Key Points• b2GPI complexed with HLA class II molecules was found to be a target for autoantibodies in APS.• More than 80% of patients with APS possess autoantibodies against b2GPI/HLA class II complexes.Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy complications. b2-glycoprotein I (b2GPI) complexed with phospholipid is recognized as a major target for autoantibodies in APS; however, less than half the patients with clinical manifestations of APS possess autoantibodies against the complexes. Therefore, the range of autoantigens involved in APS remains unclear. Recently, we found that human leukocyte antigen (HLA) class II molecules transport misfolded cellular proteins to the cell surface via association with their peptide-binding grooves. Furthermore, immunoglobulin G heavy chain/HLA class II complexes were specific targets for autoantibodies in rheumatoid arthritis. Here, we demonstrate that intact b2GPI, not peptide, forms a complex with HLA class II molecules. Strikingly, 100 (83.3%) of the 120 APS patients analyzed, including those whose antiphospholipid antibody titers were within normal range, possessed autoantibodies that recognize b2GPI/HLA class II complexes in the absence of phospholipids. In situ association between b2GPI and HLA class II was observed in placental tissues of APS patients but not in healthy controls. Furthermore, autoantibodies against b2GPI/HLA class II complexes mediated complement-dependent cytotoxicity against cells expressing the complexes. These data suggest that b2GPI/HLA class II complexes are a target in APS that might be involved in the pathogenesis. (Blood. 2015;125(18):2835-2844
IntroductionAntiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial or venous thrombosis and pregnancy complications, including recurrent spontaneous abortion.1,2 APS is associated with antiphospholipid (aPL) antibodies that bind to anionic phospholipid and serum protein complexes. [3][4][5] Interactions between aPL antibodies and vascular endothelial cells are thought to be involved in the pathogenesis of APS.6-9 b2-glycoprotein I (b2GPI) is the main phospholipid-binding molecule recognized by aPL antibodies 5,10,11 and is produced predominantly by hepatocytes, although some endothelial cells of blood vessels and placental villous tissue also express it.12,13 Plasma b2GPI circulates in a circular conformation with the aPL antibody epitopes being cryptic.14 When b2GPIassociates with anionic phospholipids such as cardiolipin (CL), the circular structure of plasma b2GPI is converted to a linear form, leading to exposure of the major epitope for aPL antibodies. [14][15][16][17][18][19] Therefore, b2GPI bound to negatively charged phospholipids or negatively charged plates is used clinically to detect antibodies.
20However, autoantibodies against the b2GPI associated with phospholipids are detected in less than half the patients with clinical manifestations of APS, [21][22][23] suggesting the existence of additional ta...
• Prenatal diagnosis for an invasive placenta is essential for perinatal planning. • Magnetic resonance imaging provides useful information for the diagnosis of invasive placenta. • The placental protrusion sign is a useful novel MRI finding for predicting invasive placenta.
Although earlier studies have shown that antiviral treatment regimens using valganciclovir (VGCV) improved hearing function in some infants with congenital cytomegalovirus (CMV) infection; its efficacy on the severity of hearing dysfunction is unclear. We conducted a prospective study among 26 infants with congenital CMV infections from 2009 to 2018. Oral VGCV (32 mg/kg/day) was administered for 6 weeks (November 2009 to June 2015; n = 20) or 6 months (July 2015 to March 2018, n = 6). Hearing function was evaluated by measuring the auditory brainstem response before VGCV treatment and at 6 months. Hearing dysfunction, defined as a V-wave threshold >40 dB, was categorized into: most severe, ≥91 dB; severe, 61–90 dB; and moderate, 41–60 dB. Hearing improvement was defined as a decrease of ≥20 dB from the pretreatment V-wave threshold. Of 52 ears in 26 infants with congenital CMV infection, 29 (56%) had hearing dysfunction, and of 29 ears, 16 (55%) improved after VGCV treatment. Although, 16 (84%) of 19 ears with moderate or severe hearing dysfunction improved after treatment (p < 0.001), 10 ears with the most severe form did not. In conclusion, VGCV treatment is effective in improving moderate and severe hearing dysfunction in infants with congenital CMV infection.
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