BackgroundAge-related macular degeneration (AMD) is the leading cause of blindness in developed countries. The polymorphism rs10490924 in the ARMS2 gene is highly associated with AMD and linked to an indel mutation (del443ins54), the latter inducing mRNA instability. At present, the function of the ARMS2 protein, the exact cellular sources in the retina and the biological consequences of the rs10490924 polymorphism are unclear.MethodsRecombinant ARMS2 was expressed in Pichia pastoris, and protein functions were studied regarding cell surface binding and complement activation in human serum using fluoresence-activated cell sorting (FACS) as well as laser scanning microscopy (LSM). Biolayer interferometry defined protein interactions. Furthermore, endogenous ARMS2 gene expression was studied in human blood derived monocytes and in human induced pluripotent stem cell-derived microglia (iPSdM) by PCR and LSM. The ARMS2 protein was localized in human genotyped retinal sections and in purified monocytes derived from AMD patients without the ARMS2 risk variant by LSM. ARMS2 expression in monocytes under oxidative stress was determined by Western blot analysis.ResultsHere, we demonstrate for the first time that ARMS2 functions as surface complement regulator. Recombinant ARMS2 binds to human apoptotic and necrotic cells and initiates complement activation by recruiting the complement activator properdin. ARMS2-properdin complexes augment C3b surface opsonization for phagocytosis. We also demonstrate for the first time expression of ARMS2 in human monocytes especially under oxidative stress and in microglia cells of the human retina. The ARMS2 protein is absent in monocytes and also in microglia cells, derived from patients homozygous for the ARMS2 AMD risk variant (rs10490924).ConclusionsARMS2 is likely involved in complement-mediated clearance of cellular debris. As AMD patients present with accumulated proteins and lipids on Bruch’s membrane, ARMS2 protein deficiency due to the genetic risk variant might be involved in drusen formation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0776-3) contains supplementary material, which is available to authorized users.

The human plasma protein ␤ 2 -glycoprotein I (␤ 2 -GPI) is the major target of autoantibodies associated with antiphospholipid syndrome. However, the biologic function of this abundant protein is still unclear. Here we identify ␤ 2 -GPI as a complement regulator. ␤ 2 -GPI circulates in the plasma in an inactive circular form. On surface binding, such as to apoptotic cells, ␤ 2 -GPI changes conformation to an elongated form that acquires C3/C3b binding activities. ␤ 2 -GPI apparently changes conformation of C3, so that the regulator factor H attaches and induces subsequent degradation by the protease factor I. ␤ 2 -GPI also mediates further cleavage of C3/C3b compared with factor H alone. Our data provide important insights into innate immune regulation by plasma protein ␤ 2 -GPI, which may be exploited in the prevention and therapy of autoimmune disease antiphospholipid syndrome. Introduction␤ 2 -glycoprotein I (␤ 2 -GPI), also termed apolipoprotein H, 1 is a 50-kDa glycosylated human plasma protein with a concentration of 200 g/mL (4M) 2 that also associates with lipoprotein particles. 3 In the autoimmune disease antiphospholipid syndrome (APS), autoantibodies to ␤ 2 -GPI are identified. [4][5][6] APS is characterized by recurrent vascular thrombosis and pregnancy loss; and in pregnant women, ␤ 2 -GPI autoantibodies trigger severe complications, resulting in miscarriage, intrauterine growth restriction, and fetal death. 7-9 ␤ 2 -GPI displays anticoagulant activity and inhibits the contact activation of the intrinsic coagulation pathway, 10 platelet prothrombinase activity 11 and adenosine diphosphate-induced platelet aggregation. 12 In addition, ␤ 2 -GPI also exerts antiangiogenic and antitumor activities. 13,14 Despite these activities, the main function of ␤ 2 -GPI is unknown.␤ 2 -GPI is composed, like complement factor H and factor H-related protein 1, of consecutive short consensus repeat elements (SCRs), also called complement control protein modules, each approximately 60 amino acids in size. 15 These repeats are frequently found in proteins with complement-regulatory functions. The fifth domain of ␤ 2 -GPI has a modified structure, as it contains a 6-residue insertion and an extra 20-amino acid-long mobile tail. Together, these additional amino acids form a binding site for negatively charged, anionic phospholipids, such as phosphatidylserine or cardiolipin, 16,17 which are exposed on apoptotic or necrotic cells. Recently, Agar et al 18 identified 2 conformations of ␤ 2 -GPI: a circular inactive form of ␤ 2 -GPI in the plasma and an elongated, active one when ␤ 2 -GPI is bound to surfaces. The circular form results from internal interaction of the N-terminal SCRI with the C-terminal SCRV of ␤ 2 -GPI. This interaction is disrupted by binding of ␤ 2 -GPI to surfaces, which generates the elongated conformation. 18 The crystal structure of ␤ 2 -GPI shows the open, J-shaped form of ␤ 2 -GPI. 19,20 As the ␤ 2 -GPI protein function is unclear, we aimed to identify the role of this human plasma protein. Given t...

DEAP-HUS (deficiency of CFHR plasma proteins and factor H [FH] autoantibody positive hemolytic uremic syndrome [HUS]) is a new form of HUS characterized by a deletion of genes coding for FH-related proteins and the presence of autoantibodies directed to FH. These disease-associated autoantibodies inhibit FH (CFH) surface binding functions, which results in a defective regulation of the alternative pathway and damage of endothelial cells. Here we describe two representative patients with DEAP-HUS who both developed end-stage renal failure with the background of homozygous deletion of CFHR1 and CFHR3 genes and the presence of FH autoantibodies. Based on the retrospective diagnosis of DEAP-HUS 2 to 12 months after the initial clinical presentation, subsequent immunosuppressive therapy was initiated. The autoantibody titers decreased, and the complement status of the patients improved, as indicated by increased C3 levels. Thus early diagnosis of DEAP-HUS and immunosuppressive treatments are important factors to treat this particular type of HUS.

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