Serum Levels of Pentraxin3 and Interlukin36 in Patients with Systemic Lupus and their Relation to Disease Activity.
Ismail Sahar M,Abd-ELWahab Marwa K,Mohamed Maha S
The Egyptian journal of immunology
Pentraxin3 (PTX3) plays an important role in inflammation, immunity, and atherosclerosis. Serum PTX3 has drawn attention as a marker that respond to local inflammation. Interleukin 36 (IL-36) is a novel inflammatory member of the IL-1 cytokine family comprising three different isoforms IL36α, IL-36β and IL-36γ. The objective of this work was to evaluate the levels of PTX3 and IL36α and to determine their relationships to disease activity in patients with systemic lupus erythematosus (SLE). Forty patients with SLE diagnosed according to SLECCA/ACR2012 criteria were allocated to the study, along with 20, age and sex matched normal control subjects. SLE patients included 20 patients with active disease, each having SLEADI score over 6 points and the other 20 patients, each of them had SLEADI score less than 6 points. Levels of serum PTX3 and IL36α was measured by quantitative sandwich enzyme immunoassay technique. There was a significant increase in the serum pentraxin3 and IL36α in SLE patients (P < 0.01) compared to normal control subjects. The significance increased in serum levels of PTX3 and IL-36α, was noted in active (P=0.000 for both) and inactive SLE patients (P=0.003 and P=0.001, respectively), compared to normal control subjects. Moreover, the active SLE patients had significant increase in the serum levels of PTX3 and IL36α (P < 0.01 for both) compared to the inactive group of patients. A significant positive correlation between each of PTX3 and IL36α, and SLEADI score (P=0.008 and P=0.024, respectively) in SLE patients was observed. In conclusion, PTX3and IL36α serum levels are increased in SLE patients when compared to normal control subjects, correlated positively with SLEDAI score and thus could be used as markers of disease activity.
IgG anti-pentraxin 3 antibodies in systemic lupus erythematosus.
Bassi N,Ghirardello A,Blank M,Zampieri S,Sarzi-Puttini P,Mantovani A,Shoenfeld Y,Doria A
Annals of the rheumatic diseases
OBJECTIVE:To evaluate the prevalence and correlates of anti-pentraxin 3 (PTX3) antibodies in systemic lupus erythematosus (SLE). METHODS:Serum samples from 130 patients with SLE, 130 age- and sex-matched healthy subjects and 130 patients with other autoimmune rheumatic diseases (oARD) were analysed by home-made ELISAs using as substrate human recombinant PTX3 and two peptides, PTX3_1 and PTX3_2, obtained from the complete protein, identified as potential antigenic sites using the Lasergene DNA program (DNA Star). Inhibition tests were performed to evaluate potential interferences between bovine serum albumin or C-reactive protein and anti-PTX3 or anti-PTX3 peptides, and between antigens and antibodies. Statistical analysis was performed using receiving operating characteristics curves, the Fisher exact test, two-tailed t test and Pearson correlations. RESULTS:Patients with SLE had higher levels and prevalence of anti-PTX3, anti-PTX3_1 and anti-PTX3_2 antibodies than patients with oARD or healthy controls (p<0.001 for all). No differences were observed between patients with oARD and healthy controls. A correlation was found between anti-PTX3 and anti-PTX3_2 antibodies (r=0.615, p<0.001). No association was observed between these antibodies and disease activity. Univariate and multivariate analyses showed that anti-PTX3 and anti-PTX3_2 antibody levels and prevalence were higher in patients without glomerulonephritis and in patients positive for antiphospholipid antibody. All inhibition tests were negative apart from PTX3 against anti-PTX3 antibody or, to a lesser extent, against anti-PTX3_2 antibody, and PTX3_2 against anti-PTX3_2 antibody, all in a dose-dependent manner. CONCLUSIONS:Anti-PTX3 antibodies are significantly prevalent in patients with SLE where they might provide protection from renal involvement. The antigenic properties of PTX3_2 peptide are similar to those of PTX3, suggesting its potential use in further analyses.
[Pentraxins - their importance in pathogenesis of systemic lupus erythematosus].
Jakuszko Katarzyna,Krajewska Magdalena,Weyde Wacław,Grzegorczyk Katarzyna,Klinger Marian
Postepy higieny i medycyny doswiadczalnej (Online)
Systemic lupus erythematosus (SLE) is an autoimmune disease, whose main pathomechanism is attributed to the disturbed apoptotic process and dysfunction of the immune cells, leading to the accumulation of undegraded cellular matrix. This paper presents molecules such as complement components, pentraxins, and collectins, which are involved in the opsonization and removal of cellular material, and shows how deficiencies in these processes may contribute to SLE development and progression. Many reports indicate the specific role of the pentraxins (C-reactive protein, serum amyloid P, pentraxin 3), which, due to enhancing the phagocytosis of damaged cells and inducing the classical pathway of complement activation, participate in masking antigens from the immune system. The influence of CRP on inhibition of development and progression of kidney disease and decreasing the immune activity markers was demonstrated on the basis of research in experimental, mouse models of SLE. The decreased pentraxin response described in systemic lupus erythematosus patients, despite the presence of high levels of interleukin-6 and other markers of disease activity, is still unclear. Anti-mCRP antibodies bind CRP to form immune complexes, which are deposited in glomeruli and may initiate or exacerbate inflammation. In the literature, the correlation between raised levels of anti-CRP antibodies and clinical and immunological activity of lupus nephritis was proved. It shows their importance as a factor determining the severity of the disease and response to treatment. Novel studies suggest that the low CRP response in SLE is due to interferon-α inhibition of gene expression and CRP synthesis. This suggests that therapeutic targets in systemic lupus erythematosus should also be based on inhibiting the synthesis of interferon-α .
Circulating Pentraxin3-Specific B Cells Are Decreased in Lupus Nephritis.
Gatto Mariele,Wiedemann Annika,Nomovi Nadja,Reiter Karin,Schrezenmeier Eva,Rose Thomas,Szelinski Franziska,Lino Andreia C,Valentino Sonia,Ghirardello Anna,Dörner Thomas,Doria Andrea
Frontiers in immunology
Pentraxin3 (PTX3) is overexpressed in kidneys of patients developing lupus nephritis (LN). Active LN is associated with reduced anti-PTX3 antibodies. However, abnormalities of B cell differentiation against PTX3 have not been characterized in systemic lupus erythematosus (SLE). Characterization of PTX3-specific (PTX3) B cells in peripheral blood of SLE patients with or without LN and healthy donors (HD). SLE patients without LN, biopsy-proven LN and matched HD were analyzed. Active LN was defined as proteinuria>0.5 g/day or CrCl<60 ml/min/1.73 m with active urinary sediment. Peripheral B cells were analyzed for direct PTX3 binding by flow cytometry using PTX3 labeled with cyanine 5 (Cy5) and phycoerythrin (PE). Initially, a flow cytometry based assay to identify PTX3 B cells was developed by demonstrating simultaneous binding of PTX3-Cy5 and PTX3-PE. Specificity of B cells was validated by blocking experiments using unlabeled PTX3. We could identify circulating PTX3 B-cells in HD and patients. Notably, LN patients showed a significantly diminished number of PTX3 B cells (SLE vs. LN = 0.033; HD vs. LN = 0.008). This decrease was identified in naïve and memory B cell compartments (naïve: SLE vs. LN = 0.028; HD vs. LN = 0.0001; memory: SLE vs. LN = 0.038, HD vs. LN = 0.011). Decreased PTX3 B cells in LN within the naïve and memory compartment suggest their negative selection at early stages of B cell development potentially related to a decreased regulatory function. PTX3 B cells could candidate for autoantigen-defined regulatory B cells as a striking abnormality of LN patients.
Serum levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and pentraxin 3 (PTX3) as markers of infection in febrile patients with systemic lupus erythematosus.
Kim J,Koh J K,Lee E Y,Park J A,Kim H A,Lee E B,Garlanda C,Cotena A,Song Y W
Clinical and experimental rheumatology
OBJECTIVE:To investigate the role of sTREM-1 and PTX3 as markers of infection in febrile patients with SLE. METHODS:In febrile (body temperature > or =38 degrees C) patients with SLE, blood samples of day 0, 1, 2, and 14 after presentation were drawn and relevant clinical data were collected. The patients were allocated to an infection group (n=19) or disease flare group (n=14). Serum levels of sTREM-1 and PTX3 were measured by ELISA using the serum samples of SLE patients and age- and sex-matched healthy controls (n=31). RESULTS:A total of 33 febrile episodes occurred in 32 SLE patients (19 infections, 14 flares) were studied. sTREM-1 levels on day 0 were significantly higher in the infection group than in the flare group (109.9 pg/ml (median) vs. 48.0 pg/ml, p=0.002), but PTX3 levels were similar in these two groups. The difference of sTREM-1 levels between infection group and flare group was persistent on day 1 and 2 (day 1, p=0.007; day 2, p=0.034). The highest diagnostic value (sensitivity=1.0, specificity=0.664) of sTREM-1 was obtained at the threshold value of 53.2 pg/mL. CONCLUSION:Serum sTREM-1 levels were significantly higher in the infection group than in the flare group of febrile SLE patients. Our findings suggest that serum sTREM-1 levels could be used to determine whether SLE patients have contracted an infection.
Anti-pentraxin 3 auto-antibodies might be protective in lupus nephritis: a large cohort study.
Yuan Mo,Tan Ying,Pang Yun,Li Yong-Zhe,Song Yan,Yu Feng,Zhao Ming-Hui
OBJECTIVES:Anti-pentraxin 3 (PTX3) auto-antibodies were found to be associated with the absence of renal involvement in systemic lupus erythematosus (SLE). This study is to investigate the prevalence of anti-PTX3 auto-antibodies and their clinical significance based on a large Chinese lupus nephritis cohort. METHODS:One hundred and ninety-six active lupus nephritis patients, 150 SLE patients without clinical renal involvement, and 100 healthy controls were enrolled. Serum anti-PTX3 auto-antibodies and PTX3 levels were screened by enzyme-linked immunosorbent assay (ELISA). The associations between anti-PTX3 auto-antibodies and clinicopathological parameters in lupus nephritis were further analyzed. RESULTS:Anti-PTX3 auto-antibodies were less prevalent in active lupus nephritis patients compared with SLE without renal involvement (19.4% (38/196) versus 40.7% (61/150), p < .001). The serum levels of anti-PTX3 auto-antibodies were negatively correlated with proteinuria in lupus nephritis (r = -.143, p = .047). The levels of proteinuria, serum creatinine, and the prevalence of thrombotic microangiopathy were significantly higher in patients with higher PTX3 levels (≥3.207 ng/ml) and without anti-PTX3 auto-antibodies compared with patients with lower PTX3 levels (<3.207 ng/ml) and with anti-PTX3 auto-antibodies (4.79 (3.39-8.28) versus 3.95 (1.78-7.0), p = .03; 168.84 ± 153.63 versus 101.44 ± 47.36, p = .01; 34.1% (14/41) versus 0% (0/9), p = .04; respectively). CONCLUSION:Anti-PTX3 auto-antibodies were less prevalent in active lupus nephritis patients compared with SLE without renal involvement and associated with less severe renal damage, especially with the combined evaluation of serum PTX3 levels.
PTX3, Anti-PTX3, and Anti-C1q Autoantibodies in Lupus Glomerulonephritis.
Bassi Nicola,Del Prete Dorella,Ghirardello Anna,Gatto Mariele,Ceol Monica,Zen Margherita,Bettio Silvano,Mantovani Alberto,Iaccarino Luca,Punzi Leonardo,Doria Andrea
Clinical reviews in allergy & immunology
Pentraxin 3 (PTX3) is an acute-phase protein involved in C1q clearance. The presence of anti-C1q and the absence of anti-PTX3 antibodies were associated with lupus glomerulonephritis (LGLN). Our aim was to assess soluble and kidney-expressed PTX3 and their relationships with anti-C1q and anti-PTX3 antibodies in LGLN. Serum PTX3, anti-C1q, anti-dsDNA, and anti-PTX3 antibodies were tested in 130 systemic lupus erythematosus (SLE) patients, 130 healthy and 127 disease controls. Twenty-nine renal biopsies from SLE patients were analyzed and PTX3 immunostaining was quantified by morphometric analysis. Parametric and nonparametric statistics were performed. PTX3 serum levels were lower in SLE versus controls, but they were correlated with proteinuria in LGLN patients (p = 0.001). LGLN patients had higher anti-C1q and lower anti-PTX3 antibody levels than those without (p < 0.0001). LGLN was more prevalent in anti-C1q(+)/anti-PTX3(-) than in anti-C1q(+)/anti-PTX3(+) patients (p < 0.001). No LGLN was observed in anti-C1q(-)/anti-PTX3(+) patients. PTX3 was expressed in glomeruli and renal interstitium. Renal PTX3 was correlated with proteinuria (p = 0.024) and interstitial fibrosis (p = 0.023). PTX3 staining and fibrosis were higher in anti-PTX3(-) than anti-PTX3(+) patients. In conclusion, PTX3 is expressed in glomeruli of LGLN patients, primarily in anti-PTX3(-) patients, where it is correlated with renal fibrosis. Anti-C1q/anti-PTX3 antibody profile seems to be useful in LGLN assessment.
Pentraxin 3 is associated with disease activity but not atherosclerosis in patients with systemic lupus erythematosus.
Shimada Yuki,Asanuma Yu Funakubo,Yokota Kazuhiro,Yoshida Yoshihiro,Kajiyama Hiroshi,Sato Kojiro,Akiyama Yuji,Mimura Toshihide
OBJECTIVES:Pentraxin 3 (PTX3) plays an important role in inflammation, immunity, and atherosclerosis. Plasma PTX3 level has drawn attention as a marker that responds to local inflammation. Systemic lupus erythematosus (SLE), a chronic inflammatory disorder which can affect multiple organs, develops atherosclerosis prematurely. We examined the hypotheses that the concentration of plasma PTX3 increases in patients with SLE and that PTX3 is associated with the disease activity and premature atherosclerosis. METHODS:Plasma PTX3 concentrations were measured in 65 patients with SLE and 53 control subjects. The patients were also evaluated with respect to their clinical characteristics, disease activity indices, and corticosteroid therapy. We performed carotid ultrasonography to measure subclinical atherosclerosis in patients with SLE. RESULTS:Plasma PTX3 concentration of the SLE patients was significantly higher than that of the healthy controls (median 3.9 vs. 2.0 ng/mL, p < 0.001). In patients with SLE, PTX3 concentrations were correlated with SLEDAI (p = 0.011), BILAG index (p < 0.001), C-reactive protein (p < 0.001), anemia (p = 0.020), hypoalbuminemia (p = 0.022), and daily dose of prednisolone (p = 0.008) after adjustment for age and sex. PTX3 was not associated with disease duration, anti-ds DNA antibody, CH50, or carotid atherosclerosis. CONCLUSIONS:Patients with SLE have increased concentrations of PTX3 compared with control subjects. PTX3 was significantly associated with disease activity but not with carotid atherosclerosis.
Lack of the long pentraxin PTX3 promotes autoimmune lung disease but not glomerulonephritis in murine systemic lupus erythematosus.
Lech Maciej,Römmele Christoph,Kulkarni Onkar P,Susanti Heni Eka,Migliorini Adriana,Garlanda Cecilia,Mantovani Alberto,Anders Hans-Joachim
The long pentraxin PTX3 has multiple roles in innate immunity. For example, PTX3 regulates C1q binding to pathogens and dead cells and regulates their uptake by phagocytes. It also inhibits P-selectin-mediated recruitment of leukocytes. Both of these mechanisms are known to be involved in autoimmunity and autoimmune tissue injury, e.g. in systemic lupus erythematosus, but a contribution of PTX3 is hypothetical. To evaluate a potential immunoregulatory role of PTX3 in autoimmunity we crossed Ptx3-deficient mice with Fas-deficient (lpr) C57BL/6 (B6) mice with mild lupus-like autoimmunity. PTX3 was found to be increasingly expressed in kidneys and lungs of B6lpr along disease progression. Lack of PTX3 impaired the phagocytic uptake of apoptotic T cells into peritoneal macrophages and selectively expanded CD4/CD8 double negative T cells while other immune cell subsets and lupus autoantibody production remained unaffected. Lack of PTX3 also aggravated autoimmune lung disease, i.e. peribronchial and perivascular CD3+ T cell and macrophage infiltrates of B6lpr mice. In contrast, histomorphological and functional parameters of lupus nephritis remained unaffected by the Ptx3 genotype. Together, PTX3 specifically suppresses autoimmune lung disease that is associated with systemic lupus erythematosus. Vice versa, loss-of-function mutations in the Ptx3 gene might represent a genetic risk factor for pulmonary (but not renal) manifestations of systemic lupus or other autoimmune diseases.
Pentraxin 3 is useful to differentiate infections from flares in patients with systemic lupus erythematosus who present systemic inflammatory response.
Aragón C C,Nieto-Aristizábal I,Ríos-Serna L J,Barrera M C,Naranjo-Escobar J,Posso-Osorio I,Lara-Erazo V,Leib P,Moreno-Angarita A,Aguirre-Valencia D,Echeverri A,Cañas C A,Tobón G J
Circulating pentraxin-3 levels in patients with systemic lupus erythematosus: a meta-analysis.
Wu Qian,Guan Shi-Yang,Dan Yi-Lin,Zhao Chan-Na,Mao Yan-Mei,Liu Li-Na,Li Xiao-Mei,Wang De-Guang,Pan Hai-Feng
Biomarkers in medicine
An existing meta-analysis have investigated the PTX3 levels in systemic lupus erythematosus (SLE) patients, but the number of studies has increased since 2015. We performed an updated meta-analysis to derive a more accurate estimation. The related literature was systematically searched in PubMed, Embase and The Cochrane Library database (up to 28 February, 2019). SLE patients had significantly higher PTX3 levels than controls (pooled SMD = 0.48; 95% CI: 0.11-0.84). Subgroup analyses indicated SLE patients from non-Caucasian population, with age ≥45 years, SLE disease activity index (SLEDAI) ≥10 and plasma samples had higher PTX3 levels. Circulating PTX3 levels are increased in SLE patients, and affected by age, ethnicity, SLEDAI and sample type.
Pentraxin 3 as a biomarker of local inflammatory response to vascular injury in systemic lupus erythematosus.
Cieślik Paweł,Hrycek Antoni
Systemic lupus erythematosus (SLE) is an autoimmune disorder with organ injury related to vasculitis. Inflammation of blood vessels results from auto-immunological activation of endothelial cells. The pentraxin 3 (PTX3), might act as an indicator of vasculitides in many diseases. The aim of this study was to determine whether PTX3 might be useful as a marker of vascular injury in SLE. This study was carried out in a group of 56 SLE women, and in the 28 female volunteers control group. All participants' plasma and serum samples were collected to estimate concentrations (ELISA) of PTX3, soluble thrombomodulin, soluble E-selectin (sE-selectin), soluble P-selectin (sP-selectin), soluble form of vascular cell adhesion molecule 1 (sVCAM-1), soluble inter-cellular adhesion molecule-1 (sICAM-1), soluble platelet endothelial cell adhesion molecule 1, monocyte chemotactic protein-1 (MCP-1) and von Willebrand factor (vWF) activity. Anthropometric, demographic and lifestyle characteristics of SLE patients were also performed. The SLE patients had higher PTX3, vWF, MCP-1, sE-selectin and sVCAM-1 levels than the controls (1.82 ± 1.56 ng/mL, 237 ± 101%, 70.05 ± 18.31 ng/mL, 111.16 ± 49.15 ng/mL and 978.78 ± 462.35 ng/mL vs. 0.86 ± 0.40 ng/mL, 138 ± 43%, 58.56 ± 13.91 ng/mL, 66.04 ± 27.18 ng/mL and 499.07 ± 125.67 ng/mL, respectively). The independent factors affecting PTX3 expression included Systemic Lupus Erythematosus Disease Activity Index, prednisone dose and anemia severity. Moreover, the PTX3 areas under the curve-receiver operating characteristics curves 0.717 ± 0.056 with cut-off level of 1.96 ng/mL was comparable to vWF, MCP-1, sE-selectin, sP-selectin and sICAM-1. PTX3 and sVCAM-1 were the only factors related to SLE activity. Other vascular injury indicators associated with PTX3 were vWF and sVCAM-1. In conclusion, PTX3 concentrations in SLE patients might serve as a indicator of the activation/dysfunction of vascular endothelium.
Interferon-α coincides with suppressed levels of pentraxin-3 (PTX3) in systemic lupus erythematosus and regulates leucocyte PTX3 in vitro.
Wirestam L,Enocsson H,Skogh T,Eloranta M L,Rönnblom L,Sjöwall C,Wetterö J
Clinical and experimental immunology
Dysfunctional elimination of cell debris, and the role of opsonins such as pentraxins, is of interest regarding systemic lupus erythematosus (SLE) pathogenesis. Interferon (IFN)-α 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-α in vitro. Serum samples from 243 patients with SLE and 100 blood donors were analysed regarding PTX3. Patient sera were analysed for IFN-α, 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-α in blood donor neutrophils and peripheral blood mononuclear cells (PBMC). Serum PTX3 was 44% lower in patients with SLE compared to blood donors (P < 0·0001) and correlated with leucocyte variables. Patients with undetectable IFN-α had 29% higher median PTX3 level than patients with detectable IFN-α (P = 0·01). PTX3 production by PBMC was inhibited by IFN-α, 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-α is detectable) compared to blood donors. In addition to its potential consumption during waste disposal, it is plausible that IFN-α also attenuates PTX3 by inhibiting synthesis by PBMC and/or exhausting PTX3 storage in neutrophil granules.
Pentraxin-3 levels are associated with vasculitis and disease activity in childhood-onset systemic lupus erythematosus.
Sahin S,Adrovic A,Barut K,Durmus S,Gelisgen R,Uzun H,Kasapcopur O
Objectives Childhood-onset systemic lupus erythematosus (cSLE) is a multisystemic autoimmune disease characterized by inflammatory organ damage by means of vasculitis. Pentraxin-3 (PTX3) is expressed locally at the sites of inflammatory processes, predominantly from endothelial cells. In adult studies, PTX3 has shown to be an indicator of active vasculitis both in large-vessel and small-vessel vasculitides, as well as in SLE. Moreover, in SLE it has found to be correlated with disease activity, and with some of the clinical manifestations and laboratory parameters. We aimed to ascertain if PTX3 might be a significant mediator in cSLE and if it might indicate active vasculitis during the course of the disease. Methods Serum PTX3 levels were measured in 76 patients with cSLE and 41 healthy subjects. We have investigated its relation with disease activity, damage, clinical features, laboratory parameters and medications. Results Serum levels of PTX3 were found to be increased in cSLE compared to healthy controls (mean ± SD; 10.6 ± 8.2 ng/mL vs 2.7 ± 1.3 ng/mL, p < 0.001). PTX3 concentrations were also in correlation with SLEDAI-2K ( r = 0.57, p < 0.001). When viewed from the clinical perspective, serum PTX3 levels were significantly higher only in patients with active vasculitis ( p < 0.001), Raynaud phenomenon ( p = 0.006) and mucocutaneous manifestations ( p < 0.001). However, an association between PTX3 and age, age at disease onset, disease duration, complement levels, PedSDI score (pediatric version of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index), ESR, CRP, procalcitonin levels, anti-ds DNA antibody, anticardiolipin antibodies was not detected. Conclusions Patients with cSLE have increased levels of serum PTX3 compared to healthy controls. Thus, serum PTX-3 level might be a significant mediator in cSLE. Apart from these, the results support that PTX3 reflects active cutaneous vasculitis in cSLE and correlates with disease activity.