Pentraxin 3 (PTX3), a long pentraxin subfamily member in the pentraxin family, plays an important role in innate immunity as a soluble pattern recognition receptor. Plasma PTX3 is elevated in sepsis (∼200 ng/ml) and correlates with mortality. The roles of PTX3 in sepsis, however, are not well understood. To investigate the ligands of PTX3 in sepsis, we performed a targeted proteomic study of circulating PTX3 complexes using magnetic bead-based immunopurification and shotgun proteomics for label-free relative quantitation via spectral counting. From septic patient fluids, we successfully identified 104 candidate proteins, including the known PTX3-interacting proteins involved in complement activation, pathogen opsonization, inflammation regulation, and extracellular matrix deposition. Notably, the proteomic profile additionally showed that PTX3 formed a complex with some of the components of neutrophil extracellular traps. Subsequent biochemical analyses revealed a direct interaction of bactericidal proteins azurocidin 1 (AZU1) and myeloperoxidase with PTX3. AZU1 exhibited high affinity binding (KD = 22 ± 7.6 nm) to full-length PTX3 in a calcium ion-dependent manner and bound specifically to an oligomer of the PTX3 N-terminal domain. Immunohistochemistry with a specific monoclonal antibody generated against AZU1 revealed a partial co-localization of AZU1 with PTX3 in neutrophil extracellular traps. The association of circulating PTX3 with components of the neutrophil extracellular traps in sepsis suggests a role for PTX3 in host defense and as a potential diagnostic target.

Pentraxin 3 (PTX3), a member of the long pentraxin subfamily within the family of pentraxins, is a soluble pattern recognition molecule that functions in the innate immune system. Innate immunity affords the infected host protection against sepsis, a potentially life-threatening inflammatory response to infection. Extracellular histones are considered to be the main cause of septic death because of their cytotoxic effect on endothelial cells, which makes them a potential therapeutic target. We found that PTX3 interacted with histones to form coaggregates, which depended on polyvalent interactions and disorder in the secondary structure of PTX3. PTX3 exerted a protective effect, both in vitro and in vivo, against histone-mediated cytotoxicity toward endothelial cells. Additionally, the intraperitoneal administration of PTX3 reduced mortality in mouse models of sepsis. The amino-terminal domain of PTX3, which was required for coaggregation with histones, was sufficient to protect against cytotoxicity. Our results suggest that the host-protective effects of PTX3 in sepsis are a result of its coaggregation with histones rather than its ability to mediate pattern recognition. This long pentraxin-specific effect provides a potential basis for the treatment of sepsis directed at protecting cells from the toxic effects of extracellular histones.

1. Mutter GL, Baak JPA, Crum CP, Richart RM, Ferenczy A, Farquir W. Endometrial precancer diagnosis by histopathology, clonal analysis and computerized morphometry.

No abstract

A 53-year-old Japanese man presented with severe chest pain. He had suffered from persistent fever, muscle pain, arthralgia, and dyspnea on exertion (New York Heart Association class I) for two and half months prior to admission. He had been treated with several antibiotics for two months and prednisolone for almost one month prior to admission. On the day of admission, he had suffered from chest pain at rest, and had come to our hospital. Electrocardiography showed a normal sinus rhythm with significant ST segment elevation in leads V3-6 and abnormal Q waves in leads V4-6. Transthoracic echocardiography demonstrated left ventricular ejection fraction of 52% with severe mitral regurgitation and an 18-mm vegetation on the anterior mitral valve leaflet. Multiple blood cultures identified Streptococcus sanguis. The diagnosis was acute myocardial infarction and mitral regurgitation associated with infective endocarditis (IE). The incidence of acute coronary syndrome caused by IE is quite low in patients with native valves. After a 6-week course of antibiotics, mitral valve replacement and partial cardiomyotomy were performed. Two years after the surgery, follow-up echocardiography showed almost normal left ventricle function and no mitral regurgitation, and the patient has been living an active life without any complications.

No abstract