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SLPI and Soluble BTLA As Immunological Markers in Severe Bacterial Infections

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SLPI and Soluble BTLA As Immunological Markers in Severe Bacterial Infections SLPI and soluble BTLA as immunological markers in severe bacterial infections To my family Örebro Studies in Medicine 211 ANNA LANGE SLPI and soluble BTLA as immunological markers in severe bacterial infections © Anna Lange, 2020 Title: SLPI and soluble BTLA as immunological markers in severe bacterial infections Publisher: Örebro University 2020 www.oru.se/publikationer Print: Örebro University, Repro 04/2020 ISSN 1652-4063 ISBN 978-91-7529-335-6 Abstract Anna Lange (2020): SLPI and soluble BTLA as immunological markers in severe bacterial infections. Örebro Studies in Medicine 211. Clinical presentation, and outcome of infections are affected by host-, and etiology- (focus of infection and pathogen) related factors. The im- mune response is controlled by a network of regulating pathways. This thesis focuses on Secretory Leukocyte Protease Inhibitor (SLPI), a protease inhibitor with anti-inflammatory properties, and the previously non-studied soluble isoform of B and T lymphocyte attenuator (sBTLA), a membrane-associated regulatory protein. Plasma concentrations of SLPI and sBTLA were assessed in relation to etiology, severity, mortality, and markers of inflammation and immunosuppression, in i) community- acquired pneumonia (CAP) (SLPI), ii) intensive care unit (ICU) treated severe sepsis and septic shock (sBTLA), and iii) dynamically in BSI (SLPI and sBTLA). Main findings were: higher expression of SLPI in pneumonia, com- pared to other sources, higher initial concentrations in Streptococcus pneumoniae, and Staphylococcus aureus BSI, compared to Escherichia coli BSI, and higher SLPI concentrations in sepsis compared to non-septic BSI. Interestingly, men with pneumonia had higher plasma levels of SLPI, both in CAP and BSI. Likewise, sBTLA was associated with severity, but preferentially at higher organ failure scores. High sBTLA was associated with increased risk of early death (28 days) in ICU-treated septic patients, and with mortality at 90 days and one year in BSI. In particular, failure to normalize sBTLA on day 7, was indicative of worse long-term out- come. SLPI was associated with decreased monocytic HLA-DR expres- sion, and sBTLA with decreased lymphocyte count, which might indicate a connection to sepsis-associated immunosuppression. In conclusion, SLPI and sBTLA show association with severity, and markers of immune dysfunction, in sepsis and BSI. SLPI differs depending on etiology, while sBTLA may have prognostic implications. Our results propose that the pathobiological role of sBTLA, and the possible utility of SLPI and sBTLA in sepsis immune-profiling, should be further ad- dressed in future studies. Keywords: SLPI, sBTLA, sepsis, bloodstream infection, pneumonia Anna Lange, School of health and Medical Sciences, Faculty of Medicine and Health, Örebro University, SE-70182 Örebro, Sweden, [email protected] Table of Contents LIST OF PAPERS .................................................................................... 11 ABBREVIATIONS .................................................................................. 12 INTRODUCTION .................................................................................. 13 Sepsis from a historical perspective ......................................................... 13 Sepsis pathophysiology and clinical features ........................................... 14 Sepsis definitions ..................................................................................... 14 Sepsis epidemiology ................................................................................. 16 Sepsis therapy .......................................................................................... 16 Protective immune responses: innate immunity ....................................... 17 Sensing danger .................................................................................... 17 Macrophages ....................................................................................... 19 Neutrophils ......................................................................................... 20 NK cells .............................................................................................. 22 Soluble factors..................................................................................... 22 Cytokines ............................................................................................ 22 Complement ........................................................................................ 23 Antimicrobial peptides and proteins.................................................... 23 Dendritic cells ..................................................................................... 24 Protective immune responses: adaptive immunity ................................... 25 T cells .................................................................................................. 25 B cells .................................................................................................. 26 Co-signaling proteins in regulation of immune responses.................... 27 Dysregulated immune response in sepsis ................................................. 28 Therapies targeting immune dysregulation in sepsis ................................ 30 Cortisone ............................................................................................ 30 Intravenous immunoglobulin (IVIg) .................................................... 31 Blood purification ............................................................................... 31 Granulocyte-macrophage colony stimulating factor ............................ 31 IFN-γ .................................................................................................. 32 IL-7 ..................................................................................................... 32 Checkpoint inhibition ......................................................................... 32 Secretory leukocyte protease inhibitor (SLPI) .......................................... 33 BTLA ...................................................................................................... 35 AIMS ....................................................................................................... 37 SUBJECTS AND METHODS ................................................................. 38 Patients .................................................................................................... 38 Paper I ................................................................................................. 38 Paper II ............................................................................................... 38 ANNA LANGE SLPI and soluble BTLA as immunological markers 9 Papers III and IV ................................................................................. 39 Storage of plasma .................................................................................... 39 Enzyme-linked Immunosorbent assay (ELISA) ........................................ 40 SLPI and sBTLA detection ....................................................................... 41 Blood and other cultures ......................................................................... 42 Clinical data ............................................................................................ 42 Comorbidity and severity scores .............................................................. 42 Statistics .................................................................................................. 43 Group comparisons ............................................................................. 43 Associations and correlations .............................................................. 44 Confounding ....................................................................................... 44 Missing data ........................................................................................ 44 Longitudinal data analysis ................................................................... 44 Mortality analyses ............................................................................... 45 RESULTS ................................................................................................ 46 SLPI ......................................................................................................... 46 CAP and controls, and in relation to source of infection ..................... 46 SLPI and bacterial etiology in BSI ........................................................ 47 Severity ................................................................................................ 48 Sex-related differences in SLPI expression ........................................... 49 Association to other biomarkers .......................................................... 50 sBTLA ..................................................................................................... 51 Sepsis, ICU controls and healthy controls ........................................... 51 sBTLA and severity ............................................................................. 52 sBTLA and mortality ........................................................................... 52 Association to other biomarkers .......................................................... 53 ETHICAL CONSIDERATIONS ............................................................. 54 DISCUSSION .......................................................................................... 55 CONCLUSIONS ....................................................................................
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