Summary Canonically, IgE mediates allergic immune responses by triggering mast cells and basophils to release histamine and Type 2 helper cytokines. Here, we report that in human systemic lupus erythematosus, IgE antibodies specific for double-stranded DNA activate plasmacytoid dendritic cells (pDCs), an immune cell type linked to viral defense, leading to the secretion of substantial amounts of interferon-α. The concentrations of dsDNA-specific IgE found in patient serum correlated with disease severity and greatly potentiated pDC functions by triggering phagocytosis via FcεRI followed by Toll-like receptor 9-mediated DNA sensing in phagosomes. These findings expand the known pathogenic mechanisms of IgE-mediated inflammation beyond those found in allergy and demonstrate that IgE can trigger interferon responses capable of exacerbating self-destructive autoimmune responses.

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BackgroundBacterial vaginosis (BV) is the most common vaginal disorder of reproductive-age women. Yet the cause of BV has not been established. To uncover key determinants of BV, we employed a multi-omic, systems-biology approach, including both deep 16S rRNA gene-based sequencing and metabolomics of lavage samples from 36 women. These women varied demographically, behaviorally, and in terms of health status and symptoms.Principal Findings16S rRNA gene-based community composition profiles reflected Nugent scores, but not Amsel criteria. In contrast, metabolomic profiles were markedly more concordant with Amsel criteria. Metabolomic profiles revealed two distinct symptomatic BV types (SBVI and SBVII) with similar characteristics that indicated disruption of epithelial integrity, but each type was correlated to the presence of different microbial taxa and metabolites, as well as to different host behaviors. The characteristic odor associated with BV was linked to increases in putrescine and cadaverine, which were both linked to Dialister spp. Additional correlations were seen with the presence of discharge, 2-methyl-2-hydroxybutanoic acid, and Mobiluncus spp., and with pain, diethylene glycol and Gardnerella spp.ConclusionsThe results not only provide useful diagnostic biomarkers, but also may ultimately provide much needed insight into the determinants of BV.

Our study indicates that anti-HLA class I antibodies play an important role in the pathogenesis of BOS and that monitoring of anti-HLA class I antibody development by a highly sensitive assay such as the PRA-STAT ELISA after LT can provide an early identification of an important subset of LT patients with an increased risk of developing BOS.

The immunological role of exosomes in allograft rejection remains unknown. We sought to determine whether exosomes are induced during lung allograft rejection and to define the antigenic compositions of human leukocyte antigen (HLA), lung associated self-antigens (SAgs), and microRNAs (miRNAs). Exosomes were isolated from sera and bronchoalveolar lavage fluid from 30 lung transplant recipients (LTxR) who were stable or had acute rejection (AR) or bronchiolitis obliterans syndrome (BOS). Exosomes were defined by flow cytometry for CD63 and Western blotting for Annexin V. SAgs, Collagen-V (Col-V), and Kα1 Tubulin were examined by electron microscopy; miRNAs were profiled by Affymetrix miRNA array. Donor HLA and SAgs were detected on exosomes from LTxRs with AR and BOS, but not from stable LTxRs. Exosomes expressing Col-V were isolated from LTxR sera 3 months before AR and 6 months before BOS diagnosis, suggesting that exosomes with SAgs may be a noninvasive rejection biomarker. Exosomes isolated from LTxRs with AR or BOS also contained immunoregulatory miRNAs. We conclude that exosomes expressing donor HLA, SAgs, and immunoregulatory miRNAs are present in the circulation and local site after human lung transplantation, playing an important role in the immune-pathogenesis of acute allograft rejection and BOS.

These data suggest that BOS is the result of an immune process, that differences at the HLA-A locus may play an important role in this process, and antibody-mediated injury may play a role in BOS.

This multicenter retrospective review of short-term outcomes supports the fact that the lung allocation score is achieving its objectives. The lung allocation score reduced waiting time and altered the distribution of lung diseases for which transplantation was done on the basis of medical necessity. After transplantation, recipients have significantly higher rates of primary graft dysfunction and intensive care unit lengths of stay. However, hospital mortality and 1-year survival have not been adversely affected.

These data suggest that bronchiolitis obliterans syndrome is the result of an immune-mediated process in which HLA antibodies and cytomegalovirus may play a significant role.