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Interferon-α coincides with suppressed levels of pentraxin-3 (PTX3) in systemic lupus erythematosus and regulates leucocyte PTX3 in vitro
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0002-2125-2931
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.ORCID iD: 0000-0002-0153-9249
Uppsala University, Sweden.
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2017 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 189, no 1, 83-91 p.Article in journal (Refereed) Published
Abstract [en]

Dysfunctional elimination of cell debris, and the role of opsonins such as pentraxins, is of interest regarding systemic lupus erythematosus (SLE) pathogenesis. Interferon (IFN)- is typically elevated during SLE flares, and inhibits hepatocyte production of the pentraxin C-reactive protein (CRP), partly explaining the poor correlation between CRP levels and SLE disease activity. The extrahepatically produced pentraxin 3 (PTX3) shares waste disposal functions with CRP, but has not been studied extensively in SLE. We analysed serum PTX3 in SLE, and assessed its interference with IFN- in vitro. Serum samples from 243 patients with SLE and 100 blood donors were analysed regarding PTX3. Patient sera were analysed for IFN-, and genotyped for three PTX3 single nucleotide polymorphisms reported previously to associate with PTX3 levels. Stimulated PTX3 release was assessed in the presence or absence of IFN- in blood donor neutrophils and peripheral blood mononuclear cells (PBMC). Serum PTX3 was 44% lower in patients with SLE compared to blood donors (Pamp;lt;00001) and correlated with leucocyte variables. Patients with undetectable IFN- had 29% higher median PTX3 level than patients with detectable IFN- (P=001). PTX3 production by PBMC was inhibited by IFN-, whereas neutrophil degranulation of PTX3 was increased. No differences in PTX3 levels were observed between the SNPs. In conclusion, median serum PTX3 is lower in SLE (especially when IFN- is detectable) compared to blood donors. In addition to its potential consumption during waste disposal, it is plausible that IFN- also attenuates PTX3 by inhibiting synthesis by PBMC and/or exhausting PTX3 storage in neutrophil granules.

Place, publisher, year, edition, pages
WILEY , 2017. Vol. 189, no 1, 83-91 p.
Keyword [en]
biomarkers; interferon-; leucocytes; pentraxin; systemic lupus erythematosus
National Category
Immunology
Identifiers
URN: urn:nbn:se:liu:diva-138881DOI: 10.1111/cei.12957ISI: 000402977200008PubMedID: 28257596OAI: oai:DiVA.org:liu-138881DiVA: diva2:1115957
Note

Funding Agencies|Swedish Society for Medical Research, Region Ostergotland; Swedish Research Council; Swedish Rheumatism Association; Swedish Society of Medicine; Professor Nanna Svartz Foundation; King Gustaf Vs 80-year foundation

Available from: 2017-06-27 Created: 2017-06-27 Last updated: 2017-09-08
In thesis
1. Biomarkers of disease activity and organ damage in systemic lupus erythematosus
Open this publication in new window or tab >>Biomarkers of disease activity and organ damage in systemic lupus erythematosus
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Systemic lupus erythematosus (SLE) is a systemic inflammatory disease. Clinically, the distinction between ongoing inflammation attributed to SLE, and organ damage due to medication or co-morbidities remains challenging. In addition, SLE is a heterogeneous disease where the various disease phenotypes complicate the search for biomarkers that adequately reflect disease activity and/or signs of increasing organ damage. The aim of the thesis was to investigate and evaluate potential new biomarkers of disease activity and/or organ damage in SLE patients.

High mobility group box protein-1 (HMGB1) is a nuclear non-histone protein that can shuttle to the cytoplasm, become secreted extracellularly, and participate in systemic inflammation. Administration of monoclonal anti-HMGB1 antibodies has been reported both to attenuate and intensify disease in animal models of arthritis and lupus. In Paper I of the thesis, circulating anti-HMGB1 was found in 23% of the SLE patients and correlated with disease activity variables. The biological role of these autoantibodies remains to be elucidated.

As a consequence of massive circulating levels of cellular debris and immune complexes, SLE patients have insufficient capacity to remove such material via the reticuloendothelial system. Pentraxin 3 (PTX3) may possibly protect against lupus flares due to classical complement activation, opsonization of apoptotic cells, and cytokine induction. In Paper II, circulating PTX3 was found to be inhibited or exhausted by interferon (IFN)-α, a key cytokine of SLE pathogenesis, and serum levels of PTX3 in SLE patients were inversely related to IFN-α levels. Suppressed PTX3 levels may contribute to a vicious circle resulting in impaired waste clearance, autoantigen exposure and autoantibody production, and sustained disease activity.

Osteopontin (OPN), a protein known to influence cell signaling and apoptosis, has been proposed as a marker of organ damage in pediatric lupus. In a Swedish cross-sectional study, circulating OPN levels were found to be raised in SLE (Paper III). In patients with recent-onset disease, OPN reflected disease activity, while in established disease, OPN appeared to mirror damage accrual and cardiovascular damage. In Paper IV, OPN was instead analyzed in an international longitudinal multi-center study based on patients with recent-onset SLE and follow-up data. OPN turned out to be a poor predictor of organ damage, but significant associations were observed between OPN and disease activity both at disease onset, as well as over 5 years of follow-up.

In conclusion, increased anti-HMGB1 antibody and decreased PTX3 levels could potentially sustain the impaired waste-disposal. Of the molecules analyzed in this thesis, OPN seems to be the best marker of disease activity. Further studies of these proteins may help to better understand SLE pathogenesis and to optimize treatment of patients.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. 55 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1576
National Category
Rheumatology and Autoimmunity Gastroenterology and Hepatology Immunology in the medical area Neurology
Identifiers
urn:nbn:se:liu:diva-140713 (URN)10.3384/diss.diva-140713 (DOI)9789176855096 (ISBN)
Public defence
2017-09-22, Hasselquistsalen, Campus US, Linköping, 09:00 (English)
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Available from: 2017-09-08 Created: 2017-09-08 Last updated: 2017-09-08Bibliographically approved

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