Histone modification signature at myeloperoxidase and proteinase 3 in patients with anti-neutrophil cytoplasmic autoantibody-associated vasculitis

Abstract Background Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease characterized by destructive vascular inflammation. Two prominent ANCA autoantigens are myeloperoxidase (MPO) and proteinase 3 (PR3), and transcription of MPO and PRTN3, the genes encoding the autoantigens, is associated with disease activity. We investigated whether patients with AAV have alterations in histone modifications, particularly those associated with transcriptional activation, at MPO and PRTN3. Results We identified a network of genes regulating histone modifications that were differentially expressed in AAV patients compared to healthy controls. We focused on four genes (EHMT1 and EHMT2, ING4, and MSL1) and found their expression correlated with expression of MPO and PRTN3. Methylation of histone H3K9, catalyzed by EHMT1 and EHMT2 and associated with gene silencing, was most depleted at MPO and PRTN3 in patients with active disease and the highest MPO and PRTN3 expression. Acetylation of histone H4K16, modified by complexes containing ING4 and MSL1 and associated with gene activation, was most enriched at MPO and PRTN3 in patients with active disease and the highest MPO and PRTN3 expression. Methylation at H3K4, a mark of transcriptional activation, was enriched at MPO and PRTN3 in patients and healthy controls. Conclusions MPO and PRTN3 in neutrophils of AAV patients with active disease have a distinct pattern of histone modifications, which implicates epigenetic mechanisms in regulating expression of autoantigen genes and suggests that the epigenome may be involved in AAV pathogenesis

Nearer My Subject to Thee : Twenty Years of a Documentary Editor\u27s Engagement with Emma Goldman

I am honored to be speaking today in the city where, in 1908, the editor of the St.Louis Mirror proclaimed that Emma Goldman was the daughter of a dream and that there was nothing wrong with her gospel except that she was 8,000 years ahead of her age. Here, at the twentieth anniversary of the Association for Documentary Editing, the Women\u27s Interest Network breakfast has become a time to bond in the early morning hours with my sister-editors (and brother-editors, too) and to reflect upon our own experience as women, as documentary editors, as people who have devoted many years of our lives to making sure that the life and work of others become an indelible part of the historical record. We are a particular kind of family, often misunderstood by the very people we assume would appreciate our work most-the historians, the archivists, the scholars and students who somehow cannot imagine how we can sustain our interest and work in something that requires such singular devotion. And yet there is much pleasure to our special field

Archival Code-Breaking: The Editor\u27s Dilemma

I became the editor of the Emma Goldman Papers while I was writing Love, Anarchy, and Emma Goldman-a biography in which the first codes broken were those of decorum. There was a kind of steamy delight on that day when I realized that the secret language in her love letters-the m\u27s , the tb , and the w -were not the Yiddish words I imagined them to be, nor the clandestine political messages, but a playful way to dodge the Comstock law against sending obscenity through the mail. Sizzling epistles went back and forth between Emma Goldman and Ben Reitman, a man who was not only her lover and road manager, but also a red light district gynecologist! When the late Sara Jackson-who many of you remember as NHPRC\u27s longtime archivist of government records-began to declassify Goldman\u27s surveillance materials, I entered a very different realm of secret codes. The opportunity to be the conduit for offering a fuller view of Goldman, as she was perceived by those who feared her, felt like a rendezvous with the destiny of history-with a capital H. Boxes of photocopied government reports arrived daily from Washington, D.C., to my Berkeley, California office. These documents confirmed my worst fears about the ineptness of the intelligence gatherers, their widespread presence all throughout the anarchist movement, the ways in which careers were made (like J. Edgar Hoover\u27s rise from the Justice Department to his orchestration of Goldman\u27s deportation, and assumption of the role of first director of the Federal Bureau of Investigation) and broken (like the liberal Assistant Secretary of Labor Louis F. Post\u27s heart-rendering dilemma upon casting Goldman out of America). I was appalled to see the documentary evidence that her constitutional rights were infringed when private communications with her lawyer while she was in jail were intercepted and transcribed by government agents. As I read reports by the woman who had infiltrated Goldman\u27s office, her racial slurs about these anarchist kikes, it made me positively paranoid

Immunoglobulins G from patients with ANCA-associated vasculitis are atypically glycosylated in both the Fc and Fab regions and the relation to disease activity.

BACKGROUND:Anti-neutrophil cytoplasmic autoantibodies (ANCA) directed against myeloperoxidase (MPO) and proteinase 3 (PR3) are pathogenic in ANCA-associated vasculitis (AAV). The respective role of IgG Fc and Fab glycosylation in mediating ANCA pathogenicity is incompletely understood. Herein we investigate in detail the changes in Fc and Fab glycosylation in MPO-ANCA and Pr3-ANCA and examine the association of glycosylation aberrancies with disease activity. METHODOLOGY:Total IgG was isolated from serum or plasma of a cohort of 30 patients with AAV (14 MPO-ANCA; 16 PR3-ANCA), and 19 healthy control subjects. Anti-MPO specific IgG was affinity-purified from plasma of an additional cohort of 18 MPO-ANCA patients undergoing plasmapheresis. We used lectin binding assays, liquid chromatography, and mass spectrometry-based methods to analyze Fc and Fab glycosylation, the degree of sialylation of Fc and Fab fragments and to determine the exact localization of N-glycans on Fc and Fab fragments. PRINCIPAL FINDINGS:IgG1 Fc glycosylation of total IgG was significantly reduced in patients with active AAV compared to controls. Clinical remission was associated with complete glycan normalization for PR3-ANCA patients but not for MPO-ANCA patients. Fc-glycosylation of anti-MPO specific IgG was similar to total IgG purified from plasma. A major fraction of anti-MPO specific IgG harbor extensive glycosylation within the variable domain on the Fab portion. CONCLUSIONS/SIGNIFICANCE:Significant differences exist between MPO and PR3-ANCA regarding the changes in amounts and types of glycans on Fc fragment and the association with disease activity. These differences may contribute to significant clinical difference in the disease course observed between the two diseases

Additional file 4: Table S3. of Histone modification signature at myeloperoxidase and proteinase 3 in patients with anti-neutrophil cytoplasmic autoantibody-associated vasculitis

Characteristics of patients with ANCA disease used for chromatin immunoprecipitation. (PDF 46.2 kb

Additional file 3: Figure S1. of Histone modification signature at myeloperoxidase and proteinase 3 in patients with anti-neutrophil cytoplasmic autoantibody-associated vasculitis

Comparison of therapy in patients during remission on expression of histone modifying genes, EHMT1, EHMT2, ING4, and MSL1. (PDF 93.6 kb