Inflammatory Biomarkers and Lipid Parameters May Predict an Increased Risk for Atrial Arrhythmias in Patients with Systemic Sclerosis.

Background/objectives: Autoimmune inflammation enhances the electrical instability of the atrial myocardium in patients with systemic sclerosis (SSc); thus, atrial arrhythmia risk is increased, which might be predicted by evaluating the P wave interval and dispersion of a 12-lead surface electrocardiogram (ECG).

Methods: We examined 26 SSc patients and 36 healthy controls and measured the P wave interval and P wave dispersion of the 12-lead surface ECG in each patient. Furthermore, echocardiography and 24-h Holter ECG were performed and levels of inflammatory laboratory parameters, including serum progranulin (PGRN), sVCAM-1, sICAM-1, leptin and C-reactive protein (CRP), were determined.

A rare association of neuromyelitis optica, antisynthetase, and antiphospholipid syndrome.

The association of neuromyelitis optica concurrently with two other autoimmune diseases is rare. Neuromyelitis optica should be taken into consideration when evaluating the symptoms of the patient as a differential diagnostic aspect.

Autologous apoptotic neutrophils inhibit inflammatory cytokine secretion by human dendritic cells, but enhance Th1 responses.

Neutrophils represent the most abundant cell type in peripheral blood and exhibit a remarkably brief (6-8 h) half-life in circulation. The fundamental role of these professional phagocytes has been established in acute inflammation, based on their potential to both initiate and receive inflammatory signals. Furthermore, neutrophils also take part in maintaining chronic inflammatory processes, such as in various autoimmune diseases.

Decreased apopto-phagocytic gene expression in the macrophages of systemic lupus erythematosus patients.

The clearance of apoptotic cells has an important role in the maintenance of tissue homeostasis and in the protection of tissues from the inflammatory and immunogenic contents of dying cells. A defect in the recognition and phagocytosis of apoptotic cells contributes to the development of chronic inflammation and autoimmune disorders. We have observed that compared with healthy donors, differentiated macrophages from patients with untreated systemic lupus erythematosus (SLE) showed decreased phagocytosis of apoptotic neutrophils.

The glucocorticoid dexamethasone programs human dendritic cells for enhanced phagocytosis of apoptotic neutrophils and inflammatory response.

GCs are powerful anti-inflammatory compounds inhibiting inflammatory cell recruitment and production of proinflammatory cytokines. We have recently found that DCs, the key players of T cell priming and polarization, respond to allogeneic apoptotic neutrophils with proinflammatory cytokine release and Th1 cell activation. Here, we show that monocyte-derived human DCs develop their capacity to engulf apoptotic cells by up-regulating a set of apoptophagocytic genes.

Differentiation and glucocorticoid regulated apopto-phagocytic gene expression patterns in human macrophages. Role of Mertk in enhanced phagocytosis.

The daily clearance of physiologically dying cells is performed safely mainly by cells in the mononuclear phagocyte system. They can recognize and engulf dying cells utilizing several cooperative mechanisms. In our study we show that the expression of a broad range of apopto-phagocytic genes is strongly up-regulated during differentiation of human monocytes to macrophages with different donor variability.

Phagocytosis of cells dying through autophagy induces inflammasome activation and IL-1β release in human macrophages.

Phagocytosis of naturally dying cells usually blocks inflammatory reactions in host cells. We have recently observed that clearance of cells dying through autophagy leads to a pro-inflammatory response in human macrophages. Investigating this response further, we found that during engulfment of MCF-7 or 293T cells undergoing autophagic death, but not apoptotic or anoikic ones, caspase-1 was activated and IL-1β was processed, then secreted in a MyD88-independent manner.

Altered sialylation on the cell-surface proteins of dexamethasone-treated human macrophages contributes to augmented uptake of apoptotic neutrophils.

Macrophages eliminate apoptotic granulocytes before their secondary necrosis during resolution of inflammation. A well-known glucocorticoid, the anti-inflammatory dexamethasone augments phagocytosis capacity of macrophages with a so far not fully clarified mechanism. We have found that sialylation of cell-surface proteins on human macrophages is markedly altered by dexamethasone.

PPARγ modulated inflammatory response of human dendritic cell subsets to engulfed apoptotic neutrophils.

The means of how phagocytes handle apoptotic cells has a great impact on the outcome of immune responses. Here, we show that phagocytosis of allogeneic, apoptotic neutrophils by human monocyte-derived DCs is slow and less efficient than that of macrophages, and CD1a(-) DCs are more active in the engulfment of apoptotic neutrophils than CD1a(+) DCs. Blocking DC-SIGN function partially interferes with the uptake of apoptotic cells, and long-term interaction of apoptotic neutrophils with DCs makes them prone to proinflammatory cytokine responses.

Transglutaminase 2 is expressed and active on the surface of human monocyte-derived dendritic cells and macrophages.

The multifunctional enzyme, transglutaminase 2 (TG2), can be found intracellularly, in the extracellular matrix and on the cell surface. Cell surface TG2 (csTG2) could not be detected by TG2-specific antibodies or autoantibodies on immunocompetent cells. A supposedly csTG2-specific antibody, 6B9, was recently shown to actually react with CD44.

Phagocytosis of cells dying through autophagy evokes a pro-inflammatory response in macrophages.

Autophagy as a natural part of cellular homeostasis usually takes place unnoticed by neighboring cells. However, its co-occurrence with cell death may contribute to the clearance of these dying cells by recruited phagocytes. Autophagy associated with programmed cell death has recently been reported to be essential for presentation of phoshatidylserine (PS) on the cell surface (Qu et al.

PPARgamma-dependent regulation of human macrophages in phagocytosis of apoptotic cells.

Macrophages acquire their capacity for efficient phagocytosis of apoptotic cells during their differentiation from monocytes. The peroxisome proliferator-activated receptor gamma (PPARgamma) is highly up-regulated during this maturation program. We report that addition of PPARgamma antagonist during differentiation of human monocytes to macrophages significantly reduced the capacity of macrophages to engulf apoptotic neutrophils, but did not influence phagocytosis of opsonized bacteria.

Inflammation and the apopto-phagocytic system.

Although under normal conditions many cells die daily mainly by apoptosis in human tissues, inflammation does not occur. The redundant function of a relatively large number of molecules are available to recognize changes occurring on the surface of apoptotic cells, to opsonize the dead cells and to engulf the apoptotic cells previously opsonized or not. Several components of the innate immune system are utilized in this process, mainly soluble factors which bind to the distinct molecular pattern of apoptotic cells.