and cognitive abilities. Statistical differences between the groups were found for the investigated analytes; albumin, ALT, AST, creatinine and γ-GT. In Paper IV, individuals from Paper II (n=569) were divided into two groups and thereafter divided into “apparently healthy”, “moderately healthy”, and “frail”. One group was subdivided into “apparently healthy”, “moderately healthy” and “frail” based on physical and cognitive abilities and the other group was divided based on the frailty index (FI). There was no statistical difference found between “apparently healthy” and “moderately healthy" groups, regardless of classification model used. Among “frail” individuals, differences in levels occurred for three out of the five investigated analytes: ALT, creatinine and g-GT, with lower levels occurring when the FI classification model was used. No differences in levels occurred for albumin or AST in “frail” individuals, regardless of classification model used. The aim of Paper III was to study whether 1-year changes in complete blood count (CBC) (including haemoglobin (Hb), red blood cell (RBC), erythrocyte volume fraction (EVF), mean corpuscular volume (MCV), mean corpuscular Hb concentration (MCHC), white blood cell (WBC) and platelet count (PLT)), C-reactive protein (CRP) and interleukin (IL)-1β, IL-1RA, IL-6, IL-8 and IL-10 are associated with survival in elderly NHRs aged >80 years. Elevated levels of CRP and IL-8 during 1-year follow-up were associated with reduced length of survival in elderly NHRs. Based on the present thesis it is clear that there is need for reference intervals that consider both age and health status in elderly individuals. A reasonable conclusion when interpreting levels of analytes in elderly individuals with disease or frailty is that individual evaluation based on the individual’s previous levels, is recommended.
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| 22. |
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| 23. |
- Ekerfelt, Christina, 1957-, et al.
(författare)
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Antibodies and T-cell reactivity to Borrelia burgdorferi in an asymptomatic population : A study of healthy blood donors in an Inland town district in the South-East of Sweden
- 2001
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Ingår i: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 0036-5548 .- 1651-1980. ; 33:11, s. 806-808
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Tidskriftsartikel (refereegranskat)abstract
- To address the issue of whether Borrelia infection can be asymptomatic, blood donors with no history of borreliosis (n = 408) were screened for antibodies against Borrelia burgdorferi. Seropositive individuals (n = 17) were further investigated with respect to Borrelia-specific T-cell reactivity, using an interferon-? ELISPOT assay. Anti-Borrelia antibodies as well as Borrelia-specific T-cell responses were evident in 9 asymptomatic donors, strongly supporting a current or previous asymptomatic Borrelia infection.
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| 24. |
- Ekerfelt, Christina, 1957-, et al.
(författare)
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Detection of spontaneous and antigen-induced human interleukin-4 responses in vitro : Comparison of ELISPOT, a novel ELISA and real-time RT-PCR
- 2002
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Ingår i: JIM - Journal of Immunological Methods. - 0022-1759 .- 1872-7905. ; 260:1-2, s. 55-67
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-4 (IL-4) is an important T-helper cell type 2 (Th2) cytokine in man, driving Th2 polarisation and exerting the most antagonistic effects to the Th1 cytokine interferon-? (IFN-?). Nevertheless, few data on spontaneous and antigen-specific secretion of IL-4 in man are available, mainly due to difficulties in the detection of IL-4. In this study, we compared three assays that can detect antigen-induced IL-4 responses, ELISPOT, ELISA after blocking the IL-4 receptor during cell culture, and real-time reverse transcription polymerase chain reaction (RT-PCR). Spontaneous, antigen- and allergen-induced responses were analysed in peripheral blood mononuclear cells from three groups with different secretion patterns for IL-4: atopic individuals, nonatopic individuals and pregnant women. ELISPOT displayed the highest sensitivity and was the only assay that could detect spontaneous secretion of IL-4 in all analysed samples. The IL-4 receptor blocking ELISA was considered best for the detection of in vitro antigen- and allergen-induced responses, since the results obtained from the ELISPOT and real-time RT-PCR displayed lower specificity, possibly because of seemingly aberrant IL-4 responses in the group of pregnant women. The real-time RT-PCR for detection of IL-4 mRNA proved to be sensitive, but expression of IL-4 mRNA was not correlated with the secretion of IL-4.
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| 25. |
- Ekerfelt, Christina, 1957-, et al.
(författare)
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Lyme borreliosis in Sweden - Diagnostic performance of five commercial Borrelia serology kits using sera from well-defined patient groups
- 2004
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Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - : Wiley. - 0903-4641 .- 1600-0463. ; 112:1, s. 74-78
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Tidskriftsartikel (refereegranskat)abstract
- Five commercial Borrelia serology kits available in Sweden were evaluated and compared for their diagnostic performance in sera from clinically well-characterized patient groups. With the clinically defined groups as the gold standard, i.e. without knowledge of antibody status in serum and cerebrospinal fluid, the diagnostic performance of the kits was compared and important differences in diagnostic usefulness were found. The kits from Abbot and DAKO, that often predict clinically relevant Borrelia infection and do not detect antibodies in sera from patients without strong suspicion of Borrelia infection, were considered the most useful in the population studied. This kind of validation study is an important part of good laboratory practice and should be performed by laboratories serving patient populations with varying endemicity of Borrelia.
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