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Immune responses against pathogens require that microbial components promote the activation of antigen-presenting cells (APCs). Autoimmune diseases and graft rejections occur in the absence of pathogens; in these conditions, endogenous molecules, the so-called ‘innate adjuvants’, activate APCs. Necrotic cells contain and release innate adjuvants; necrotic cells also release high-mobility group B1 protein (HMGB1), an abundant and conserved constituent of vertebrate nuclei. Here, we show that necrotic HMGB1-/- cells have a reduced ability to activate APCs, and HMGB1 blockade reduces the activation induced by necrotic wild-type cell supernatants. In vivo, HMGB1 enhances the primary antibody responses to soluble antigens and transforms poorly immunogenic apoptotic lymphoma cells into efficient vaccines. [ABSTRACT FROM AUTHOR]

Phagocytosis of apoptotic cells can be facilitated by complement components and short pentraxins, such as serum amyloid P (SAP). In contrast, the long pentraxin PTX3 was shown to inhibit phagocytosis of apoptotic Jurkat cells by dendritic cells and to bind late apoptotic polymorphonuclear leukocytes (PMNs). Recently, levels of the pentraxin PTX3 were shown to parallel disease activity in small‐vessel vasculitis, which is often characterized by leukocytoclasia, a persistence of leukocyte remnants in the vessel wall. We undertook this study to test our hypothesis that PTX3 inhibits phagocytosis of late apoptotic PMNs by macrophages, thereby leading to their accumulation in the vessel wall. Macrophages were allowed to phagocytose late apoptotic or secondary necrotic PMNs that were incubated with or without PTX3 for 30 minutes prior to phagocytosis. Phagocytosis was allowed to occur in the presence of 30% normal human serum with or without SAP and with or without depletion of complement. To discriminate between an inhibitory effect of PTX3 on binding and the internalization of apoptotic PMNs into macrophages, internalization was blocked by cytochalasin B. SAP and complement were both necessary for effective in vitro phagocytosis. In contrast, PTX3 inhibited phagocytosis in a dose‐dependent manner, from 11% inhibition at 6.25 μg/ml to almost complete inhibition at 100 μg/ml. Furthermore, PTX3 partly affected binding of apoptotic PMNs to macrophages. PTX3, in contrast to SAP and complement, inhibits phagocytosis of late apoptotic PMNs by monocyte‐derived macrophages in a dose‐dependent manner. Therefore, PTX3 can play a role in the development of leukocytoclasia by affecting the clearance of apoptotic PMNs, thereby inducing their accumulation in the vessel wall. [ABSTRACT FROM AUTHOR]

Cells commonly die without eliciting autoimmunity. However, dying cells are a potential initiating stimulus for systemic lupus erythematosus (SLE). Our goal was to verify whether immune adjuvants influence the autoimmunity induction that ensues following in vivo injection of dying cells. Mice were immunized with apoptotic thymocytes in the presence of artificial moieties, such as Freund's incomplete adjuvant (IFA), or natural adjuvants, such as dendritic cells (DCs). Renal involvement and the development of autoantibodies were monitored. Apoptotic cells failed to induce clinical disease or to sustain production of autoantibodies in (NZB × NZW)F1 mice. In contrast, autoimmunity developed in the presence of IFA or DCs. The characteristics of the adjuvant influenced the array of autoantibodies, the kinetics of their development, and the severity of the disease. DCs were required for induction of anti–β2-glycoprotein I IgG. Adjuvants alone did not elicit disease. A “two-hit” signal composed of autoantigens and adjuvants initiates systemic autoimmunity. Moreover, environmental signals at the site of clearance of dead cells shape the features and the severity of the autoimmune disease. Strategies aimed at preventing the accumulation of dying cells and at modulating endogenous adjuvants may be beneficial for the treatment of SLE. [ABSTRACT FROM AUTHOR]