Publications by authors named "Barbara Bottazzi"

116 Publications

Monocyte-macrophage polarization and recruitment pathways in the tumour microenvironment of B-cell acute lymphoblastic leukaemia.

Br J Haematol 2021 Mar 13. Epub 2021 Mar 13.

Centro Ricerca Tettamanti, Pediatric Dep, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy.

B-cell acute lymphoblastic leukaemia (B-ALL) reprograms the surrounding bone marrow (BM) stroma to create a leukaemia-supportive niche. To elucidate the contribution of immune cells to the leukaemic microenvironment, we investigated the involvement of monocyte/macrophage compartments, as well as several recruitment pathways in B-ALL development. Immunohistochemistry analyses showed that CD68-expressing macrophages were increased in leukaemic BM biopsies, compared to controls and predominantly expressed the M2-like markers CD163 and CD206. Furthermore, the "non-classical" CD14 CD16 monocyte subset, expressing high CX3CR1 levels, was significantly increased in B-ALL patients' peripheral blood. CX3CL1 was shown to be significantly upregulated in leukaemic BM plasma, thus providing an altered migratory pathway possibly guiding NC monocyte recruitment into the BM. Additionally, the monocyte/macrophage chemoattractant chemokine ligand 2 (CCL2) strongly increased in leukaemic BM plasma, possibly because of the interaction of leukaemic cells with mesenchymal stromal cells and vascular cells and due to a stimulatory effect of leukaemia-related inflammatory mediators. C5a, a macrophage chemoattractant and M2-polarizing factor, further appeared to be upregulated in the leukaemic BM, possibly as an effect of PTX3 decrease, that could unleash complement cascade activation. Overall, deregulated monocyte/macrophage compartments are part of the extensive BM microenvironment remodelling at B-ALL diagnosis and could represent valuable targets for novel treatments to be coupled with classical chemotherapy.
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http://dx.doi.org/10.1111/bjh.17330DOI Listing
March 2021

Circulating pentraxin 3 in severe COVID-19 or other pulmonary sepsis.

Eur J Clin Invest 2021 May 13;51(5):e13530. Epub 2021 Mar 13.

Department of Anaesthesia and Critical Care, Azienda Ospedaliero-Universitaria S. Luigi Gonzaga, Orbassano, Italy.

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http://dx.doi.org/10.1111/eci.13530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995110PMC
May 2021

Control of Complement Activation by the Long Pentraxin PTX3: Implications in Age-Related Macular Degeneration.

Front Pharmacol 2020 26;11:591908. Epub 2020 Nov 26.

Department of Biomedical Sciences, Humanitas University, Milan, Italy.

Dysregulation of the complement system is central to age-related macular degeneration (AMD), the leading cause of blindness in the developed world. Most of the genetic variation associated with AMD resides in complement genes, with the greatest risk associated with polymorphisms in the () gene; factor H (FH) is the major inhibitor of the alternative pathway (AP) of complement that specifically targets C3b and the AP C3 convertase. Long pentraxin 3 (PTX3) is a soluble pattern recognition molecule that has been proposed to inhibit AP activation via recruitment of FH. Although present in the human retina, if and how PTX3 plays a role in AMD is still unclear. In this work we demonstrated the presence of PTX3 in the human vitreous and studied the PTX3-FH-C3b crosstalk and its effects on complement activation in a model of retinal pigment epithelium (RPE). RPE cells cultured in inflammatory AMD-like conditions overexpressed the PTX3 protein, and up-regulated AP activating genes. PTX3 bound RPE cells in a physiological setting, however this interaction was reduced in inflammatory conditions, whereby PTX3 had no complement-inhibiting activity on inflamed RPE. However, on non-cellular surfaces, PTX3 formed a stable ternary complex with FH and C3b that acted as a "hot spot" for complement inhibition. Our findings suggest a protective role for PTX3 in response to complement dysregulation in AMD and point to a novel mechanism of complement regulation by this pentraxin with potential implications in pathology and pharmacology of AMD.
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http://dx.doi.org/10.3389/fphar.2020.591908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725797PMC
November 2020

Macrophage expression and prognostic significance of the long pentraxin PTX3 in COVID-19.

Nat Immunol 2021 01 18;22(1):19-24. Epub 2020 Nov 18.

Humanitas Clinical and Research Center-IRCCS, Milan, Italy.

Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation. The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19). RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.
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http://dx.doi.org/10.1038/s41590-020-00832-xDOI Listing
January 2021

Interleukin-15 and cancer: some solved and many unsolved questions.

J Immunother Cancer 2020 11;8(2)

Immunology Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy

Soluble interleukin (IL)-15 exists under two forms: as monomer (sIL-15) or as heterodimeric complex in association with sIL-15Rα (sIL-15/IL-15Rα). Both forms have been successfully tested in experimental tumor murine models and are currently undergoing investigation in phase I/II clinical trials. Despite more than 20 years research on IL-15, some controversial issues remain to be addressed. A first point concerns the detection of the sIL-15/IL-15Rα in plasma of healthy donors or patients with cancer and its biological significance. The second and third unsolved question regards the protumorigenic role of the IL-15/IL-15Rα complex in human cancer and the detrimental immunological consequences associated to prolonged exposure of natural killer (NK) cells to both forms of soluble IL-15, respectively. Data suggest that in vivo prolonged or repeated exposure to monomeric sIL-15 or the soluble complex may lead to NK hypo-responsiveness through the expansion of the CD8/CD44 T cell subset that would suppress NK cell functions. In vitro experiments indicate that soluble complex and monomeric IL-15 may cause NK hyporesponsiveness through a direct effect caused by their prolonged stimulation, suggesting that this mechanism could also be effective in vivo. Therefore, a better knowledge of IL-15 and a more appropriate use of both its soluble forms, in terms of concentrations and time of exposure, are essential in order to improve their therapeutic use. In cancer, the overproduction of sIL-15/IL-15Rα could represent a novel mechanism of immune escape. The soluble complex may act as a decoy cytokine unable to efficiently foster NK cells, or could induce NK hyporesponsiveness through an excessive and prolonged stimulation depending on the type of IL-15Rα isoforms associated. All these unsolved questions are not merely limited to the knowledge of IL-15 pathophysiology, but are crucial also for the therapeutic use of this cytokine. Therefore, in this review, we will discuss key unanswered issues on the heterogeneity and biological significance of IL-15 isoforms, analyzing both their cancer-related biological functions and their therapeutic implications.
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http://dx.doi.org/10.1136/jitc-2020-001428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674108PMC
November 2020

Circulating biomarkers and cardiac function over 3 years after chemotherapy with anthracyclines: the ICOS-ONE trial.

ESC Heart Fail 2020 08 1;7(4):1452-1466. Epub 2020 May 1.

Department of Cardiovascular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Aims: A multicentre trial, ICOS-ONE, showed increases above the upper limit of normality of cardiac troponin (cTn) in 27% of patients within 12 months after the end of cancer chemotherapy (CT) with anthracyclines, whether cardiac protection with enalapril was started at study entry in all (prevention arm) or only upon first occurrence on supra-normal cTn (troponin-triggered arm). The aims of the present post hoc analysis were (i) to assess whether anthracycline-based treatment could induce cardiotoxicity over 36 month follow-up and (ii) to describe the time course of three cardiovascular biomarkers (i.e. troponin I cTnI-Ultra, B-type natriuretic peptide BNP, and pentraxin 3 PTX3) and of left ventricular (LV) function up to 36 months.

Methods And Results: Eligible patients were those prescribed first-in-life CT, without evidence of cardiovascular disease, normal cTn, LV ejection fraction (EF) >50%, not on renin-angiotensin aldosterone system antagonists. Patients underwent echocardiography and blood sampling at 24 and 36 months. No differences were observed in biomarker concentration between the two study arms, 'prevention' vs. 'troponin-triggered'. During additional follow-up 13 more deaths occurred, leading to a total of 23 (9.5%), all due to a non-cardiovascular cause. No new occurrences of LV-dysfunction were reported. Two additional patients were admitted to the hospital for cardiovascular causes, both for acute pulmonary embolism. No first onset of raised cTnI-Ultra was reported in the extended follow-up. BNP remained within normal range: at 36 months was 23.4 ng/L, higher (N.S.) than at baseline, 17.6 ng/L. PTX3 peaked at 5.2 ng/mL 1 month after CT and returned to baseline values thereafter. cTnI-Ultra peaked at 26 ng/L 1 month after CT and returned to 3 ng/L until the last measurement at 36 months. All echocardiographic variables remained stable during follow-up with a median LVEF of 63% and left atrial volume index about 24 mL/m .

Conclusions: First-in-life CT with median cumulative dose of anthracyclines of 180 mg/m does not seem to cause clinically significant cardiac injury, as assessed by circulating biomarkers and echocardiography, in patients aged 51 years (median), without pre-existing cardiac disease. This may suggest either a 100% efficacy of enalapril (given as preventive or troponin-triggered) or a reassuringly low absolute cardiovascular risk in this cohort of patients, which may not require intensive cardiologic follow-up.
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http://dx.doi.org/10.1002/ehf2.12695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373944PMC
August 2020

Immunization with Pentraxin3 prevents transition from subclinical to clinical lupus nephritis in lupus-prone mice: Insights from renal ultrastructural findings.

J Autoimmun 2020 07 4;111:102443. Epub 2020 Apr 4.

Unit of Rheumatology, Department of Medicine (DIMED), University of Padova, Padova, Italy. Electronic address:

Background: Pentraxin3 (PTX3) is an emerging player in lupus nephritis (LN). Anti-PTX3 antibodies showed to delay LN occurrence in vivo.

Aim: To evaluate renal changes following immunization with PTX3 in a murine model of LN.

Materials And Methods: Twenty-two lupus-prone New Zealand Black/White (NZB/W)F1 mice were divided into two groups (n = 11) and subcutaneously injected with human recombinant (hr)PTX3 100 μg or phosphate buffer saline (PBS) 200 μl, three times 3 weeks apart, starting before development of proteinuria. Five mice from each group were scheduled for sacrifice at week 22 and 6 from each group at week 29. Renal lesions included electron-dense deposits (EDD), glomerular deposition of IgG, complement and PTX3 as markers of renal inflammation. They were evaluated by immunofluorescence (IF), confocal and immunoelectron microscopy (IEM). Validated semiquantitative scores were used when available to score renal lesions. Chi-squared test with Fisher exact test was used for comparison.

Results: Nineteen out of 22 mice were sacrificed as scheduled. Only hrPTX3-immunized mice developed anti-PTX3 antibodies. Compared to PBS-injected mice, they displayed a dramatic decrease in glomerular deposits of IgG, C1q and PTX3, as well as in the amount of EDD (p = 0.006) and podocyte effacement (p = 0.043). Importantly, PTX3 was pinpointed inside the EDD and co-localized with nuclear material.

Conclusions: Immunization with PTX3 prevented progression from the preclinical to the clinical stage of LN, inciting anti-PTX3 antibodies and preventing renal PTX3 deposition. PTX3 is a novel component of EDD, submitting it as one initiating autoantigen in LN and as potential target for early treatment.
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http://dx.doi.org/10.1016/j.jaut.2020.102443DOI Listing
July 2020

Editorial: Immunomodulation of Innate Immune Cells.

Front Immunol 2020 11;11:101. Epub 2020 Feb 11.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melborne, VIC, Australia.

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http://dx.doi.org/10.3389/fimmu.2020.00101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026236PMC
March 2021

The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins.

FEBS Lett 2020 08 12;594(16):2480-2501. Epub 2020 Feb 12.

Department of Immunology and Inflammation, Humanitas Clinical and Research Institute - IRCCS, Milan, Italy.

Aspergillosis is a life-threatening infection mostly affecting immunocompromised individuals and primarily caused by the saprophytic fungus Aspergillus fumigatus. At the host-pathogen interface, both cellular and humoral components of the innate immune system are increasingly acknowledged as essential players in the recognition and disposal of this opportunistic mold. Fundamental hereof is the contribution of the complement system, which deploys all three activation pathways in the battle against A. fumigatus, and functionally cooperates with other soluble pattern recognition molecules, including pentraxins. In particular, preclinical and clinical observations point to the long pentraxin PTX3 as a nonredundant and complement-dependent effector with protective functions against A. fumigatus. Based on past and current literature, here we discuss how the complement participates in the immune response to this fungal pathogen, and illustrate its crosstalk with the pentraxins, with a focus on PTX3. Emphasis is placed on the molecular mechanisms underlying such processes, the genetic evidence from human epidemiology, and the translational potential of the currently available knowledge.
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http://dx.doi.org/10.1002/1873-3468.13744DOI Listing
August 2020

Characterization of potential biomarkers of reactogenicity of licensed antiviral vaccines: randomized controlled clinical trials conducted by the BIOVACSAFE consortium.

Sci Rep 2019 12 30;9(1):20362. Epub 2019 Dec 30.

GSK, Siena, Italy.

Biomarkers predictive of inflammatory events post-vaccination could accelerate vaccine development. Within the BIOVACSAFE framework, we conducted three identically designed, placebo-controlled inpatient/outpatient clinical studies (NCT01765413/NCT01771354/NCT01771367). Six antiviral vaccination strategies were evaluated to generate training data-sets of pre-/post-vaccination vital signs, blood changes and whole-blood gene transcripts, and to identify putative biomarkers of early inflammation/reactogenicity that could guide the design of subsequent focused confirmatory studies. Healthy adults (N = 123; 20-21/group) received one immunization at Day (D)0. Alum-adjuvanted hepatitis B vaccine elicited vital signs and inflammatory (CRP/innate cells) responses that were similar between primed/naive vaccinees, and low-level gene responses. MF59-adjuvanted trivalent influenza vaccine (ATIV) induced distinct physiological (temperature/heart rate/reactogenicity) response-patterns not seen with non-adjuvanted TIV or with the other vaccines. ATIV also elicited robust early (D1) activation of IFN-related genes (associated with serum IP-10 levels) and innate-cell-related genes, and changes in monocyte/neutrophil/lymphocyte counts, while TIV elicited similar but lower responses. Due to viral replication kinetics, innate gene activation by live yellow-fever or varicella-zoster virus (YFV/VZV) vaccines was more suspended, with early IFN-associated responses in naïve YFV-vaccine recipients but not in primed VZV-vaccine recipients. Inflammatory responses (physiological/serum markers, innate-signaling transcripts) are therefore a function of the vaccine type/composition and presence/absence of immune memory. The data reported here have guided the design of confirmatory Phase IV trials using ATIV to provide tools to identify inflammatory or reactogenicity biomarkers.
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http://dx.doi.org/10.1038/s41598-019-56994-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937244PMC
December 2019

Editorial: The Role of Pentraxins: From Inflammation, Tissue Repair and Immunity to Biomarkers.

Front Immunol 2019 3;10:2817. Epub 2019 Dec 3.

Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.

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http://dx.doi.org/10.3389/fimmu.2019.02817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901624PMC
November 2020

Determination of pentraxin 3 levels in cerebrospinal fluid during central nervous system infections.

Eur J Clin Microbiol Infect Dis 2020 Apr 8;39(4):665-670. Epub 2019 Dec 8.

Department of Infectious Diseases, University Hospital of Trieste, Trieste, Italy.

Pentraxin 3 (PTX3) is an acute phase protein; its plasmatic levels significantly rise during severe infections. Data on PTX3 levels in cerebrospinal fluid (CSF) of patients with central nervous system (CNS) infections are lacking. We aimed (a) to assess the diagnostic potential of measuring CSF PTX3 levels in patients with CNS infections and (b) to establish CSF PTX3 cutoffs to distinguish between bacterial and aseptic meningoencephalitis (ROC curve). PTX3 levels were measured in CSF from 19 patients admitted to Trieste Hospital, Italy, with CNS infection. A diagnosis of bacterial infection and aseptic meningoencephalitis was made in 7 (37%) and 12 (63%) patients, respectively. Subjects with bacterial infections showed significantly higher PTX3 levels (13.5 vs 1.27 ng/mL in aseptic meningoencephalitis, p = 0.010). We identified two different CSF PTX3 levels cutoffs. (1) The best cutoff to maximise Youden's J was 9.6 ng/mL with a sensitivity, specificity, positive predictive value and negative predictive value (NPV) of 71.4%, 91.4%, 83.3%, 84.6%, respectively. (2) The cutoff with higher NPV (100%) was 3.6 ng/mL; a diagnosis of bacterial infections was obtained in 0% patients with CSF PTX3 levels < 3.6 ng/mL vs 58% of those with CSF PTX3 levels ≥ 3.6 ng/mL (p = 0.017). CSF PTX3 levels are higher in bacterial meningitis than aseptic meningoencephalitis. A cutoff of 3.6 ng/mL of CSF PTX3 has a high NPV and can be used to exclude bacterial CNS infections.
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http://dx.doi.org/10.1007/s10096-019-03767-wDOI Listing
April 2020

The Long Pentraxin PTX3 in Bone Homeostasis and Pathology.

Front Immunol 2019 8;10:2628. Epub 2019 Nov 8.

Department of Immunology and Inflammation, Humanitas Clinical and Research Institute - IRCCS, Milan, Italy.

The innate immune system is equipped with a number of germ-line encoded soluble pattern recognition molecules (PRMs) that collectively mediate the humoral host response to infection and damage in cooperation with cells and tissues of the immune and non-immune compartments. Despite the impressive diversity in structure, source, and regulation across PRMs, these all share remarkably similar functions inasmuch as they recognize microbes and damaged tissues, activate complement, exert opsono-phagocytic activities, and regulate inflammation. The long pentraxin 3 (PTX3) is a prototypic soluble PRM. Long known as a major player in innate immunity, inflammation and matrix remodeling, only recently has PTX3 emerged as a mediator of bone homeostasis in rodents and humans. -targeted mice exhibit reduced trabecular volume during bone development, and impaired callus mineralization following experimental fracture. The murine gene is expressed by non-hematopoietic periosteal cells in the early phases of fracture healing, and by maturing osteoblasts. Human osteoblasts do express the PTX3 protein, whose levels positively correlate with bone density and osteoblast proliferation and maturation , thus pointing to a role in bone deposition. Contrasting evidence, however, suggest osteoclastogenesis-promoting effects of PTX3, where its expression has been associated with periodontitis, arthritis, and bone metastasis, conditions hallmarked by inflammation and bone resorption. Here, we review past and recent literature on the functions exerted by this long pentraxin in bone biology, with major emphasis on physiological skeletal remodeling, fracture healing, and chronic diseases of the bone.
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http://dx.doi.org/10.3389/fimmu.2019.02628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856142PMC
November 2020

Imbalance between angiogenic and anti-angiogenic factors in sera from patients with large-vessel vasculitis.

Clin Exp Rheumatol 2020 Mar-Apr;38 Suppl 124(2):23-30. Epub 2019 Sep 17.

Medicine and Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, and Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.

Objectives: To investigate serum levels of a panel of angiogenic inducers (VEGF, FGF-2, Angiopoietin 1, -2, soluble VCAM-1) and inhibitors (angiostatin, endostatin, pentraxin-3) in patients with giant cell arteritis (GCA) and Takayasu's arteritis (TAK), in order to gain further insights into the molecular mechanisms driving angiogenesis dysregulation in large-vessel vasculitis (LVV).

Methods: Sera were obtained from 33 TAK patients and 14 GCA patients and from two groups of age-matched normal controls (NC). Disease activity was assessed using 18F-FDG PET/CT and clinical indices including NIH/Kerr criteria and ITAS. Angiogenic and anti-angiogenic factor serum levels were evaluated using commercial ELISA kits. Pentraxin 3 (PTX3) serum levels were evaluated by non-commercial ELISA, as already described.

Results: Among the angiogenic factors, only VEGF serum levels were significantly higher in TAK patients compared to NC. No difference was found between angiogenic factor levels in GCA patients compared to those detected in NC. Anti-angiogenic factor (Angiostatin, Endostatin, PTX3) serum levels were significantly higher in both GCA and TAK patients compared to NC. Significant associations were observed between VEGF and PTX3 levels and disease activity evaluated using PET scan and clinical indices. Cluster analysis based on PET scan scores in TAK patients showed significant ordered differences in VEGF and angiostatin serum levels. Indeed, we noted a progressive increase of VEGF and angiostatin from NC to the cluster including patients with the highest and more diffuse scan positivity.

Conclusions: Our overall results demonstrate a circulating molecular profile characterised by a prevailing expression of anti-angiogenic soluble factors.
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September 2020

The Atypical Receptor CCRL2 Is Essential for Lung Cancer Immune Surveillance.

Cancer Immunol Res 2019 Nov 4;7(11):1775-1788. Epub 2019 Sep 4.

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.

CCRL2 is a nonsignaling seven-transmembrane domain receptor. CCRL2 binds chemerin, a protein that promotes chemotaxis of leukocytes, including macrophages and natural killer (NK) cells. In addition, CCRL2 controls the inflammatory response in different pathologic settings, such as hypersensitivity, inflammatory arthritis, and experimental autoimmune encephalitis. Here, we investigated the role of CCRL2 in the regulation of lung cancer-related inflammation. The genetic deletion of promoted tumor progression in urethane-induced and in / lung tumor mouse models. Similarly, a -mutant lung tumor displayed enhanced growth in -deficient mice. This phenotype was associated with a reduced inflammatory infiltrate characterized by the impaired recruitment of several leukocyte populations including NK cells. Bone marrow chimeras showed that CCRL2 expression by the nonhematopoietic cell compartment was responsible for the increased tumor formation observed in -mutant -deficient mice. In human and mouse lungs, CCRL2 was expressed by a fraction of CD31 endothelial cells, where it could control NK infiltration. Elevated CCRL2 expression in biopsies from human lung adenocarcinoma positively correlated with clinical outcome. These results provide evidence for a crucial role of CCRL2 in shaping an anti-lung tumor immune response.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176487PMC
November 2019

Coronary Inflammation by Computed Tomography Pericoronary Fat Attenuation in MINOCA and Tako-Tsubo Syndrome.

J Am Heart Assoc 2019 09 29;8(17):e013235. Epub 2019 Aug 29.

Cardiology and Radiology Departments Parma University Hospital Parma Italy.

Background The pericoronary fat attenuation index (pFAI) has emerged as a marker of coronary inflammation, which is measurable from standard coronary computed tomography angiography (CCTA). It compares well with gold-standard methods for the assessment of coronary inflammation and can predict future cardiovascular events. pFAI could prove invaluable to differentiate an inflammatory from a noninflammatory coronary artery status, helping unravel the mechanisms subtending an event classified as myocardial infarction with nonobstructive coronary arteries (MINOCA) or Tako-Tsubo syndrome (TTS). Methods and Results Patients admitted with MINOCA and TTS between 2011 and 2018, who had both CCTA and cardiac magnetic resonance during or shortly after the acute phase, were selected and pFAI measured in their CCTA; pFAI was also measured in control subjects who had CCTA for atypical chest pain workup, no obstructive coronary artery disease found in their CCTA, and no cardiac events at 2-year follow-up. In the n=106 MINOCA/TTS patients, mean pFAI was -68.37±8.29 versus -78.03±6.20 in the n=106 controls (P<0.0001), and the difference was confirmed also when comparing mean pFAI in each coronary artery between MINOCA/TTS and controls (P<0.0001). Nonobstructive coronary plaques at CCTA, high-risk plaques in particular, were more frequently found (P<0.01) in the MINOCA/TTS group compared with controls. Conclusions In MINOCA and TTS patients, CCTA is not only able to detect angiographically invisible atherosclerotic plaques, but its diagnostic yield can be expanded using the simple measurement of pFAI to characterize pericoronary fat tissue; in MINOCA/TTS mean pFAI demonstrates higher values compared with controls, a finding that has been associated with coronary artery inflammation.
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http://dx.doi.org/10.1161/JAHA.119.013235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755824PMC
September 2019

The macrophage tetraspan MS4A4A enhances dectin-1-dependent NK cell-mediated resistance to metastasis.

Nat Immunol 2019 08 1;20(8):1012-1022. Epub 2019 Jul 1.

Humanitas Clinical and Research Center, Scientific Institute for Research and Healthcare, Rozzano, Italy.

The plasma membrane tetraspan molecule MS4A4A is selectively expressed by macrophage-lineage cells, but its function is unknown. Here we report that MS4A4A was restricted to murine and human mononuclear phagocytes and was induced during monocyte-to-macrophage differentiation in the presence of interleukin 4 or dexamethasone. Human MS4A4A was co-expressed with M2/M2-like molecules in subsets of normal tissue-resident macrophages, infiltrating macrophages from inflamed synovium and tumor-associated macrophages. MS4A4A interacted and colocalized with the β-glucan receptor dectin-1 in lipid rafts. In response to dectin-1 ligands, Ms4a4a-deficient macrophages showed defective signaling and defective production of effector molecules. In experimental models of tumor progression and metastasis, Ms4a4a deficiency in macrophages had no impact on primary tumor growth, but was essential for dectin-1-mediated activation of macrophages and natural killer (NK) cell-mediated metastasis control. Thus, MS4A4A is a tetraspan molecule selectively expressed in macrophages during differentiation and polarization, essential for dectin-1-dependent activation of NK cell-mediated resistance to metastasis.
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http://dx.doi.org/10.1038/s41590-019-0417-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176488PMC
August 2019

Pentraxin 3 in Cardiovascular Disease.

Front Immunol 2019 17;10:823. Epub 2019 Apr 17.

Department of Cardiovascular Research, Mario Negri Institute for Pharmacological Research IRCCS, Milan, Italy.

The long pentraxin PTX3 is a member of the pentraxin family produced locally by stromal and myeloid cells in response to proinflammatory signals and microbial moieties. The prototype of the pentraxin family is C reactive protein (CRP), a widely-used biomarker in human pathologies with an inflammatory or infectious origin. Data so far describe PTX3 as a multifunctional protein acting as a functional ancestor of antibodies and playing a regulatory role in inflammation. Cardiovascular disease (CVD) is a leading cause of mortality worldwide, and inflammation is crucial in promoting it. Data from animal models indicate that PTX3 can have cardioprotective and atheroprotective roles regulating inflammation. PTX3 has been investigated in several clinical settings as possible biomarker of CVD. Data collected so far indicate that PTX3 plasma levels rise rapidly in acute myocardial infarction, heart failure and cardiac arrest, reflecting the extent of tissue damage and predicting the risk of mortality.
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http://dx.doi.org/10.3389/fimmu.2019.00823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481278PMC
September 2020

The Long Pentraxin PTX3 as a Humoral Innate Immunity Functional Player and Biomarker of Infections and Sepsis.

Front Immunol 2019 12;10:794. Epub 2019 Apr 12.

Department of Inflammation and Immunology, Humanitas Clinical and Research Center-IRCCS, Milan, Italy.

The first line of defense in innate immunity is provided by cellular and humoral mediators. Pentraxins are a superfamily of phylogenetically conserved humoral mediators of innate immunity. PTX3, the first long pentraxin identified, is a soluble pattern recognition molecule rapidly produced by several cell types in response to primary pro-inflammatory signals and microbial recognition. PTX3 acts as an important mediator of innate immunity against pathogens of fungal, bacterial and viral origin, and as a regulator of inflammation, by modulating complement activation and cell extravasation, and facilitating pathogen recognition by myeloid cells. In sepsis, PTX3 plasma levels are associated with severity of the condition, patient survival, and response to therapy. In combination with other established biomarkers, PTX3 could improve stratification of sepsis patients and thus, complement the system of classification and monitoring of this disease.
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http://dx.doi.org/10.3389/fimmu.2019.00794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473065PMC
August 2020

The Long Pentraxin PTX3 as a Link Between Innate Immunity, Tissue Remodeling, and Cancer.

Front Immunol 2019 4;10:712. Epub 2019 Apr 4.

Humanitas Clinical and Research Institute-IRCCS, Milan, Italy.

The innate immune system comprises a cellular and a humoral arm. Humoral pattern recognition molecules include complement components, collectins, ficolins, and pentraxins. These molecules are involved in innate immune responses by recognizing microbial moieties and damaged tissues, activating complement, exerting opsonic activity and facilitating phagocytosis, and regulating inflammation. The long pentraxin PTX3 is a prototypic humoral pattern recognition molecule that, in addition to providing defense against infectious agents, plays several functions in tissue repair and regulation of cancer-related inflammation. Characterization of the PTX3 molecular structure and biochemical properties, and insights into its interactome and multiple roles in tissue damage and remodeling support the view that microbial and matrix recognition are evolutionarily conserved functions of humoral innate immunity molecules.
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http://dx.doi.org/10.3389/fimmu.2019.00712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459138PMC
September 2020

Interaction of C1q With Pentraxin 3 and IgM Revisited: Mutational Studies With Recombinant C1q Variants.

Front Immunol 2019 14;10:461. Epub 2019 Mar 14.

Université Grenoble Alpes, CEA, CNRS, IBS, Grenoble, France.

Pentraxins and complement defense collagens are soluble recognition proteins that sense pathogens and altered-self elements, and trigger immune responses including complement activation. PTX3 has been shown to interact with the globular recognition domains (gC1q) of the C1q protein of the classical complement pathway, thereby modulating complement activity. The C1q-PTX3 interaction has been characterized previously by site-specific mutagenesis using individual gC1q domains of each of the three C1q chains. The present study is aimed at revisiting this knowledge taking advantage of full-length recombinant C1q. Four mutations targeting exposed amino acid residues in the gC1q domain of each of the C1q chains (LysAsp-LysAsp, ArgAsp-ArgGlu, TyrLeu, and LysGlu) were introduced in recombinant C1q and the interaction properties of the mutants were analyzed using surface plasmon resonance. All C1q mutants retained binding to C1r and C1s proteases and mannose-binding lectin-associated serine proteases, indicating that the mutations did not affect the function of the collagen-like regions of C1q. The effect of these mutations on the interaction of C1q with PTX3 and IgM, and both the PTX3- and IgM-mediated activation of the classical complement pathway were investigated. The LysAsp-LysAsp and LysGlu mutants retained partial interaction with PTX3 and IgM, however they triggered efficient complement activation. In contrast, the ArgAsp-ArgGlu mutation abolished C1q binding to PTX3 and IgM, and significantly decreased complement activation. The TyrLeu mutant exhibited decreased PTX3- and IgM-dependent complement activation. Therefore, we provided evidence that, in the context of the full length C1q protein, a key contribution to the interaction with both PTX3 and IgM is given by the B chain Arg residues that line the side of the gC1q heterotrimer, with a minor participation of a Lys residue located at the apex of gC1q. Furthermore, we generated recombinant forms of the human PTX3 protein bearing either D or A at position 48, a polymorphic site of clinical relevance in a number of infections, and observed that both allelic variants equally recognized C1q.
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http://dx.doi.org/10.3389/fimmu.2019.00461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426777PMC
September 2020

Pentraxin 3 deficiency protects from the metabolic inflammation associated to diet-induced obesity.

Cardiovasc Res 2019 Nov;115(13):1861-1872

Department of Excellence of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, Milan, Italy.

Aims: Low-grade chronic inflammation characterizes obesity and metabolic syndrome. Here, we aim at investigating the impact of the acute-phase protein long pentraxin 3 (PTX3) on the immune-inflammatory response occurring during diet-induced obesity.

Methods And Results: PTX3 deficiency in mice fed a high-fat diet for 20 weeks protects from weight gain and adipose tissue deposition in visceral and subcutaneous depots. This effect is not related to changes in glucose homeostasis and lipid metabolism but is associated with an improved immune cell phenotype in the adipose tissue of Ptx3 deficient animals, which is characterized by M2-macrophages polarization and increased angiogenesis. These findings are recapitulated in humans where carriers of a PTX3 haplotype (PTX3 h2/h2 haplotype), resulting in lower PTX3 plasma levels, presented with a reduced prevalence of obesity and decreased abdominal adiposity compared with non-carriers.

Conclusion: Our results support a critical role for PTX3 in the onset of obesity by promoting inflammation and limiting adipose tissue vascularization and delineate PTX3 targeting as a valuable strategy for the treatment of adipose tissue-associated inflammatory response.
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http://dx.doi.org/10.1093/cvr/cvz068DOI Listing
November 2019

Aging, inflammation and cancer.

Semin Immunol 2018 12 6;40:74-82. Epub 2018 Nov 6.

Humanitas Clinical and Research Center, via Manzoni 56, 20089, Rozzano, Milan, Italy; Humanitas University, via Rita Levi Montalcini, 20090, Pieve Emanuele, Milan, Italy; The William Harvey Research Institute, Queen Mary University of London, London, UK. Electronic address:

Aging is a key aspect of neoplasia at the level of cells, individuals and populations. Unrestrained expression and production of inflammatory mediators is a key feature of aging at the cellular and organism level. Inflammatory cells and mediators are a key component of the tumor microenvironment and drive tumor progression. Non-resolving smoldering inflammation increases the risk of cancer (the extrinsic pathway connecting inflammation and cancer). In the intrinsic pathway, genetic events that cause neoplasia (oncogenes and oncosupressor genes) orchestrate the construction of cancer-related inflammation. We argue that uncontrolled smoldering inflammation drives carcinogenesis in aging and acts as a common denominator linking aging and cancer.
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http://dx.doi.org/10.1016/j.smim.2018.10.011DOI Listing
December 2018

Pentraxin 3 regulates synaptic function by inducing AMPA receptor clustering via ECM remodeling and β1-integrin.

EMBO J 2019 01 5;38(1). Epub 2018 Nov 5.

Humanitas Clinical and Research Center - IRCCS, Rozzano, Milano, Italy

Control of synapse number and function in the developing central nervous system is critical to the formation of neural circuits. Astrocytes play a key role in this process by releasing factors that promote the formation of excitatory synapses. Astrocyte-secreted thrombospondins (TSPs) induce the formation of structural synapses, which however remain post-synaptically silent, suggesting that completion of early synaptogenesis may require a two-step mechanism. Here, we show that the humoral innate immune molecule Pentraxin 3 (PTX3) is expressed in the developing rodent brain. PTX3 plays a key role in promoting functionally-active CNS synapses, by increasing the surface levels and synaptic clustering of AMPA glutamate receptors. This process involves tumor necrosis factor-induced protein 6 (TSG6), remodeling of the perineuronal network, and a β1-integrin/ERK pathway. Furthermore, PTX3 activity is regulated by TSP1, which directly interacts with the N-terminal region of PTX3. These data unveil a fundamental role of PTX3 in promoting the first wave of synaptogenesis, and show that interplay of TSP1 and PTX3 sets the proper balance between synaptic growth and synapse function in the developing brain.
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http://dx.doi.org/10.15252/embj.201899529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315291PMC
January 2019

The Long Pentraxin 3 Plays a Role in Bone Turnover and Repair.

Front Immunol 2018 5;9:417. Epub 2018 Mar 5.

Humanitas Clinical and Research Center, Milan, Italy.

Pentraxin 3 (PTX3) is an inflammatory mediator acting as a fluid-phase pattern recognition molecule and playing an essential role in innate immunity and matrix remodeling. Inflammatory mediators also contribute to skeletal homeostasis, operating at multiple levels in physiological and pathological conditions. This study was designed to investigate the role of PTX3 in physiological skeletal remodeling and bone healing. Micro-computed tomography (μCT) and bone histomorphometry of distal femur showed that PTX3 gene-targeted female and male mice ( ) had lower trabecular bone volume than their wild-type ( ) littermates (BV/TV by μCT: 3.50 ± 1.31 vs 6.09 ± 1.17 for females,  < 0.0001; BV/TV 9.06 ± 1.89 vs 10.47 ± 1.97 for males,  = 0.0435). In addition, μCT revealed lower trabecular bone volume in second lumbar vertebra of mice. PTX3 was increasingly expressed during osteoblast maturation and was able to reverse the negative effect of fibroblast growth factor 2 (FGF2) on osteoblast differentiation. This effect was specific for the -terminal domain of PTX3 that contains the FGF2-binding site. By using the closed transversal tibial fracture model, we found that female mice formed significantly less mineralized callus during the anabolic phase following fracture injury compared to mice (BV/TV 17.05 ± 4.59 vs 20.47 ± 3.32,  = 0.0195). Non-hematopoietic periosteal cells highly upregulated PTX3 expression during the initial phase of fracture healing, particularly CD51 and αSma osteoprogenitor subsets, and callus tissue exhibited concomitant expression of PTX3 and FGF2 around the fracture site. Thus, PTX3 supports maintenance of the bone mass possibly by inhibiting FGF2 and its negative impact on bone formation. Moreover, PTX3 enables timely occurring sequence of callus mineralization after bone fracture injury. These results indicate that PTX3 plays an important role in bone homeostasis and in proper matrix mineralization during fracture repair, a reflection of the function of this molecule in tissue homeostasis and repair.
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http://dx.doi.org/10.3389/fimmu.2018.00417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845433PMC
June 2019

PTX3, a Humoral Pattern Recognition Molecule, in Innate Immunity, Tissue Repair, and Cancer.

Physiol Rev 2018 04;98(2):623-639

Humanitas Clinical and Research Center, Rozzano, Milan , Italy ; Humanitas University, Rozzano, Milan , Italy ; Department of Medical Biotechnologies and Translational Medicine, University of Milan , Milan , Italy ; and The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.

Innate immunity includes a cellular and a humoral arm. PTX3 is a fluid-phase pattern recognition molecule conserved in evolution which acts as a key component of humoral innate immunity in infections of fungal, bacterial, and viral origin. PTX3 binds conserved microbial structures and self-components under conditions of inflammation and activates effector functions (complement, phagocytosis). Moreover, it has a complex regulatory role in inflammation, such as ischemia/reperfusion injury and cancer-related inflammation, as well as in extracellular matrix organization and remodeling, with profound implications in physiology and pathology. Finally, PTX3 acts as an extrinsic oncosuppressor gene by taming tumor-promoting inflammation in murine and selected human tumors. Thus evidence suggests that PTX3 is a key homeostatic component at the crossroad of innate immunity, inflammation, tissue repair, and cancer. Dissecting the complexity of PTX3 pathophysiology and human genetics paves the way to diagnostic and therapeutic exploitation.
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http://dx.doi.org/10.1152/physrev.00016.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985957PMC
April 2018

Molecular Signatures of Immunity and Immunogenicity in Infection and Vaccination.

Front Immunol 2017 15;8:1563. Epub 2017 Nov 15.

Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands.

Vaccinology aims to understand what factors drive vaccine-induced immunity and protection. For many vaccines, however, the mechanisms underlying immunity and protection remain incompletely characterized at best, and except for neutralizing antibodies induced by viral vaccines, few correlates of protection exist. Recent omics and systems biology big data platforms have yielded valuable insights in these areas, particularly for viral vaccines, but in the case of more complex vaccines against bacterial infectious diseases, understanding is fragmented and limited. To fill this gap, the EC supported ADITEC project (http://www.aditecproject.eu/; http://stm.sciencemag.org/content/4/128/128cm4.full) featured a work package on "Molecular signatures of immunity and immunogenicity," aimed to identify key molecular mechanisms of innate and adaptive immunity during effector and memory stages of immune responses following vaccination. Specifically, technologies were developed to assess the human immune response to vaccination and infection at the level of the transcriptomic and proteomic response, T-cell and B-cell memory formation, cellular trafficking, and key molecular pathways of innate immunity, with emphasis on underlying mechanisms of protective immunity. This work intersected with other efforts in the ADITEC project. This review summarizes the main achievements of the work package.
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http://dx.doi.org/10.3389/fimmu.2017.01563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699440PMC
November 2017

Inflammatory Long Pentraxin 3 is Associated with Leukocyte Telomere Length in Night-Shift Workers.

Front Immunol 2017 9;8:516. Epub 2017 May 9.

Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

Aging is an emerging worldwide threat to public health, even in the workplace, as it links with risk of illness and death. Bewildered inflammatory responses and stressful conditions associate with age-related disorders. Additionally, circadian rhythm disruption, a critical health issue in night-shift workers, correlates with premature aging. We investigated the hypothesis of a link between altered inflammatory response, detected by plasmatic long pentraxin 3 (PTX3), and biological aging, measured by leukocyte telomere length (LTL), attrition, and possibly induced by night-shift work. Within the framework of a cross-sectional study, such possible relationships were appraised by simultaneous equation model (SEM) technique among day and night-shift hospital workers. PTX3 levels, modulated by several aging conditions [i.e., body mass index (BMI) (beta = -0.22;  = 0.022), C-reactive protein (CRP) (beta = -0.07;  = 0.000), and cardiovascular diseases with hypertension included (CVD) (beta = -0.12;  = 0.000)], positively associate with LTL (coefficient = 0.15;  = 0.033). LTL, in turn is reduced by CVD (beta = -0.15;  = 0.000), binge drinking (beta = -0.10;  = 0.004), and CRP (beta = -0.05;  = 0.026). On the other hand, night-shift work, found to be remarkably free from aging risk factors [i.e., age (beta = -0.13;  = 0.017), BMI (beta = -0.17;  = 0.030), CVD (beta = -0.14;  = 0.000), and binge drinking (beta = -0.13;  = 0.000)], does associate almost significantly with reversed PTX3 (coefficient = -0.09;  = 0.089) and even with CRP (beta = 0.17;  = 0.000). In conclusion, the SEM analysis indicates that PTX3 is positively linked to LTL. The finding suggests a possible new role of this long pentraxin that, by orchestrating an efficient governance of inflammatory processes, may protect telomere from attrition, ensuring therefore the genetic stability of cells. The higher CRP levels among night-shift workers suggest that night-shift work is associated with increased systemic inflammation. This would make nocturnal workers more susceptible to premature aging.
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http://dx.doi.org/10.3389/fimmu.2017.00516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422482PMC
May 2017

Plasma complement and vascular complement deposition in patients with coronary artery disease with and without inflammatory rheumatic diseases.

PLoS One 2017 31;12(3):e0174577. Epub 2017 Mar 31.

Department of Rheumatology, Lillehammer Hospital for Rheumatic Diseases, Lillehammer, Norway.

Purpose: Inflammatory rheumatic diseases (IRD) are associated with accelerated coronary artery disease (CAD), which may result from both systemic and vascular wall inflammation. There are indications that complement may be involved in the pathogenesis of CAD in Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA). This study aimed to evaluate the associations between circulating complement and complement activation products with mononuclear cell infiltrates (MCI, surrogate marker of vascular inflammation) in the aortic media and adventitia in IRDCAD and non-IRDCAD patients undergoing coronary artery bypass grafting (CABG). Furthermore, we compared complement activation product deposition patterns in rare aorta adventitial and medial biopsies from SLE, RA and non-IRD patients.

Methods: We examined plasma C3 (p-C3) and terminal complement complexes (p-TCC) in 28 IRDCAD (SLE = 3; RA = 25), 52 non-IRDCAD patients, and 32 IRDNo CAD (RA = 32) from the Feiring Heart Biopsy Study. Aortic biopsies taken from the CAD only patients during CABG were previously evaluated for adventitial MCIs. The rare aortic biopsies from 3 SLE, 3 RA and 3 non-IRDCAD were assessed for the presence of C3 and C3d using immunohistochemistry.

Results: IRDCAD patients had higher p-TCC than non-IRDCAD or IRDNo CAD patients (p<0.0001), but a similar p-C3 level (p = 0.42). Circulating C3 was associated with IRD duration (ρ, p-value: 0.46, 0.03). In multiple logistic regression analysis, IRD remained significantly related to the presence and size of MCI (p<0.05). C3 was present in all tissue samples. C3d was detected in the media of all patients and only in the adventitia of IRD patients (diffuse in all SLE and focal in one RA).

Conclusion: The independent association of IRD status with MCI and the observed C3d deposition supports the unique relationship between rheumatic disease, and, in particular, SLE with the complement system. Exaggerated systemic and vascular complement activation may accelerate CVD, serve as a CVD biomarker, and represent a target for new therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174577PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5375133PMC
August 2017