| 1. |
- Beziat, Vivien, et al.
(författare)
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NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 121:14, s. 2678-2688
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Tidskriftsartikel (refereegranskat)abstract
- Human natural killer (NK) cells are functionally regulated by killer cell immunoglobulin-like receptors (KIRs) and their interactions with HLA class I molecules. As KIR expression in a given NK cell is genetically hard-wired, we hypothesized that KIR repertoire perturbations reflect expansions of unique NK-cell subsets and may be used to trace adaptation of the NK-cell compartment to virus infections. By determining the human KIR-ome at a single-cell level in more than 200 donors, we were able to analyze the magnitude of NK cell adaptation to virus infections in healthy individuals. Strikingly, infection with human cytomegalovirus (CMV), but not with other common herpesviruses, induced expansion and differentiation of KIR-expressing NK cells, visible as stable imprints in the repertoire. Education by inhibitory KIRs promoted the clonal-like expansion of NK cells, causing a bias for self-specific inhibitory KIRs. Furthermore, our data revealed a unique contribution of activating KIRs (KIR2DS4, KIR2DS2, or KIR3DS1), in addition to NKG2C, in the expansion of human NK cells. These results provide new insight into the diversity of KIR repertoire and its adaptation to virus infection, suggesting a role for both activating and inhibitory KIRs in immunity to CMV infection.
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| 2. |
- Björkström, Niklas K, et al.
(författare)
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Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus
- 2011
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 208:1, s. 13-21
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Tidskriftsartikel (refereegranskat)abstract
- Natural killer (NK) cells are known to mount a rapid response to several virus infections. In experimental models of acute viral infection, this response has been characterized by prompt NK cell activation and expansion followed by rapid contraction. In contrast to experimental model systems, much less is known about NK cell responses to acute viral infections in humans. We demonstrate that NK cells can rapidly expand and persist at highly elevated levels for >60 d after human hantavirus infection. A large part of the expanding NK cells expressed the activating receptor NKG2C and were functional in terms of expressing a licensing inhibitory killer cell immunoglobulin-like receptor (KIR) and ability to respond to target cell stimulation. These results demonstrate that NK cells can expand and remain elevated in numbers for a prolonged period of time in humans after a virus infection. In time, this response extends far beyond what is considered normal for an innate immune response.
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| 3. |
- Blomberg, Hans, 1963-, et al.
(författare)
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Impact of prehospital trauma life support (PHTLS) training of ambulance caregivers on the outcome of traffic injury victims – a nation-wide study.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Prehospital trauma life support (PHTLS) is a widely implemented educational program for prehospital trauma care. Evidence for improved patient outcome is, however, limited. The primary aim of this nation-wide study was to investigate the association between regional implementation of PHTLS training and mortality after traffic injuries.Methods: We extracted from the Swedish National Patient Registry and the Cause of Death Registry information on victims of motor vehicle traffic injuries in Sweden from 2001 to 2004 (n=28 041). During this time period, PHTLS training was implemented at a varying pace in different regions. We used a Bayesian approach with Markov chain Monte Carlo to estimate odds ratios (OR) for prehospital and 30-day mortality. We entered region and hospital into hierarchical models and controlled for the calendar year for each injury. We analyzed the time to death and time to return to work using Cox’s proportional hazards frailty models.Results: A total of 1395 individuals died before being admitted to hospital. After multivariable adjustment, the OR for prehospital mortality with PHTLS-trained prehospital staff was 1.11 (95% credibility interval, 0.88 to 1.38). For 30-day mortality (365 deaths), the adjusted OR was 0.80 (95% credibility interval, 0.53 to 1.17). There was no association between PHTLS training and time to death (hazard ratio 0.99; 95% confidence interval, 0.85 to 1.14) or time to return to work (hazard ratio 0.98, 95% confidence interval, 0.92 to 1.05).Conclusion: The implementation of PHTLS training did not appear to reduce mortality or disability after motor vehicle traffic injuries. .
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| 4. |
- Blomberg, Hans, 1963-
(författare)
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Influence of The Education and Training of Prehospital Medical Crews on Measures of Performance and Patient Outcomes
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prehospital care has developed dramatically the last decades with the implementation of new devices and educational concepts. Clinical decisions and treatments have moved out from the hospitals to the prehospital setting. In Sweden this has been accompanied by an increase in the level of competence, i.e. by introducing nurses in the ambulances. With some exceptions the scientific support for these changes is poor.This thesis deals with such changes in three different subsets of prehospital care: Cardiopulmonary resuscitation (CPR), the stroke chain of survival and trauma care.We assessed the performance of ambulance crews during CPR, using a mechanical compression device, as compared to CPR using manual compressions. There was a strikingly poor quality of compressions using the mechanical device compared to CPR with manual compressions. The result calls for caution when implementing a chest compression device in clinical practice and reinforce the importance of randomised controlled trials to evaluate new interventions. Careful attention should be given to the assurance of correct application of the device. Further implementation without evaluation of the quality of mechanical compressions in a clinical setting is discouraged.Among patients with a prehospital suspicion of stroke we analysed the ambulance nurses’ ability to select the correct patient subset eligible for a CT scan as a preparation for potential thrombolysis. The results do not support an implementation of a bypass of the emergency department, using ambulance nurse competence to select patients eligible and suitable for a CT scan without a preceding assessment by a physician.The association between the Prehospital Trauma Life Support (PHTLS) course and the outcome in victims of trauma was analysed in two observational studies. A study covering one county gave some support for a protective effect from PHTLS, but the estimate had a low precision. A nationwide study, covering all of Sweden, could not confirm those results. Although there was a reduction in mortality over time coinciding with the implementation of PHTLS, it did not appear to be associated with the implementation of PHTLS. Thus, we could not detect any clear beneficial impact of the PHTLS course on the outcome of trauma patients.
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| 5. |
- Blomberg, Hans, et al.
(författare)
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Prehospital Trauma Life Support Training of Ambulance Caregivers and the Outcomes of Traffic-Injury Victims in Sweden
- 2013
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Ingår i: Journal of the American College of Surgeons. - : Ovid Technologies (Wolters Kluwer Health). - 1072-7515 .- 1879-1190. ; 217:6, s. 1010-1019
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:There is limited evidence that the widely implemented Prehospital Trauma Life Support (PHTLS) educational program improves patient outcomes. The primary aim of this national study in Sweden was to investigate the association between regional implementation of PHTLS training and mortality after traffic injuries.STUDY DESIGN:We extracted information from the Swedish National Patient Registry and the Cause of Death Registry on victims of motor-vehicle traffic injuries in Sweden from 2001 to 2004 (N = 28,041). During this time period, PHTLS training was implemented at a varying pace in different regions. To control for other influences on patient outcomes related to regional and hospital-level effects, such as variations in performance of trauma care systems, we used Bayesian hierarchical regression models to estimate odds ratios for prehospital mortality and 30-day mortality after hospital admission. We also controlled for the calendar year for each injury to account for period effects. We analyzed the time to death after hospital admission and time to return to work using Cox's proportional hazards frailty models.RESULTS:After multivariable adjustment, the odds ratio for prehospital mortality with PHTLS-trained prehospital staff was 1.54 (95% credibility interval, 1.07-2.13). For 30-day mortality among those surviving to hospital admission, the odds ratio was 0.85 (95% credibility interval, 0.45-1.48). There was no association between PHTLS training and time to death (hazard ratio = 0.99; 95% CI, 0.85-1.14) or time to return to work (hazard ratio = 0.98; 95% CI, 0.92-1.05).CONCLUSIONS:In this observational study, the implementation of PHTLS training did not appear to be associated with reduced mortality or ability to return to work after motor-vehicle traffic injuries.
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| 6. |
- Buggert, Marcus, et al.
(författare)
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T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+ T Cells in HIV Infection.
- 2014
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- CD8+ T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8+ T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8+ T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8+ T cells was elevated in chronically infected individuals and highly associated with a T-betdimEomeshi expressional profile. Interestingly, both resting and activated HIV-specific CD8+ T cells in chronic infection were almost exclusively T-betdimEomeshi cells, while CMV-specific CD8+ T cells displayed a balanced expression pattern of T-bet and Eomes. The T-betdimEomeshi virus-specific CD8+ T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8+ T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8+ T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8+ T cells to control the viral replication post-ART cessation.
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| 7. |
- Engblom, Camilla, et al.
(författare)
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Spatial transcriptomics of B cell and T cell receptors reveals lymphocyte clonal dynamics
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 382:6675, s. 8486-
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Tidskriftsartikel (refereegranskat)abstract
- The spatial distribution of lymphocyte clones within tissues is critical to their development, selection, and expansion. We have developed spatial transcriptomics of variable, diversity, and joining (VDJ) sequences (Spatial VDJ), a method that maps B cell and T cell receptor sequences in human tissue sections. Spatial VDJ captures lymphocyte clones that match canonical B and T cell distributions and amplifies clonal sequences confirmed by orthogonal methods. We found spatial congruency between paired receptor chains, developed a computational framework to predict receptor pairs, and linked the expansion of distinct B cell clones to different tumor-associated gene expression programs. Spatial VDJ delineates B cell clonal diversity and lineage trajectories within their anatomical niche. Thus, Spatial VDJ captures lymphocyte spatial clonal architecture across tissues, providing a platform to harness clonal sequences for therapy.
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| 8. |
- Evren, Elza, et al.
(författare)
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Distinct developmental pathways from blood monocytes generate human lung macrophage diversity
- 2021
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Ingår i: Immunity. - : Elsevier. - 1074-7613 .- 1097-4180. ; 51, s. 35-35
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Tidskriftsartikel (refereegranskat)abstract
- The study of human macrophages and their ontogeny is an important unresolved issue. Here, we use a humanized mouse model expressing human cytokines to dissect the development of lung macrophages from human hematopoiesis in vivo. Human CD34+ hematopoietic stem and progenitor cells (HSPCs) generated three macrophage populations, occupying separate anatomical niches in the lung. Intravascular cell labeling, cell transplantation, and fate-mapping studies established that classical CD14+ blood monocytes derived from HSPCs migrated into lung tissue and gave rise to human interstitial and alveolar macrophages. In contrast, non-classical CD16+ blood monocytes preferentially generated macrophages resident in the lung vasculature (pulmonary intravascular macrophages). Finally, single-cell RNA sequencing defined intermediate differentiation stages in human lung macrophage development from blood monocytes. This study identifies distinct developmental pathways from circulating monocytes to lung macrophages and reveals how cellular origin contributes to human macrophage identity, diversity, and localization in vivo.
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| 9. |
- Forkel, Marianne, et al.
(författare)
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Composition and functionality of the intrahepatic innate lymphoid cell-compartment in human nonfibrotic and fibrotic livers
- 2017
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 47:8, s. 1280-1294
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Tidskriftsartikel (refereegranskat)abstract
- Human innate lymphoid cells have been described to exist in different organs, with functional deregulation of these cells contributing to several disease states. Here, we performed the first detailed characterization of the phenotype, tissue-residency properties, and functionality of ILC1s, ILC2s, and ILC3s in the human adult and fetal liver. In addition, we investigated changes in the ILC compartment in liver fibrosis. A unique composition of tissue-resident ILCs was observed in nonfibrotic livers as compared with that in mucosal tissues, with NKp44− ILC3s accounting for the majority of total intrahepatic ILCs. The frequency of ILC2s, representing a small fraction of ILCs in nonfibrotic livers, increased in liver fibrosis and correlated directly with the severity of the disease. Notably, intrahepatic ILC2s secreted the profibrotic cytokine IL-13 when exposed to IL-33 and thymic stromal lymphopoetin (TSLP); these cytokines were produced by hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells in response to TLR-3 stimulation. In summary, the present results provide the first detailed characterization of intrahepatic ILCs in human adult and fetal liver. The results indicate a role for ILC2s in human liver fibrosis, implying that targeting ILC2s might be a novel therapeutic strategy for its treatment.
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| 10. |
- Forkel, Marianne, et al.
(författare)
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Distinct Alterations in the Composition of Mucosal Innate Lymphoid Cells in Newly Diagnosed and Established Crohns Disease and Ulcerative Colitis
- 2019
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Ingår i: Journal of Crohn's & Colitis. - : OXFORD UNIV PRESS. - 1873-9946 .- 1876-4479. ; 13:1, s. 67-78
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Innate lymphoid cells [ILC] have been suggested to play a role in inflammatory bowel disease [IBD]. Here, we investigated the ILC compartment in intestinal biopsies and blood from distinct patient groups with Crohns disease [CD] and ulcerative colitis [UC], either newly diagnosed or with disease established for at least 1 year. This approach allowed us to simultaneously investigate temporal, disease-specific, and tissue-specific changes in ILC composition in IBD. Methods: ILC subset frequencies, phenotype, and transcription factor profile in blood and intestinal biopsies were investigated by multi-parameter flow cytometry analysis. Endoscopic disease severity was judged using the ulcerative colitis endoscopic index of severity and the simple endoscopic score for Crohns disease. Results: The frequency of NKp44(+)ILC3 was decreased in inflamed tissue, both in patients with CD and those with UC, already at the time of diagnosis, and correlated with disease severity. Simultaneously, the frequency of ILC1 was increased in patients with CD, whereas the frequency of ILC2 was increased in patients with UC. However, in patients with established UC or CD, both ILC1 and ILC2 were increased. In contrast to the ILC composition in inflamed tissue, ILC in non-inflamed tissue or blood were unchanged compared with non-IBD controls. Finally, in patients undergoing treatment with an anti-alpha(4)beta(7) antibody the frequencies of ILC in peripheral blood remained unchanged. Conclusions: We report both shared and distinct changes in ILC composition depending on diagnosis and disease duration. The alterations in ILC composition in IBD occur selectively at inflamed sites in the gut.
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