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Biomarkers of disease activity and organ damage in systemic lupus erythematosus
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
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. , p. 55
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: urn:nbn:se:liu:diva-140713DOI: 10.3384/diss.diva-140713ISBN: 9789176855096 (print)OAI: oai:DiVA.org:liu-140713DiVA, id: diva2:1139641
Public defence
2017-09-22, Hasselquistsalen, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2017-09-08 Created: 2017-09-08 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Antibodies against High Mobility Group Box protein-1 (HMGB1) versus other anti-nuclear antibody fine-specificities and disease activity in systemic lupus erythematosus
Open this publication in new window or tab >>Antibodies against High Mobility Group Box protein-1 (HMGB1) versus other anti-nuclear antibody fine-specificities and disease activity in systemic lupus erythematosus
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2015 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, no 338Article in journal (Refereed) Published
Abstract [en]

Introduction: The non-histone nuclear protein high mobility group box protein-1 (HMGB1) is typically associated with nucleosomes, but may shuttle between the nucleus and the cytoplasm, and under some conditions also be released extracellularly and participate in systemic inflammation. Monoclonal HMGB1-targeting antibodies can ameliorate murine polyarthritis and lupus-like disease. Interestingly, autoantibodies against HMGB1 have also been described in patients with systemic lupus erythematosus (SLE), but their clinical implications remain elusive. The main aims of this study were to detect serum anti-HMGB1 antibodies in patients with SLE and relate them to other types of antinuclear antibodies (ANA), and to disease activity. Methods: 188 Swedish SLE patients meeting the 1982 American College of Rheumatology classification criteria and/or the 2012 Systemic Lupus International Collaborating Clinics classification criteria participated in the study. Anti-HMGB1 antibody levels were analysed in patient and control (n = 112) sera by an in-house ELISA using recombinant histidine-tagged HMGB1. SLE sera were also analysed for ANA by immunofluorescence (IF) microscopy (IF-ANA) using fixed HEp-2 cells, and by a line-blot assay for antigen fine-specificities. To quantify antibodies to double-stranded DNA, a fluoroenzyme-immunoassay was employed. Results: At inclusion, 23 % of the SLE patients were anti-HMGB1 antibody positive compared to 5 % of the controls. Anti-HMGB1 antibodies occurred in 49 % of the IF-ANA positive SLE patients, and in 34 % of IF-ANA negative cases (p = 0.004). Levels of anti-HMGB1 antibodies correlated with anti-dsDNA antibody levels (r = 0.49; p less than 0.001). Significant, but less pronounced correlations were found regarding anti-HMGB1 and SLE disease activity index (SLEDAI-2K: r = 0.15; p = 0.04), classical complement function (r = -0.24; p = 0.002) and complement protein C4 (r = -0.23; p = 0.002). Average anti-HMGB1 antibody levels were significantly higher among patients with homogenous +/- other IF-ANA staining patterns (median 180 AU) compared to IF-ANA negative cases (median 83 AU) (p = 0.004). Rabbit anti-HMGB1 antibodies gave rise to cytoplasmic, but not nuclear, staining of HEp-2 cells. Conclusions: We confirm that anti-HMGB1 antibodies are common in SLE and correlate with disease activity variables. Although anti-HMGB1 antibodies measured by ELISA often coincide with nuclear IF-ANA staining, our results indicate that anti-HMGB1 antibodies do not give rise to nuclear staining of the predominantly used commercial HEp-2 cell slides.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD, 2015
Keywords
HMGB1; Autoantibodies; SLE; Antinuclear antibodies; Inflammation; Clinical phenotype; Complement proteins
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-123521 (URN)10.1186/s13075-015-0856-2 (DOI)000365252900001 ()26596890 (PubMedID)
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: 2015-12-22 Created: 2015-12-21 Last updated: 2018-01-10
2. Interferon-α coincides with suppressed levels of pentraxin-3 (PTX3) in systemic lupus erythematosus and regulates leucocyte PTX3 in vitro
Open this publication in new window or tab >>Interferon-α coincides with suppressed levels of pentraxin-3 (PTX3) in systemic lupus erythematosus and regulates leucocyte PTX3 in vitro
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2017 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 189, no 1, p. 83-91Article 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
Keywords
biomarkers; interferon-; leucocytes; pentraxin; systemic lupus erythematosus
National Category
Immunology
Identifiers
urn:nbn:se:liu:diva-138881 (URN)10.1111/cei.12957 (DOI)000402977200008 ()28257596 (PubMedID)
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
3. Osteopontin is associated with disease severity and antiphospholipid syndrome in well characterised Swedish cases of SLE
Open this publication in new window or tab >>Osteopontin is associated with disease severity and antiphospholipid syndrome in well characterised Swedish cases of SLE
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2017 (English)In: Lupus Science and Medicine, ISSN 2053-8790, E-ISSN 1625-9823, Vol. 4, no 1, p. 7article id 000225Article in journal (Refereed) Published
Abstract [en]

Objective The variety of disease phenotypes among patients with SLE challenges the identification of new biomarkers reflecting disease activity and/or organ damage. Osteopontin (OPN) is an extracellular matrix protein with immunomodulating properties. Although raised levels have been reported, the pathogenic implications and clinical utility of OPN as a biomarker in SLE are far from clear. Thus, the aim of this study was to characterise OPN in SLE.

Methods Sera from 240 well-characterised adult SLE cases classified according to the American College of Rheumatology (ACR) and/or the Systemic Lupus International Collaborating Clinics (SLICC) criteria, and 240 population-based controls were immunoassayed for OPN. The SLE Disease Activity Index 2000 (SLEDAI-2K) was used to evaluate disease activity and the SLICC/ACR Damage Index (SDI) to detect damage accrual.

Results Serum OPN levels were in average raised fourfold in SLE cases compared with the controls (p<0.0001). OPN correlated with SLEDAI-2K, especially in patients with a disease duration of <12 months (r=0.666, p=0.028). OPN was highly associated with SDI (p<0.0001), especially in the renal (p<0.0001), cardiovascular (p<0.0001) and malignancy (p=0.012) domains. Finally, OPN associated with coherent antiphospholipid syndrome (APS; p=0.009), and both clinical and laboratory criteria of APS had significant positive impact on OPN levels.

Conclusions In this cross-sectional study, circulating OPN correlates with disease activity in recent-onset SLE, reflects global organ damage and associates with APS. Longitudinal studies to dissect whether serum OPN also precedes and predicts future organ damage are most warranted.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2017. p. 7
National Category
Rheumatology and Autoimmunity Neurology Clinical Laboratory Medicine Cardiac and Cardiovascular Systems Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-140711 (URN)10.1136/lupus-2017-000225 (DOI)
Available from: 2017-09-08 Created: 2017-09-08 Last updated: 2017-09-08Bibliographically approved

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