| 1. |
- Venkata Ramanarao, Parasa, et al.
(författare)
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Enhanced CD8(+) cytolytic T cell responses in the peripheral circulation of patients with sarcoidosis and non-Lofgrens disease
- 2018
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Ingår i: Respiratory Medicine. - : W B SAUNDERS CO LTD. - 0954-6111 .- 1532-3064. ; 138, s. S38-S44
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Tidskriftsartikel (refereegranskat)abstract
- Background: The role of CD4(+) T cells in the immunopathogenesis of pulmonary sarcoidosis is well-established, while less is known about the phenotype and function of CD8(+) cytolytic T cells (CTLs). Methods: CD8(+) CTLs were explored in peripheral blood and bronchoalveolar lavage (BAL) samples obtained from up to 25 patients with sarcoidosis and 25 healthy controls. The proportion of CTLs was assessed by the expression of cytolytic effector molecules perforin, granzyme B and granulysin in CD8(+) T cells, using flow cytometry. Cytolytic function in blood lymphocytes was assessed using a standard 51Cr-release assay. Patients with Lofgrens syndrome (LS) and an acute disease onset, were compared to non-LS patients with an insidious onset. Results: Higher proportions of peripheral CD8(+) CTLs expressing perforin and granzyme B were observed in sarcoidosis compared to healthy controls. Blood CTLs from non-LS patients had significantly higher expression of perforin, granzyme B and granulysin compared to matched BAL, while LS patients maintained lower levels of effector molecules in both compartments. Mitogen-stimulated peripheral lymphocytes from sarcoidosis patients, particularly from the non-LS group, showed a higher target cell lysis compared to controls. Conclusion: These results demonstrated enhanced peripheral CD8(+) CTL responses in sarcoidosis, especially in non-LS patients who have an increased risk of chronic disease. Further comprehensive clinical studies are warranted to increase our understanding of CD8(+) CTL responses in sarcoidosis.
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| 2. |
- Bobbio, Emanuele, et al.
(författare)
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Clinical Outcomes and Predictors of Long-Term Survival in Patients With and Without Previously Known Extracardiac Sarcoidosis Using Machine Learning: A Swedish Multicenter Study.
- 2023
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Ingår i: Journal of the American Heart Association. - 2047-9980. ; 12:15
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Tidskriftsartikel (refereegranskat)abstract
- Background Cardiac involvement can be an initial manifestation in sarcoidosis. However, little is known about the association between various clinical phenotypes of cardiac sarcoidosis (CS) and outcomes. We aimed to analyze the relation of different clinical manifestations with outcomes of CS and to investigate the relative importance of clinical features influencing overall survival. Methods and Results A retrospective cohort of 141 patients with CS enrolled at 2 Swedish university hospitals was studied. Presentation, imaging studies, and outcomes of de novo CS and previously known extracardiac sarcoidosis were compared. Survival free of primary composite outcome (ventricular arrhythmias, heart transplantation, or death) was assessed. Machine learning algorithm was used to study the relative importance of clinical features in predicting outcome. Sixty-two patients with de novo CS and 79 with previously known extracardiac sarcoidosis were included. De novo CS showed more advanced New York Heart Association class (P=0.02), higher circulating levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) (P<0.001), and troponins (P<0.001), as well as a higher prevalence of right ventricular dysfunction (P<0.001). During a median (interquartile range) follow-up of 61 (44-77) months, event-free survival was shorter in patients with de novo CS (P<0.001). The top 5 features predicting worse event-free survival in order of importance were as follows: impaired tricuspid annular plane systolic excursion, de novo CS, reduced right ventricular ejection fraction, absence of β-blockers, and lower left ventricular ejection fraction. Conclusions Patients with de novo CS displayed more severe disease and worse outcomes compared with patients with previously known extracardiac sarcoidosis. Using machine learning, right ventricular dysfunction and de novo CS stand out as strong overall predictors of impaired survival.
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| 3. |
- Dehara, Marina, et al.
(författare)
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Menopausal hormone therapy and risk of sarcoidosis : a population-based nested case–control study in Sweden
- 2024
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Ingår i: European Journal of Epidemiology. - : Springer Nature. - 0393-2990 .- 1573-7284. ; 39:3, s. 313-322
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Tidskriftsartikel (refereegranskat)abstract
- Sarcoidosis incidence peaks in women between 50 and 60 years old, which coincides with menopause, suggesting that certain sex hormones, mainly estrogen, may play a role in disease development. We investigated whether menopausal hormone therapy (MHT) was associated with sarcoidosis risk in women and whether the risk varied by treatment type. We performed a nested case–control study (2007–2020) including incident sarcoidosis cases from the Swedish National Patient Register (n = 2593) and matched (1:10) to general population controls (n = 20,003) on birth year, county, and living in Sweden at the time of sarcoidosis diagnosis. Dispensations of MHT were obtained from the Swedish Prescribed Drug Register before sarcoidosis diagnosis/matching. Adjusted odds ratios (aOR) of sarcoidosis were estimated using conditional logistic regression. Ever MHT use was associated with a 25% higher risk of sarcoidosis compared with never use (aOR 1.25, 95% CI 1.13–1.38). When MHT type and route of administration were considered together, systemic estrogen was associated with the highest risk of sarcoidosis (aOR 1.51, 95% CI 1.23–1.85), followed by local estrogen (aOR 1.25, 95% CI 1.11–1.42), while systemic estrogen-progestogen combined was associated with the lowest risk compared to never users (aOR 1.12, 95% CI 0.96–1.31). The aOR of sarcoidosis did not differ greatly by duration of MHT use. Our findings suggest that a history of MHT use is associated with increased risk of sarcoidosis, with women receiving estrogen administered systemically having the highest risk.
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| 4. |
- Dehara, Marina, et al.
(författare)
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Reproductive and hormonal risk factors for sarcoidosis : a nested case–control study
- 2022
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Ingår i: BMC Pulmonary Medicine. - : BMC. - 1471-2466. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sarcoidosis incidence peaks in females around the fifth decade of life, which coincides with menopause, suggesting hormonal factors play a role in disease development. We investigated whether longer exposure to reproductive and hormonal factors is associated with reduced sarcoidosis risk. Methods: We conducted a matched case–control study nested within the Mammography Screening Project. Incident sarcoidosis cases were identified via medical records and matched to controls on birth and questionnaire date (1:4). Information on hormonal factors was obtained through questionnaires prior to sarcoidosis diagnosis. Multilevel modelling was used to estimate adjusted odds ratios with 95% credible intervals (OR; 95% CI). Results: In total, 32 sarcoidosis cases and 124 controls were included. Higher sarcoidosis odds were associated with older age at menarche (OR 1.19: 95% CI 0.92–1.55), natural menopause versus non-natural (OR 1.53: 95% CI 0.80–2.93), later age at first pregnancy (OR 1.11: 95% CI 0.76–1.63) and ever hormone replacement therapy (HRT) use (OR 1.40: 95% CI 0.76–2.59). Lower odds were associated with older age at menopause (OR 0.90: 95% CI 0.52–1.55), longer duration of oral contraceptive use (OR 0.70: 95% CI 0.45–1.07), longer duration of HRT use (OR 0.61: 95% CI 0.22–1.70), ever local estrogen therapy (LET) use (OR 0.83: 95% CI 0.34–2.04) and longer duration of LET use (OR 0.78: 95% CI 0.21–2.81). However, the CIs could not rule out null associations. Conclusion: Given the inconsistency and modest magnitude in our estimates, and that the 95% credible intervals included one, it still remains unclear whether longer estrogen exposure is associated with reduced sarcoidosis risk.
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| 5. |
- Eldhagen, Per, et al.
(författare)
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Phenotypic and HLA-DRB1 allele characterization of Swedish cardiac sarcoidosis patients.
- 2022
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Ingår i: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 359, s. 108-112
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Tidskriftsartikel (refereegranskat)abstract
- Early detection and initiation of treatment in cardiac sarcoidosis (CS) is believed to be crucial to reduce morbidity and mortality. The diagnosis of CS is challenging, especially in isolated CS (ICS). Certain human leukocyte antigen (HLA-DRB1) alleles associate with different phenotypes of sarcoidosis. Phenotypic and genotypic characterization of patients with CS may improve our ability to identify patients being at risk for developing CS.87 patients with CS, identified at two Swedish university hospitals were included. Phenotypic characteristics were extracted from the medical records and the patients were HLA-DRB1 typed.Median age at diagnosis was 55years, 37% were women. HLA-DRB1 distribution was similar to a general sarcoidosis population. A majority of patients (51/87) had CS as the first sarcoidosis presentation. They were younger (p=0.04), more often presenting with ventricular tachycardia (VT) or atrioventricular block (AVB) grade II or III (p<0.001), had lower left ventricular ejection fraction (LVEF) (p=0.002), lower serum angiotensin converting enzyme (s-ACE) (p=0.025), and fewer extra cardiac manifestations (ECM) (p=0.02) than those presenting with CS later.Of Swedish CS patients, 59% presented with cardiac involvement as first manifestation. They had more severe cardiac symptoms than patients presenting with CS later. This phenotype disclosed less ECM and lower s-ACE thus diagnosis can be missed or delayed. We did not observe significant differences in HLA-DRB1 allele frequency between patients with CS compared to sarcoidosis in general. Awareness of CS as a primary manifestation can enable early detection and adequate intervention.
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| 6. |
- Kullberg, Susanna, et al.
(författare)
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Microglial activation, emergence of ED1-expressing cells and clusterin upregulation in the aging rat CNS, with special reference to the spinal cord
- 2001
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Ingår i: Brain Research. - 0006-8993 .- 1872-6240. ; 899:1-2, s. 169-186
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Tidskriftsartikel (refereegranskat)abstract
- With advancing age, the incidence of neuronal atrophy and dystrophy increases and, in parallel, behavioural sensorimotor impairment becomes overt. Activated microglia has been implicated in cytotoxic and inflammatory processes in neurodegenerative diseases as well as during aging. Here we have used immunohistochemistry and in situ hybridization to examine the expression of OX42, ED1, ED2, GFAP and clusterin in CNS of young adult and behaviourally tested aged rats (30-month-old), to study the occurrence of activated microglia/ED1 positive macrophages in senescence and to what extent this correlates with astrogliosis and signs of sensorimotor impairment among the individuals. The results show a massive region-specific increase in activated microglia and ED1 expressing cell profiles in aged rats. The infiltration was most prominent in the spinal cord dorsal columns, including their sensory relay nuclei, and the outer portions of the lateral and ventral columns. At such sites the occurrence of macrophages coincided with increased levels of GFAP and positive correlations were evident between the labeling for, on the one hand, OX42 and, on the other, GFAP and ED1. Also, the ventral and dorsal roots were heavily infiltrated by ED1 positive cells. The signs of gliosis were most pronounced among aged rats with advanced sensorimotor impairment. In contrast, the grey matter of aged rats showed very few activated microglia/ED1 labeled cells despite signs of focal astrogliosis. ED2 expression was confined to perivascular cells and leptominges with a similar labeling pattern in young and aged rats. In aged rats increased expression of clusterin was observed in GFAP-immunoreactive profiles of the white matter only. It is suggested that this increase may reflect a response to degenerative/inflammatory processes.
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| 7. |
- Kullberg, Susanna
(författare)
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On age related changes in axons and glia of the central nervous system
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A growing body of evidence shows that phenotypic changes including axon aberrations, rather than loss of neurons, account for behavioral impairments during aging. The present thesis was undertaken to investigate the occurrence of axon aberrations in relation to transmitter identity, glial reaction and sensorimotor disturbances. To shed light on possible underlying mechanisms, signs of oxidative stress and inflammation were also examined. The studies were performed on behaviorally defined aged (30 months old) and young adult (2-3 months old) Sprague Dawley rats, by using electron microscopy, immunohistochemistry, in situ hybridization and reverse transcriptase-polymerase chain reaction. The results show that many aged motoneurons lose a significant portion of their bouton covering, due to a decreased number of apposing boutons. Consistent with the more pronounced sensorimotor disturbances observed in the hind- in comparison with the forelimbs, lumbar motoneurons appeared more severely affected than cervical motoneurons. In the neuropil of the motor nucleus, aberrant axons were encountered. Ultrastructural analysis of aberrant axons in relation to content of amino acid neurotransmitters and the free radical scavenger glutathione (GSH) revealed that many of the aberrant axons contained high levels of glutamate-immunoreactivity (-IR) and were often enriched with GSH-IR. Increased levels of GSH-IR were also encountered in glutamate-IR terminals with a preserved ultrastructure, suggesting that a changed redox status may be mechanistic in the development of axon aberrations. GABA- and glycine-IR terminals were more rarely affected, suggesting that excitatory and inhibitory pathways are differentially affected. In the aged rats, immunohistochemistry showed a reduced fiber density and axon aberrations of cholinergic and monoaminergic axons in both the spinal cord and the hippocampus. In contrast, the innervation of alpha-motonearons by C boutons was preserved in senescence. However, the C boutons showed a decreased labeling for cholinergic markers. Regions disclosing axon terminal loss and aberrations showed increased expression of glial fibrillary acidic protein (GFAP, the main intermediate filament of astrocytes). Using Marchi staining on spinal cord sections, the outer parts of the white matter showed signs of a changed myelin metabolism and/or dysmyelination in aged rats. In the same regions, astro- and microglial cells showed conspicuous signs of activation, most pronounced in rats disclosing the most severe sensorimotor disturbances. The glial reaction appeared less pronounced in brain white matter compared to the spinal cord white matter. The spinal cord white matter of aged rats also disclosed a changed expression of several cytokines, while the majority of investigated cytokines were unaltered in the hippocampus. One of the most prominent changes was an upregulation of the proinflammatory cytokine IFN-gamma, encountered in both the hippocampus and the spinal cord. There was a robust upregulation of TGFbeta-1 and IL1-beta in astroglia of spinal cord white matter, while no change was evident in the hippocampus. CNTF levels were unaltered in aged rats, however, IR appeared reduced in oligodendroglia-like cells, while it seemed increased in astroglia of the spinal cord white matter. IGF-1, a molecule with similar effects as CNTF, was upregulated in hippocampus but not in die spinal cord.
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| 8. |
- Lepzien, Rico, et al.
(författare)
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Monocytes in sarcoidosis are potent tumour necrosis factor producers and predict disease outcome
- 2021
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 58:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Pulmonary sarcoidosis is an inflammatory disease characterised by granuloma formation and heterogeneous clinical outcome. Tumour necrosis factor (TNF) is a pro-inflammatory cytokine contributing to granuloma formation and high levels of TNF have been shown to associate with progressive disease. Mononuclear phagocytes (MNPs) are potent producers of TNF and highly responsive to inflammation. In sarcoidosis, alveolar macrophages have been well studied. However, MNPs also include monocytes/monocyte-derived cells and dendritic cells, which are poorly studied in sarcoidosis, despite their central role in inflammation.Objective To determine the role of pulmonary monocyte-derived cells and dendritic cells during sarcoidosis.Methods We performed in-depth phenotypic, functional and transcriptomic analysis of MNP subsets from blood and bronchoalveolar lavage (BAL) fluid from 108 sarcoidosis patients and 30 healthy controls. We followed the clinical development of patients and assessed how the repertoire and function of MNP subsets at diagnosis correlated with 2-year disease outcome.Results Monocytes/monocyte-derived cells were increased in blood and BAL of sarcoidosis patients compared to healthy controls. Interestingly, high frequencies of blood intermediate monocytes at time of diagnosis associated with chronic disease development. RNA sequencing analysis showed highly inflammatory MNPs in BAL of sarcoidosis patients. Furthermore, frequencies of BAL monocytes/ monocyte-derived cells producing TNF without exogenous stimulation at time of diagnosis increased in patients that were followed longitudinally. In contrast to alveolar macrophages, the frequency of TNFproducing BAL monocytes/monocyte-derived cells at time of diagnosis was highest in sarcoidosis patients that developed progressive disease.Conclusion Our data show that pulmonary monocytes/monocyte-derived cells are highly inflammatory and can be used as a predictor of disease outcome in sarcoidosis patients.
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| 9. |
- Lepzien, Rico, et al.
(författare)
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Pulmonary and blood dendritic cells from sarcoidosis patients more potently induce IFNγ-producing Th1 cells compared with monocytes
- 2022
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Ingår i: Journal of Leukocyte Biology. - 0741-5400 .- 1938-3673. ; 111:4, s. 857-866
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Tidskriftsartikel (refereegranskat)abstract
- Sarcoidosis is a systemic inflammatory disease mainly affecting the lungs. The hallmark of sarcoidosis are granulomas that are surrounded by activated T cells, likely targeting the disease-inducing antigen. IFNγ-producing Th1 and Th17.1 T cells are elevated in sarcoidosis and associate with disease progression. Monocytes and dendritic cells (DCs) are antigen-presenting cells (APCs) and required for T cell activation. Several subsets of monocytes and DCs with different functions were identified in sarcoidosis. However, to what extent different monocyte and DC subsets can support activation and skewing of T cells in sarcoidosis is still unclear. In this study, we performed a transcriptional and functional side-by-side comparison of sorted monocytes and DCs from matched blood and bronchoalveolar lavage (BAL) fluid of sarcoidosis patients. Transcriptomic analysis of all subsets showed upregulation of genes related to T cell activation and antigen presentation in DCs compared with monocytes. Allogeneic T cell proliferation was higher after coculture with monocytes and DCs from blood compared with BAL and DCs induced more T cell proliferation compared with monocytes. After coculture, proliferating T cells showed high expression of the transcription factor Tbet and IFNγ production. We also identified Tbet and RORγt coexpressing T cells that mainly produced IFNγ. Our data show that DCs rather than monocytes from sarcoidosis patients have the ability to activate and polarize T cells towards Th1 and Th17.1 cells. This study provides a useful in vitro tool to better understand the contribution of monocytes and DCs to T cell activation and immunopathology in sarcoidosis.
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