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SLPI and soluble BTLA as immunological markers in severe bacterial infections
Örebro University, School of Medical Sciences.ORCID iD: 0000-0001-7679-7253
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Clinical presentation, and outcome of infections are affected by host-, and etiology- (focus of infection and pathogen) related factors. The immune 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, compared 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 outcome. SLPI was associated with decreased monocytic HLA-DR expression, 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 addressed in future studies.

Place, publisher, year, edition, pages
Örebro: Örebro University , 2020. , p. 82
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 211
Keywords [en]
SLPI, sBTLA, sepsis, bloodstream infection, pneumonia
National Category
General Practice
Identifiers
URN: urn:nbn:se:oru:diva-80161ISBN: 978-91-7529-335-6 (print)OAI: oai:DiVA.org:oru-80161DiVA, id: diva2:1395715
Public defence
2020-05-29, Örebro universitet, Campus USÖ, hörsal C1, Södra Grev Rosengatan 32, Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2020-02-24 Created: 2020-02-24 Last updated: 2020-05-13Bibliographically approved
List of papers
1. Antimicrobial peptide plasma concentrations in patients with community-acquired pneumonia
Open this publication in new window or tab >>Antimicrobial peptide plasma concentrations in patients with community-acquired pneumonia
2013 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 6, p. 432-437Article in journal (Refereed) Published
Abstract [en]

Background: Community-acquired pneumonia (CAP) is a common and potentially life-threatening infection. Innate immunity is the first line of defence, and antimicrobial peptides (AMPs) produced by white blood cells and at epithelial barriers participate by killing microorganisms and neutralizing bacterial toxins. We wanted to investigate whether concentrations of AMPs (1) are increased in CAP, (2) predict the clinical outcome, and (3) differ depending on the causative microbe. Methods: Plasma concentrations of AMPs were measured using an enzyme-linked immunosorbent assay in 89 patients with CAP, 21 patients with non-respiratory tract infections (non-RTI), and 63 healthy control subjects. Results: In subjects with CAP, mean plasma concentrations of secretory leukocyte protease inhibitor (SLPI) and bactericidal/permeability-increasing protein (BPI) were significantly higher than in healthy control subjects (85 vs 45 ng/ml, p < 0.001 and 48 vs 10 ng/ml, p < 0.001, respectively), but less markedly increased in patients with non-RTI (68 ng/ml, p = 0.06 and 41 ng/ml, p = 0.43). LL-37 and human neutrophil peptides 1-3 (HNP 1-3) levels were not increased in subjects with CAP. Levels of BPI and SLPI did not correlate to severity of disease, and AMP levels did not differ depending on the causative agent. Interestingly, male subjects with CAP displayed increased concentrations of SLPI compared to females. This was not observed in subjects with non-RTI and healthy control subjects. Conclusions: Subjects with CAP showed increased plasma concentrations of SLPI and BPI compared to healthy control subjects. The finding of higher SLPI levels in male subjects with CAP implies that there are sex-dependent immunological differences in SLPI turnover.

Keywords
Community-acquired pneumonia, antimicrobial peptides, secretory leukocyte protease inhibitor (SLPI), bactericidal/permeability-increasing protein (BPI)
National Category
Infectious Medicine
Identifiers
urn:nbn:se:oru:diva-56572 (URN)10.3109/00365548.2012.760844 (DOI)000318940400003 ()23317166 (PubMedID)
Available from: 2017-03-20 Created: 2017-03-20 Last updated: 2020-05-04Bibliographically approved
2. Soluble B and T Lymphocyte Attenuator Correlates to Disease Severity in Sepsis and High Levels Are Associated with an Increased Risk of Mortality
Open this publication in new window or tab >>Soluble B and T Lymphocyte Attenuator Correlates to Disease Severity in Sepsis and High Levels Are Associated with an Increased Risk of Mortality
2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, article id e0169176Article in journal (Refereed) Published
Abstract [en]

Introduction and aims: B- and T-lymphocyte Attenuator (BTLA), Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed Death 1 (PD-1) are co-inhibitory receptors that regulate T cell activation. In the present study of ICU-treated patients we measured plasma concentrations of their soluble isoforms, with the aim to evaluate their potential as sepsis biomarkers and utility as prognostic indicators.

Methods: 101 patients with sepsis, 28 patients with non-infectious critical illness (ICU controls) and 31 blood donors (healthy controls, HC) were included in the study. Plasma concentrations of soluble BTLA (sBTLA), CTLA-4 (sCTLA-4) and PD-1 (sPD-1) were measured with ELISA in serial blood samples. Comparisons were made with Mann-Whitney U test and correlations were assessed with Spearman's Rank correlation test. Cox proportional hazard models, with sBTLA and sPD-1 as fixed and sBTLA as time-varying covariates, were used to determine association with 28-day mortality.

Results: sBTLA levels were significantly higher in the sepsis cohort (median 14 ng/mL, IQR 8-29) compared to ICU controls (9 ng/mL, IQR 5-26, p = 0.048) and HC (2.9 ng/mL, IQR 0.9-9.1, p<0.01), and correlated to SOFA score. sBTLA levels were higher in 28 day sepsis non-survivors than in survivors (baseline median 28 ng/mL, IQR 13-41 vs 13 ng/mL, IQR 8-23, p = 0.04). After adjustment for age and comorbidities, the relative risk of 28 day mortality was nearly 5-fold higher in sepsis patients with a baseline sBTLA > 21 ng/mL, compared to those with a level below this threshold. sBTLA was even more associated with mortality in the time-varying analysis. sPD-1 levels were lower in the sepsis cohort compared to HC but not compared to ICU controls and were not associated with mortality. sCTLA-4 was detectable in only one subject.

Conclusion: Plasma concentrations of soluble BTLA were increased early in sepsis/septic shock and correlated to severity of disease. A baseline concentration >21ng/mL was associated with a poor prognosis.

Place, publisher, year, edition, pages
San Francisco: Public Library of Science, 2017
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:oru:diva-54384 (URN)10.1371/journal.pone.0169176 (DOI)000391639100023 ()28056053 (PubMedID)2-s2.0-85008970210 (Scopus ID)
Note

Funding Agencies:

Research Committee Region Örebro County

Nyckelfonden Region Örebro County

Olle Engkvist fund

Signe and Olof Wallenius trust

ALF

Karolinska University Hospital, Huddinge, Research Foundation

Available from: 2017-02-07 Created: 2017-01-10 Last updated: 2020-05-04Bibliographically approved
3. Plasma concentrations of secretory leukocyte protease inhibitor (SLPI) differ depending on etiology and severity in community-onset bloodstream infection
Open this publication in new window or tab >>Plasma concentrations of secretory leukocyte protease inhibitor (SLPI) differ depending on etiology and severity in community-onset bloodstream infection
Show others...
2019 (English)In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 38, no 8, p. 1425-1434Article in journal (Refereed) Published
Abstract [en]

The severity of bloodstream infections (BSI) depends on pathogen, source, and host factors. Secretory leukocyte protease inhibitor (SLPI) counteracts tissue damage, balances inflammation, and is increased in pneumonia and sepsis. We aimed to evaluate whether SLPI production differs depending on etiology, disease severity, and sex in BSI and to correlate SLPI with markers of inflammation and immunosuppression. Of the adult patients with BSI, 109 were included and sampled repeatedly, from hospital admission through day 28. Controls (blood donors) were sampled twice. SLPI in plasma was measured with enzyme-linked immunosorbent assay (ELISA) technique. Streptococcus pneumoniae and Staphylococcus aureus etiology were associated with higher SLPI than Escherichia coli on days 1-2 and 3. On day 1-2, subjects with sepsis had higher SLPI concentrations than those with non-septic BSI. Pneumonia was associated with higher SLPI than a non-pulmonary source of infection. SLPI co-varied with inflammatory markers. SLPI concentrations did not differ with regard to sex in the full cohort, but men with pneumonia had higher SLPI than women on day 1-2. S. pneumoniae and S. aureus BSI were associated with higher SLPI, when compared to E. coli. Severity and pneumonia, as well as male sex in the pneumonia sub-cohort, were factors independently associated with higher SLPI.

Place, publisher, year, edition, pages
Springer, 2019
Keywords
Bloodstream infection, SLPI, Secretory leukocyte protease inhibitor, Sepsis, Sepsis immunology
National Category
Infectious Medicine
Identifiers
urn:nbn:se:oru:diva-74324 (URN)10.1007/s10096-019-03567-2 (DOI)000476492200005 ()31089838 (PubMedID)2-s2.0-85065985128 (Scopus ID)
Funder
Stiftelsen Olle Engkvist Byggmästare
Note

Funding Agencies:

Research Committee of Region Örebro County

Nyckelfonden Region Orebro County

Signe and Olof Wallenius trust

ALF project funding

Available from: 2019-05-20 Created: 2019-05-20 Last updated: 2020-05-04Bibliographically approved
4. Sustained elevation of soluble B- and T- lymphocyte attenuator predicts long-term mortality in patients with bacteremia and sepsis
Open this publication in new window or tab >>Sustained elevation of soluble B- and T- lymphocyte attenuator predicts long-term mortality in patients with bacteremia and sepsis
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Infectious Medicine
Identifiers
urn:nbn:se:oru:diva-81440 (URN)
Available from: 2020-05-04 Created: 2020-05-04 Last updated: 2020-05-04Bibliographically approved

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