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Biomarkers in sepsis and other severe infections

Janols, Helena LU (2014) In Lund University, Faculty of Medicine, Doctoral Dissertation Series 2014:50.
Abstract (Swedish)
Popular Abstract in Swedish

Det är en utmaning att behandla patienter med allvarliga infektioner eftersom immunförsvaret reagerar olika på olika mikroorganismer. Immunförsvarets reaktion har i sin tur en stor betydelse för symtombild, kliniska fynd och prognos. Vid blodförgiftning (sepsis) förändras dessutom sannolikt immunsvaret under det kliniska förloppet. Man tror att det inledningsvis vid sepsis sker en aktivering av det proinflammatoriska immunförsvaret. I de fall där aktiveringen blir för kraftig skapas en förödande antiinflammatorisk negativ återkoppling med risk för sekundära infektioner och död.



Den här avhandlingens mål var att undersöka om en utökad analys av vita blodkroppar kan ge... (More)
Popular Abstract in Swedish

Det är en utmaning att behandla patienter med allvarliga infektioner eftersom immunförsvaret reagerar olika på olika mikroorganismer. Immunförsvarets reaktion har i sin tur en stor betydelse för symtombild, kliniska fynd och prognos. Vid blodförgiftning (sepsis) förändras dessutom sannolikt immunsvaret under det kliniska förloppet. Man tror att det inledningsvis vid sepsis sker en aktivering av det proinflammatoriska immunförsvaret. I de fall där aktiveringen blir för kraftig skapas en förödande antiinflammatorisk negativ återkoppling med risk för sekundära infektioner och död.



Den här avhandlingens mål var att undersöka om en utökad analys av vita blodkroppar kan ge information av värde för diagnostik och behandling av patienter med allvarliga infektioner med fokus på sepsis.



I den första studien granskade vi ytmarkörer på vita blodkroppar från patienter med antingen sepsis, borrelia, tuberkulos, körtelfeber, influensa eller bindvävssjukdom. Vi kunde där se att vissa markörer framträdde vid en halvakut bakteriell infektion eller en bindvävssjukdom. Den här typen av analys skulle kanske i en del fall kunna hjälpa till att skilja mellan bakterie- och virusinfektioner. Vår slutsats är att metoden skulle kunna hjälpa till i diagnostiken av vissa patienter med oklar feber.



Den andra artikeln var en studie av dendritiska celler som, genom att de presenterar antigener för lymfocyter, fungerar som en viktig brygga mellan det medfödda och det förvärvade immunförsvaret. Vi kunde visa att det specifika proteinet Wnt5a hämmade bildandet av speciella dendritiska celler med ursprung från monocyter. Vi kunde också visa att när monocyter stimulerades med Wnt5a började de tillverka IL-6. Wnt5a’s egenskaper skulle kunna vara en av förklaringarna till det minskade antalet dendritiska celler hos patienter med sepsis.



I vår tredje artikel undersökte vi det aktiverande och det hämmande immunsvaret hos patienter med sepsis, septisk chock och allvarliga virusinfektioner. Vi såg att tecken på immunhämning dominerade hos patienter med grampositiv sepsis och septisk chock medan monocytaktivering var vanligt hos patienter med gramnegativ sepsis. Det viktigaste fyndet var dock de uttalade individuella variationerna. Våra data antyder att det är viktigt att undersöka hur immunförsvaret reagerat hos den enskilde sepsis patienten innan man ger behandling för att undertrycka eller stimulera det.



I vårt fjärde arbete undersökte vi förekomsten och funktionen av en särskild sorts immunhämmande celler, myeloid derived suppressor cells (MDSCs), hos patienter med sepsis. MDSCs är en nyupptäckt celltyp känd för att dämpa immunförsvaret vid cancer. I studien såg vi att olika bakterier kan framkalla generering av olika typer av MDSCs. Vi såg också att MDSCs kan hämma tillväxten av T-celler. (Less)
Abstract
Infectious diseases constitute a major global health problem. The presenting clinical picture results from a mixture of direct toxic actions by the microbiological agent and of the immune response mounted by the host. There is often a rapid onset, which may constitute a diagnostic and therapeutic challenge, whereas in other cases an extensive investigation over a long time period can fail to identify a causal microbial agent.



The aim with this thesis was to study the cellular immune response with phenotypical assays, in patients with severe infections with focus on sepsis. We assessed if our findings could serve as biomarkers and provide valuable diagnostic and possible also therapeutic information.



... (More)
Infectious diseases constitute a major global health problem. The presenting clinical picture results from a mixture of direct toxic actions by the microbiological agent and of the immune response mounted by the host. There is often a rapid onset, which may constitute a diagnostic and therapeutic challenge, whereas in other cases an extensive investigation over a long time period can fail to identify a causal microbial agent.



The aim with this thesis was to study the cellular immune response with phenotypical assays, in patients with severe infections with focus on sepsis. We assessed if our findings could serve as biomarkers and provide valuable diagnostic and possible also therapeutic information.



In the first part (paper I) we examined surface markers on white blood cells from patients with severe infections. In some instances our analysis could differentiate between infections of bacterial and viral origin. In the second part (paper II-IV) we examined the incidence and nature of the immune alterations found in patients with sepsis and septic shock. We identified a protein (Wnt5a) that inhibited differentiation of monocytes to monocyte-derived myeloid dendritic cells (Mo-mDC), which may play a role in the DC depletion often seen in sepsis. Also, as indicated by cell surface phenotype, a large inter-individual variation of immune activation and immunosuppression was detected in patients with sepsis, with a dominance of immunosuppression in patients with septic shock. Finally, different types of immature myeloid immunosuppressive cells, myeloid-derived suppressor cells (MDSCs) were found in patients with sepsis; Mo-MDSCs were preferentially expanded in patients with gram-negative sepsis, whereas granulocytic MDSCs (PMN-MDSCs) accumulated in patients with gram-positive sepsis.



We conclude that the immune response during severe infections shows large inter-individual variations and biomarker guided therapy could be useful in individualised treatment. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Vikerfors, Tomas
organization
publishing date
type
Thesis
publication status
published
subject
keywords
immunosuppression, myeloid-derived suppressor cells, T cells, dendritic cells, monocytes, sepsis, Biomarkers
in
Lund University, Faculty of Medicine, Doctoral Dissertation Series
volume
2014:50
pages
166 pages
publisher
Department of Clinical Sciences, Lund University
defense location
The main lecture hall, Pathology Building, Skåne University Hospital, Malmö
defense date
2014-05-16 13:00
ISSN
1652-8220
ISBN
978-91-87651-76-2
language
English
LU publication?
yes
id
95e313bf-9b12-43d3-9a8b-2806710affa1 (old id 4406483)
date added to LUP
2014-04-28 14:43:36
date last changed
2016-09-19 08:44:45
@phdthesis{95e313bf-9b12-43d3-9a8b-2806710affa1,
  abstract     = {Infectious diseases constitute a major global health problem. The presenting clinical picture results from a mixture of direct toxic actions by the microbiological agent and of the immune response mounted by the host. There is often a rapid onset, which may constitute a diagnostic and therapeutic challenge, whereas in other cases an extensive investigation over a long time period can fail to identify a causal microbial agent. <br/><br>
<br/><br>
The aim with this thesis was to study the cellular immune response with phenotypical assays, in patients with severe infections with focus on sepsis. We assessed if our findings could serve as biomarkers and provide valuable diagnostic and possible also therapeutic information. <br/><br>
<br/><br>
In the first part (paper I) we examined surface markers on white blood cells from patients with severe infections. In some instances our analysis could differentiate between infections of bacterial and viral origin. In the second part (paper II-IV) we examined the incidence and nature of the immune alterations found in patients with sepsis and septic shock. We identified a protein (Wnt5a) that inhibited differentiation of monocytes to monocyte-derived myeloid dendritic cells (Mo-mDC), which may play a role in the DC depletion often seen in sepsis. Also, as indicated by cell surface phenotype, a large inter-individual variation of immune activation and immunosuppression was detected in patients with sepsis, with a dominance of immunosuppression in patients with septic shock. Finally, different types of immature myeloid immunosuppressive cells, myeloid-derived suppressor cells (MDSCs) were found in patients with sepsis; Mo-MDSCs were preferentially expanded in patients with gram-negative sepsis, whereas granulocytic MDSCs (PMN-MDSCs) accumulated in patients with gram-positive sepsis. <br/><br>
<br/><br>
We conclude that the immune response during severe infections shows large inter-individual variations and biomarker guided therapy could be useful in individualised treatment.},
  author       = {Janols, Helena},
  isbn         = {978-91-87651-76-2},
  issn         = {1652-8220},
  keyword      = {immunosuppression,myeloid-derived suppressor cells,T cells,dendritic cells,monocytes,sepsis,Biomarkers},
  language     = {eng},
  pages        = {166},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine, Doctoral Dissertation Series},
  title        = {Biomarkers in sepsis and other severe infections},
  volume       = {2014:50},
  year         = {2014},
}