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Objective: Patients undergoing anti-tumour necrosis factor-alpha (TNF-alpha) treatment often develop autoantibodies. Apoptotic cell antigens are a potential initiating stimulus for autoantibodies. Our goal was to verify whether anti-cytokine therapy causes the release of nucleosomes, a major autoantigen generated during cell death.Design: Laboratory research study with comparison group.Setting: Clinical Immunology Unit and Lab, H San Raffaele University Hospital, Italy.Subjects: Eleven healthy controls and 87 rheumatic patients were studied, including 51 with rheumatoid arthritis (RA) and 33 patients with systemic lupus erythematosus (SLE).Interventions: Vein blood samples were taken via the antecubital vein. Blood was retrieved from 11 patients before and after injection of anti-TNF-alpha humanized antibodies. Nucleosomes were measured with an enzyme-linked immunosorbent assay. Cell death induced by anti-TNF-alpha antibodies and by the soluble cytokine was assessed in vitro.Main Outcome Measures: Nucleosome level by treatment.Results: Enzyme-linked immunosorbent assay effectively detected nucleosomes either released by dying cells in vitro or circulating in the plasma. SLE but not RA patients had circulating nucleosomes at the steady state. Eight of 11 patients had significantly higher levels of plasma nucleosomes after infliximab. Minute amounts of TNF-alpha enabled infliximab to induce cell death in vitro.Conclusions: The accumulation of nucleosomes possibly fosters the development of autoantibodies in subjects with appropriate genetic backgrounds. [ABSTRACT FROM AUTHOR]

Vessel walls are the primary inflammatory sites in systemic vasculitides. In most cases the initiating event is unknown, and a self-sustaining circuit attracts and activates inflammatory leucocytes in the wall of vessels of various size and anatomical characteristics. Recent studies have revealed homeostatic roles of vascular inflammation and have identified the action of humoral innate immunity, in particular injury-associated signals and acute phase proteins, on the activation of circulating leucocytes, platelets and endothelial cells. These advances have provided clues to the molecular mechanisms underlying the vicious circle that maintains and amplifies vessel and tissue injury. [ABSTRACT FROM AUTHOR]

D'Auria F, Rovere-Querini P, Giazzon M, Ajello P, Baldissera E, Manfredi AA, Sabbadini MG (H San Raffaele Scientific Institute and Vita-Salute University, Milan, Italy). Accumulation of plasma nucleosomes upon treatment with anti-tumour necrosis factor-α antibodies. J Intern Med 2004; 255: 409–418. Patients undergoing anti-tumour necrosis factor-α (TNF-α) treatment often develop autoantibodies. Apoptotic cell antigens are a potential initiating stimulus for autoantibodies. Our goal was to verify whether anti-cytokine therapy causes the release of nucleosomes, a major autoantigen generated during cell death. Laboratory research study with comparison group. Clinical Immunology Unit and Lab, H San Raffaele University Hospital, Italy. Eleven healthy controls and 87 rheumatic patients were studied, including 51 with rheumatoid arthritis (RA) and 33 patients with systemic lupus erythematosus (SLE). Vein blood samples were taken via the antecubital vein. Blood was retrieved from 11 patients before and after injection of anti-TNF-α humanized antibodies. Nucleosomes were measured with an enzyme-linked immunosorbent assay. Cell death induced by anti-TNF-α antibodies and by the soluble cytokine was assessed in vitro. Nucleosome level by treatment. Enzyme-linked immunosorbent assay effectively detected nucleosomes either released by dying cells in vitro or circulating in the plasma. SLE but not RA patients had circulating nucleosomes at the steady state. Eight of 11 patients had significantly higher levels of plasma nucleosomes after infliximab. Minute amounts of TNF-α enabled infliximab to induce cell death in vitro. The accumulation of nucleosomes possibly fosters the development of autoantibodies in subjects with appropriate genetic backgrounds. [ABSTRACT FROM AUTHOR]

Coordinated programmes of resolution are thought to initiate early after an inflammatory response begins, actively terminating leucocyte recruitment, allowing their demise via apoptosis and their clearance by phagocytosis. In this review we describe an event that could be implicated in the resolution of inflammation, i.e. the establishment of a refractory state in human neutrophils that had phagocytosed apoptotic cells. Adherent neutrophils challenged with apoptotic cells generate neutrophil extracellular traps ( NETs), filaments of decondensed chromatin decorated with bioactive molecules that are involved in the capture of various microbes and in persistent sterile inflammation. In contrast, neutrophils that had previously phagocytosed apoptotic cells lose their capacity to up-regulate β2 integrins and to respond to activating stimuli that induce NET generation, such as interleukin ( IL)-8. A defective regulation of NET generation might contribute to the persistent inflammation and tissue injury in diseases in which the clearance of apoptotic cells is jeopardized, including systemic lupus erythematosus and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. [ABSTRACT FROM AUTHOR]

Swift and regulated clearance of apoptotic cells prevents the accumulation of cell remnants in injured tissues and contributes to the shift of macrophages towards alternatively activated reparatory cells that sustain wound healing. Environmental signals, most of which are unknown, in turn control the efficiency of the clearance of apoptotic cells and as such determine whether tissues eventually heal. In this study we show that vessel-associated stem cells (mesoangioblasts) specifically modulate the expression of genes involved in the clearance of apoptotic cells and in macrophage alternative activation, including those of scavenger receptors and of molecules that bridge dying cells and phagocytes. Mesoangioblasts, but not immortalized myoblasts or neural precursor cells, enhance CD163 membrane expression in vitro as assessed by flow cytometry, indicating that the effect is specific. Mesoangioblasts transplanted in acutely or chronically injured skeletal muscles determine the expansion of the population of CD163+ infiltrating macrophages and increase the extent of CD163 expression. Conversely, macrophages challenged with mesoangioblasts engulf significantly better apoptotic cells in vitro. Collectively, the data reveal a feed-forward loop between macrophages and vessel-associated stem cells, which has implications for the skeletal muscle homeostatic response to sterile injury and for diseases in which homeostasis is jeopardized, including muscle dystrophies and inflammatory myopathies. [ABSTRACT FROM AUTHOR]

Vascular inflammation contributes to the defence against invading microbes and to the repair of injured tissues. In most cases it resolves before becoming apparent. Vasculitis comprises heterogeneous clinical entities that are characterized by the persistence of vascular inflammation after it has served its homeostatic function. Most underlying mechanisms have so far remained elusive. Intravascular immunity refers to the surveillance of the vasculature by leucocytes that sense microbial or sterile threats to vessel integrity and initiate protective responses that entail most events that determine the clinical manifestations of vasculitis, such as end-organ ischaemia, neutrophil extracellular traps generation and thrombosis, leucocyte extravasation and degranulation. Understanding how the resolution of vascular inflammation goes awry in patients with systemic vasculitis will facilitate the identification of novel pharmacological targets and bring us a step closer in each patient to the selection of more effective and less toxic treatments. [ABSTRACT FROM AUTHOR]

The registry is a prospective, European, multicentric, longitudinal study, which follows a cohort of children born to mothers with antiphospholipid syndrome (APS). It was started in 2003. In this report, we update the results obtained from the study of 110 mothers and 112 children (two twin births). Eighty per cent of the mothers (n = 86) had primary APS. Purely obstetrical, thrombotic and mixed (obstetrical and thrombotic) APS represent 65.5 %, 21.8 % and 12.7 % of the whole cohort respectively. Isolated antiphospholipid antibodies and isolated anticardiolipin antibodies positivity were present in 50 of 109 (46%) and in 34 of 109 (31%) of the pregnant women, respectively. In the babies, in spite of a high rate of prematurity (14.3%) with four (3.6%) of the premature babies born before 33 weeks of gestation and an increased number of newborns small for gestational age (17%), the large majority of the neonates were healthy. Thirty-one infants are now older than 24 months. Among them, three displayed behavioural abnormalities before 3 years of age. After completing data, there will be the possibility to evaluate the newborn status in relation to themothers' diseases, treatments and antibodies and to follow the neuropsychological development and immunological evolution of the babies during the next 5 years. [ABSTRACT FROM AUTHOR]

The impact of hypertension in the pregnancies from autoimmune patients is not unequivocally defined. We have prospectively followed 168 pregnancies from 135 patients from four Italian centres to verify the potential impact of hypertension in the antiphospholipid syndrome (APS). The rate of preeclampsia, mean neonatal weight and gestational age at delivery were significantly lower in patients with both APS and hypertension than in patients with hypertension or APS alone. This information may be relevant for counselling and care of these patients. [ABSTRACT FROM AUTHOR]

Background and purpose: Systemic lupus erythematosus (SLE) is an immune‐mediated disease that may affect the nervous system. We explored the topographical organization of structural and functional brain connectivity in patients with SLE and its correlation with neuropsychiatric (NP) involvement and autoantibody profiles. Methods: Graph theoretical analysis was applied to diffusion tensor magnetic resonance imaging (MRI) and resting‐state functional MRI data from 32 patients with SLE and 32 age‐ and sex‐matched healthy controls. Structural and functional connectivity matrices between 116 cortical/subcortical brain regions were estimated using a bivariate correlation analysis, and global and nodal network metrics were calculated. Results: Structural, but not functional, global network properties (strength, transitivity, global efficiency and path length) were abnormal in patients with SLE versus controls (P < 0.0001), especially in patients with anti‐double‐stranded DNA (ADNA) autoantibodies (P = 0.03). No difference was found according to NP involvement or anti‐phospholipid autoantibody status. Patients with SLE and controls shared identical structural hubs and the majority of functional hubs. In patients with SLE, all structural hubs showed reduced strength and clustering coefficient compared with controls (P from 0.001 to <0.0001), especially in patients with ADNA autoantibodies. Only a few differences in functional hub properties were found between patients with SLE and controls. Structural and functional hub measures did not differ according to NP involvement or anti‐phospholipid autoantibody status. Significant correlations were found between clinical, MRI and network measures (r from −0.56 to 0.60, P from 0.0003 to 0.05). Conclusions: Abnormalities of global and nodal structural connectivity occur in patients with SLE, especially with ADNA autoantibodies, with a diffuse disruption of structural integrity. Functional network integrity may contribute to preserve clinical functions. [ABSTRACT FROM AUTHOR]