Role Of Decay-accelerating Factor Research Articles

The Role of Decay Accelerating Factor in Environmentally Induced and Idiopathic Systemic Autoimmune Disease

Decay accelerating factor (DAF) plays a complex role in the immune system through complement-dependent and -independent regulation of innate and adaptive immunity. Over the past five years there has been accumulating evidence for a significant role of DAF in negatively regulating adaptive T-cell responses and autoimmunity in both humans and experimental models. This review discusses the relationship between DAF and the complement system and highlights major advances in our understanding of the biology of DAF in human disease, particularly systemic lupus erythematosus. The role of DAF in regulation of idiopathic and environmentally induced systemic autoimmunity is discussed including studies showing that reduction or absence of DAF is associated with autoimmunity. In contrast, DAF-mediated T cell activation leads to cytokine expression consistent with T regulatory cells. This is supported by studies showing that interaction between DAF and its molecular partner, CD97, modifies expression of autoimmunity promoting cytokines. These observations are used to develop a hypothetical model to explain how DAF expression may impact T cell differentiation via interaction with CD97 leading to T regulatory cells, increased production of IL-10, and immune tolerance.

A new FH autoantibody-induced murine aHUS model reveals a major protective role of decay-accelerating factor in the pathogenesis of ahus due to FH dysfunction

A new FH autoantibody-induced murine aHUS model reveals a major protective role of decay-accelerating factor in the pathogenesis of ahus due to FH dysfunction

Role of decay-accelerating factor in regulating survival of human cervical cancer cells

Decay-accelerating factor (DAF) is one of the key molecules involved in cell protection against autologous complement, which restricts the action of complement at critical stages of the cascade reaction. The effect of DAF on the survival of human cervical cancer cell (ME180) has not been demonstrated. In this study we applied, for the first time, small interference RNA (siRNA) to knock down the expression of the DAF with the aim of exploiting complement more effectively for tumor cell damage. Meanwhile, we investigated the effects of DAF on the viability and migration, moreover the proliferation of ME180 cell. The results showed that the expression of DAF was significantly increased in human cervical cancer tissues. SiRNA inhibition of DAF expression enhanced complement-dependent cytolysis up to 32% in ME180 cells, which contributed to the control of C3 activation and increased the cells viability, migration and augment the number of ME180 cells. These data indicated that DAF siRNA described in this study may offer an additional alternative to improve the efficacy of antibody- and complement-based cancer immunotherapy.

Role of DAF in Protecting against T-Cell Autoreactivity that Leads to Experimental Autoimmune Uveitis

To investigate the role of decay-accelerating factor (DAF), a cell surface complement regulator that recently has been linked to T-cell responses and autoimmunity in the pathogenesis of experimental autoimmune uveitis (EAU). EAU was induced in wild-type (WT) and Daf1(-/-) mice, and their disease severities, IRBP specific Th1/Th17 responses, and cytokine expression profiles were compared. In a test of the efficacy of treatment with soluble mouse DAF protein, EAU was induced in disease-susceptible B10.RIII mice, and they were treated with 0.5 mg soluble DAF protein or equal volume of PBS IP every other day. Retinal histology and IRBP-specific T-cell responses were compared after 14 days. Both EAU incidence and histopathology scores were significantly greater in Daf1(-/-) mice. There was a >10-fold greater mononuclear cell influx into the retina together with severe vasculitic lesions, retinal folding, and photoreceptor cell layer destruction. There were 5- to 7-fold greater Th1 and 3- to 4-fold greater Th17 responses against IRBP in Daf1(-/-) mice with EAU, and they expressed significantly elevated levels of GM-CSF, IL-2, IL-3, and IFN-gamma. WT B10.RIII mice that received soluble DAF protein treatments exhibited decreased IRBP-specific Th1/Th17 responses and were protected from retinal injury compared with the mice that received PBS treatments. DAF significantly influences IRBP-specific Th1 and Th17 responses and disease severity in EAU. Systemic upregulation of DAF levels could be used to suppress retinal antigen(s)-specific autoimmunity to treat autoimmune posterior uveitis.

The Role of Decay-accelerating Factor as a Receptor for Helicobacter pylori and a Mediator of Gastric Inflammation

Persistent gastritis induced by Helicobacter pylori is the strongest known risk factor for peptic ulcer disease and distal gastric adenocarcinoma, a process for which adherence of H. pylori to gastric epithelial cells is critical. Decay-accelerating factor (DAF), a protein that protects epithelial cells from complement-mediated lysis, also functions as a receptor for several microbial pathogens. In this study, we investigated whether H. pylori utilizes DAF as a receptor and the role of DAF within H. pylori-infected gastric mucosa. In vitro studies showed that H. pylori adhered avidly to Chinese hamster ovary cells expressing human DAF but not to vector controls. In H. pylori, disruption of the virulence factors vacA, cagA, and cagE did not alter adherence, but deletion of DAF complement control protein (CCP) domains 1-4 or the heavily O-glycosylated serine-threonine-rich COOH-terminal domain reduced binding. In cultured gastric epithelial cells, H. pylori induced transcriptional up-regulation of DAF, and genetic deficiency of DAF attenuated the development of inflammation among H. pylori-infected mice. These results indicate that DAF may regulate H. pylori-epithelial cell interactions relevant to pathogenesis.

Role of decay-accelerating factor in regulating complement activation on the erythrocyte surface as revealed by gene targeting.

Decay-accelerating factor (DAF) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein that inhibits both the classical and the alternative pathways of complement activation. DAF has been studied extensively in humans under two clinical settings: when absent from the erythrocytes of paroxysmal nocturnal hemoglobinuria (PNH) patients, who suffer from complement-mediated hemolytic anemia, and in transgenic pigs expressing human DAF, which have been developed to help overcome complement-mediated hyperacute rejection in xenotransplantation. Nevertheless, the exact role of DAF in regulating complement activation in vivo on the cell surface and the species specificity of this molecule remain to be fully characterized. To address these issues, we have used gene targeting to produce mice lacking GPI-anchored DAF. We found that erythrocytes from mice deficient in GPI-anchored DAF showed no increase in spontaneous complement activation in vivo but exhibited impaired regulation of zymosan-initiated bystander and antibody-triggered classical pathway complement activation in vitro, resulting in enhanced complement deposition. Despite a high level of C3 fixation, no homologous hemolysis occurred. It is noteworthy that GPI-linked DAF knockout erythrocytes, when tested with human and guinea pig sera, were more susceptible to heterologous complement lysis than were normal erythrocytes. These results suggest that DAF is capable of regulating homologous as well as heterologous complement activation via the alternative or the classical pathway. They also indicate that DAF deficiency alone is not sufficient to cause homologous hemolysis. In contrast, when the assembly of the membrane-attack complex is not properly regulated, as in the case of heterologous complement activation or in PNH patients, impaired erythrocyte DAF activity and enhanced C3 deposition could lead to increased hemolytic reaction.

Membrane factors responsible for homologous species restriction of complement-mediated lysis: evidence for a factor other than DAF operating at the stage of C8 and C9.

Species-restricted lysis of complement refers to the relative inefficiency of complement to lyse cells from the homologous species. Restriction occurs at least at the steps involving C3/C5 convertase formation and the C9 insertion phase of the complement cascade, and is presumed to be mediated by inhibitory factors in the target cell membrane. In this study, we have examined whether decay accelerating factor (DAF), a membrane protein known to modulate C3/C5 convertase activities on cell surfaces, acts as a regulatory protein in species-restricted lysis of human erythrocyte (E). The role of DAF was assessed in homologous lysis by the classic pathway, in reactive lysis, and in lytic steps requiring C8 and C9. The results indicated that DAF participated in regulating C3/C5 deposition on the surface of homologous E, but had no effect on homologous restriction in reactive lysis and in the reaction of C8 and C9 with antibody-sensitized E C1-7. Treatment of E with pronase or with dithiothreitol (DTT) abolished the restricting effect of homologous C8/C9, indicating that species-restricted lysis by C5b-9 involves membrane factor(s) sensitive to pronase and DTT.