Roberto Leone

PTX3 as a paradigm for the interaction of pentraxins with the complement system.

Pentraxins are highly conserved components of the humoral arm of innate immunity. They include the short pentraxins C reactive protein (CRP) and serum amyloid P component (SAP), and the long pentraxin PTX3. These are soluble pattern-recognition molecules that are present in the blood and body fluids, and share the ability to recognize pathogens and promote their disposal. CRP and SAP are produced systemically in the liver while PTX3 is produced locally in a number of tissues, macrophages and neutrophils being major sources of this long pentraxin. Pentraxins interact with components of the classical and lectin pathways of Complement as well as with Complement regulators. In particular, PTX3 recognizes C1q, factor H, MBL and ficolins, where these interactions amplify the repertoire of microbial recognition and effector functions of the Complement system. The complex interaction of pentraxins with the Complement system at different levels has broad implications for host defence and regulation of inflammation.

Pentraxin-3 in patients with severe sepsis or shock: the ALBIOS trial

The long pentraxin PTX3 is a key component of the humoral arm of innate immunity related to sepsis severity and mortality. We evaluated the clinical and prognostic significance of circulating PTX3 in the largest cohort ever reported of patients with severe sepsis or septic shock.

Driver mutations (JAK2V617F, MPLW515L/K or CALR), pentraxin-3 and C-reactive protein in essential thrombocythemia and polycythemia vera

BackgroundThe driver mutations JAK2V617F, MPLW515L/K and CALR influence disease phenotype of myeloproliferative neoplasms (MPNs) and might sustain a condition of chronic inflammation. Pentraxin 3 (PTX3) and high-sensitivity C-reactive protein (hs-CRP) are inflammatory biomarkers potentially useful for refining prognostic classification of MPNs.MethodsWe evaluated 305 with essential thrombocythemia (ET) and 172 polycythemia vera (PV) patients diagnosed according to the 2016 WHO criteria and with full molecular characterization for driver mutations.ResultsPTX3 levels were significantly increased in carriers of homozygous JAK2V617F mutation compared to all the other genotypes and triple negative ET patients, while hs-CRP levels were independent of the mutational profile. The risk of haematological evolution and death from any cause was about 2- and 1.5-fold increased in individuals with high PTX-3 levels, while the thrombosis rate tended to be lower. High hs-CRP levels were associated with risk of haematological evolution, death and also major thrombosis. After sequential adjustment for potential confounders (age, gender, diagnosis and treatments) and the presence of JAK2V617F homozygous status, high hs-CRP levels remained significant for all outcomes, while JAK2V617F homozygous status as well as treatments were the factors independently accounting for adverse outcomes among patients with high PTX3 levels.ConclusionsThese results provide evidence that JAK2V617F mutation influences MPN-associated inflammation with a strong correlation between allele burden and PTX3 levels. Plasma levels of hs-CRP and PTX3 might be of prognostic value for patients with ET and PV, but their validation in future prospective studies is needed.

Anti-rheumatic treatment is not associated with reduction of pentraxin 3 in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis

Background Pentraxin 3 is proposed to be a marker of inflammation and cardiovascular risk, but its role in inflammatory rheumatic diseases (IRDs) is still uncertain. Therefore, we wanted to examine if anti-rheumatic treatment reduced serum PTX3 (s-PTX3) levels in IRDs, and if s-PTX3 levels were related to other markers of inflammation and to endothelial function (EF). Methods We examined s-PTX3, EF and established inflammatory biomarkers in 114 IRD patients from the PSARA study before and after 6 weeks and 6 months of treatment with methotrexate (MTX) or anti-tumor necrosis factor alpha (anti-TNF) therapy with or without MTX co-medication. Results s-PTX3 levels in all IRD diagnoses were above the upper limit of the reference range. In contrast to established inflammatory markers, in particular CRP and ESR, s-PTX3 levels did not change significantly after 6 weeks and 6 months of anti-rheumatic therapy. There was no difference in change in s-PTX3 levels from baseline to 6 weeks and 6 months between MTX monotherapy and anti-TNF regimens. CRP, ESR and EF were not related to changes in s-PTX3 neither in crude nor adjusted analyses. Conclusion IRD patients have increased s-PTX3 levels, which, in contrast to other inflammatory markers, do not seem to improve within 6 months of therapy with MTX and/or anti-TNF. Thus, s-PTX3 might reflect a persisting immune process, even a causal factor of inflammation, not inhibited by the standard anti-rheumatic treatment. Furthermore, even though s-PTX3 is thought to be a strong predictor of cardiovascular prognosis, it was not related to EF.

Pentraxin 3 plasma levels at graft-versus-host disease onset predict disease severity and response to therapy in children given haematopoietic stem cell transplantation

Acute Graft-versus-Host Disease (GvHD) remains a major complication of allogeneic haematopoietic stem cell transplantation, with a significant proportion of patients failing to respond to first-line systemic corticosteroids. Reliable biomarkers predicting disease severity and response to treatment are warranted to improve its management. Thus, we sought to determine whether pentraxin 3 (PTX3), an acute-phase protein produced locally at the site of inflammation, could represent a novel acute GvHD biomarker. Using a murine model of the disease, we found increased PTX3 plasma levels after irradiation and at GvHD onset. Similarly, plasma PTX3 was enhanced in 115 pediatric patients on day of transplantation, likely due to conditioning, and at GvHD onset in patients experiencing clinical symptoms of the disease. PTX3 was also found increased in skin and colon biopsies from patients with active disease. Furthermore, PTX3 plasma levels at GvHD onset were predictive of disease outcome since they resulted significantly higher in both severe and therapy-unresponsive patients. Multiple injections of rhPTX3 in the murine model of GvHD did not influence the disease course. Taken together, our results indicate that PTX3 constitutes a biomarker of GvHD severity and therapy response useful to tailor treatment intensity according to early risk-stratification of GvHD patients.

Inflammatory long pentraxin 3 is associated with leukocyte telomere length in night-shift workers

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; p = 0.022), C-reactive protein (CRP) (beta = −0.07; p = 0.000), and cardiovascular diseases with hypertension included (CVD) (beta = −0.12; p = 0.000)], positively associate with LTL (coefficient = 0.15; p = 0.033). LTL, in turn is reduced by CVD (beta = −0.15; p = 0.000), binge drinking (beta = −0.10; p = 0.004), and CRP (beta = −0.05; p = 0.026). On the other hand, night-shift work, found to be remarkably free from aging risk factors [i.e., age (beta = −0.13; p = 0.017), BMI (beta = −0.17; p = 0.030), CVD (beta = −0.14; p = 0.000), and binge drinking (beta = −0.13; p = 0.000)], does associate almost significantly with reversed PTX3 (coefficient = −0.09; p = 0.089) and even with CRP (beta = 0.17; p = 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.

Biomarkers of oxidative-stress and inflammation in exhaled breath condensate from hospital cleaners.

Abstract Objective: We studied the impact of chlorinated agents exposure on exhaled breath condensate (EBC) biomarkers in cleaners. Methods: Malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), nitrites (), nitrates (), pH, hydrogen peroxide (H2O2) and ammonium () were tested in EBC of 40 cleaners and 40 non-exposed controls. Pentraxin-3 (PTX3) and soluble type II receptor of IL-1 (sIL-1RII) were analyzed also in plasma. Results: Levels of MDA-EBC, 4-HNE-EBC and -EBC were higher, while pH-EBC values were lower, in cleaners. MDA-EBC was associated with 4-HNE-EBC, -EBC and pH. 4-HNE-EBC correlated with PTX3. Conclusion: Professional exposure to chlorinated agents increases EBC biomarkers of oxidative stress and inflammation.

Outcome of long-term complications after permanent metallic left bronchial stenting in children

OBJECTIVES We describe the way we treated 7 children with critical long-term complications after metallic balloon-expandable stenting in the left mainstem bronchus. METHODS Endoscopic follow-up included a first bronchoscopy 3 weeks after stenting, then monthly for 3 months, every 4-6 months up to 1 year and at scheduled times to calibrate stent diameter up to final calibration. When major complications occurred, patients underwent chest computed tomographic angiography. RESULTS In 1 of the 7 children (median age 2.8 years), metallic left bronchial stenting served as a bridge to surgery. After a median 4-year follow-up, all 7 children experienced recurrent stent ovalizations with stent breakage in 3 and erosion in 1. In 4 children, computed tomographic angiography showed abundant peribronchial fibrous tissue, in 2 left mediastinal rotation and in 1 displacement along the left bronchus after pulmonary re-expansion as the cause of stent-related complication. Of the 7 children, 6 underwent surgery (5 posterior aortopexy and 1 section of the ligamentum arteriosus) and 3 required nitinol stents placement within the metallic ones. One patient completed the follow-up, and 1 patient was lost to follow-up. All 5 remaining children still have permanent bronchial stents in place, patent and re-epithelialized after a median 10.5-year follow-up. There were no deaths. CONCLUSIONS Satisfactory anatomical relationships when children have stents placed in the left mainstem bronchus alone do not guarantee the final success. Several mechanisms intervene to cause critical stent-related complications in children during growth. Permanent metallic stents should be used carefully, and only in selected patients.

Airway stenting as a salvage procedure in a child with a lethal spondyloepiphyseal dysplasia congenita: 13 years follow-up

We describe the case of a term infant with broad and protruding forehead, micrognathia, wide cleft palate, short neck and stocky body with small thoracic cage, short limbs, bilateral clubfeet and triventricular hydrocephalus. A G313S mutation in the gene for type II-collagen(COL2A1)was demonstrated. Soon after birth, the infant had respiratory distress with repeated obstructive apnea, leading to nasotracheal intubation. Despite mechanical ventilation(MV)with high positive pressure, he showed desaturations, leading to tracheotomy. An endoscopy showed severe tracheo-bronchomalacia. At 5 months a polyflex self-expanding silicone stent was placed in the trachea(10x30, replaced by12x20 and removed after 4 years), with two stainless steel stents in the mainstem bronchi(Palmaz 104right and Palmaz 128left). After 5 years 2 stents were overlapped to the previous in each of the mainstem bronchus(2 Jomed 12-10/12). At 10.5 years a Y Dumon stent(11-7-7) has been placed in the trachea and removed after 2 years. To date he is a 13 year old child, he has a tracheotomy(4.5mm cuffed Shiley with speech valve)and occasionally needs of night ventilatory support. He attends the secondary school with fairly good performance. G313S mutation has been described in a lethal case with respiratory insufficiency at birth, with spondyloepiphyseal dysplasia congenita. In our case, the airway malacia has been promptly treated by stenting with immediate improvement of the airway ventilation. Stenting, although is a palliative treatment given the cage narrowness, has allowed a child who was expected to die at birth, to reach adolescence in good condition and with a certain degree of autonomy.