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Soluble B and T Lymphocyte Attenuator Correlates to Disease Severity in Sepsis and High Levels Are Associated with an Increased Risk of Mortality
Örebro University, School of Medical Sciences. Department of Infectious Diseases.
Division of Infectious Diseases and Center for Infectious Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden.
School of Medical Sciences, Örebro University, Örebro, Sweden . (Clinical Epidemiology and Biostatistics)
Örebro University, School of Medical Sciences. Department of Microbiology and Immunology, School of Medical Sciences, Örebro University, Örebro, Sweden.
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. Vol. 12, no 1, article id e0169176
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:oru:diva-54384DOI: 10.1371/journal.pone.0169176ISI: 000391639100023PubMedID: 28056053Scopus ID: 2-s2.0-85008970210OAI: oai:DiVA.org:oru-54384DiVA, id: diva2:1072082
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
In thesis
1. SLPI and soluble BTLA as immunological markers in severe bacterial infections
Open this publication in new window or tab >>SLPI and soluble BTLA as immunological markers in severe bacterial infections
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
SLPI, sBTLA, sepsis, bloodstream infection, pneumonia
National Category
General Practice
Identifiers
urn:nbn:se:oru:diva-80161 (URN)978-91-7529-335-6 (ISBN)
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

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