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High mobility group box protein B1 (HMGB1), a nuclear protein reportedly involved in the structural organisation of DNA, is released from necrotic cells or upon cellular activation. After its release into the extracellular space, HMGB1 serves as a mediator of inflammation. In contrast to necrotic cells, apoptotic ones usually do not release HMGB1. Formation and release of membranous vesicles is a well-known feature of apoptotic cell death. Only recently, subcellular membrane vesicles, such as those released during apoptotic cell death have been identified as immune regulators and as mediators of cell to cell communication. We and others have previously detected nuclear antigens within apoptosis-released membranous vesicles and HMGB1 together with nuclear antigens has been discussed to be a key player in etiology and pathogenesis of autoimmune diseases. On this background, we analysed whether HMGB1 is included in the membranous vesicles generated by apoptosing cells. Employing immune blots we observed abundand amounts of HMGB1 in the fraction of the small membraneous particles isolated from cell culture supernatants and conclude that HMGB1 is translocated into vesicles generated during apoptosis.

A characteristic of apo cell death is the shedding of membrane vesicles from the dying cell. This process is also referred to as apo membrane blebbing. These apo particles contain various autoantigens and are effectively engulfed by phagocytes. A defective phagocytosis has been described in autoimmune diseases like systemic lupus erythematosus and this defect might lead to an accumulation of apo cells and bodies. Thus, we investigated the interactions between apototic cell-derived membrane vesicles (ACdMV), and myeloid dendritic cell (DC). ACdMV were isolated from the supernatant of apo lymphocytes. These isolated ACdMV were morphologically characterized as membrane coated vesicles of an average size of 500 nm. Coincubating isolated ACdMV with iDC we observed CD83 surface expression of the latter. Accumulation of ACdMV may contribute to an inflammatory immune response in autoimmune diseases.

While several characteristics of systemic lupus erythematosus (SLE) have been investigated, the distinct pathogenetic mechanisms leading to autoimmunity and chronic inflammation are not understood yet. A central role for apo has been implicated in the pathogenesis of SLE and an increased rate of apo or a defective clearance of apo cells have repeatedly been described in SLE patients, which show elevated levels of alpha-interferon (alphaIFN) as well as an enhanced expression of alphaIFN-alpha inducible genes referred to as alphaIFN signature. Recent publications link alphaIFN and apo: apo cell-derived microparticles can directly stimulate plasmacytoid dendritic cells to secret alphaIFN. This review highlights the role of apo material as source for AAg and as a trigger for chronic inflammation in the pathogenesis of SLE.

In contrast to nec, the apo is not accompanied by local inflammation. The immunosuppressive effects of apo cells have been repeatedly reported and a dysregulation of apo is discussed to play a major role in the pathogenesis of autoimmune disorders. The intracellular executioners of apo are the cysteine-aspartic acid proteases, also known as caspases that cleave a variety of intracellular substrates and mediate the morphological changes observed during apo. The association of autoimmune diseases with defects in caspase function indicates the necessity for functional integrity of caspases in the apo cell death machinery. Here, we describe that cells undergoing apo in presence of the pancaspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone stimulated MPhi to secrete proinflammatory cytokines. These findings indicate that caspase signalling is of central importance for silent and non- or anti-inflammatory cell death.

Primary systemic vasculitis (PSV) as well as the related disorders behcet disease (BD) and relapsing polychondritis (RP) are a heterogenous group of autoimmune diseases with the potency for a severe and life threatening course. Patients with PSV seem to be ideal candidates for HSCT: First, when first line treatment has failed the patients are in high risk of severe organ damage or death due to active disease or treatment toxicity. Moreover, the chance to achieve complete remission with standard doses of cyclophosphamide-still standard treatment of severe manifestations of PSV- predicts that dose escalation to high dose chemotherapy will increase the effectiveness. The experience with HSCT in patients with severe PSV as published in case reports and from EULAR and EBMT-databases gives preliminary evidence that HSCT might be an effective treatment option in refractory cases of PSV and related diseases. Validated scores of disease activity and damage such as the Birmingham vasculitis activity score (BVAS) and the vasculitis activity damage index (VDI) could help to identify patients which might profit from HSCT.

In order to maintain homeostasis, multicellular organisms must tightly regulate proliferation and elimination of cells. Removal of superfluous cells is a crucial event during development of multice...

A characteristic feature of many autoimmune diseases like systemic lupus erythematodes (SLE) is the development of autoantibodies against various cytoplasmatic or nuclear antigens. The mechanisms l...