Dysregulation of autoantigen genes in ANCA-associated vasculitis involves alternative transcripts and new protein synthesis.
Proteinase 3 (PR3) and myeloperoxidase (MPO) are two major autoantigens in patients with vasculitis with ANCA. The genes encoding these autoantigens are abnormally expressed in peripheral granulocytes of patients with active ANCA-associated vasculitis. This study provides evidence that this transcri...
| Published in: | Journal of the American Society of Nephrology (JASN) Vol. 26; no. 2; pp. 390 - 400 |
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| Main Authors: | , , , , , , , , , , |
| Format: | research Journal Article |
| Published: |
Lippincott Williams & Wilkins
2015 Feb
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=107770099&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 107770099 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 10466673 1X25 jtl: Journal of the American Society of Nephrology (JASN) issn: 10466673 maglogo: N pubinfo: dt: 2015 Feb vid: 26 iid: 2 pid: 433 pub: Lippincott Williams & Wilkins place: Baltimore, Maryland artinfo: ui: 107770099 107770099 NLM25060059 2012889185 10.1681/ASN.2013101092 NLM25060059 PMC4310652 107770099 ppf: 390 ppct: 10 formats: tig: atl: Dysregulation of autoantigen genes in ANCA-associated vasculitis involves alternative transcripts and new protein synthesis. aug: au: McInnis, Elizabeth A Badhwar, Anshul K Muthigi, Akhil Lardinois, Olivier M Allred, S Colby Yang, Jiajin Free, Meghan E Jennette, J Charles Preston, Gloria A Falk, Ronald J Ciavatta, Dominic J affil: University of North Carolina Kidney Center, Division of Nephrology and Hypertension, Department of Medicine and. sug: subj: Autoimmune Diseases Antigens Proteins RNA Adult Aged Aged, 80 and Over Amino Acids Autoimmune Diseases Metabolism Autoimmune Diseases Physiopathology Antigens Physiology Nucleotides Case Control Studies Cells, Cultured Genes Genes Physiology Female Human Male Middle Age Documentation Peptide Hydrolases Peptide Hydrolases Metabolism Neutrophils Metabolism Neutrophils Pathology Oxidoreductases Oxidoreductases Metabolism Proteins Physiology RNA Physiology Adult: 19-44 years Aged: 65+ years Aged, 80 & over Middle Aged: 45-64 years Female Male ab: Proteinase 3 (PR3) and myeloperoxidase (MPO) are two major autoantigens in patients with vasculitis with ANCA. The genes encoding these autoantigens are abnormally expressed in peripheral granulocytes of patients with active ANCA-associated vasculitis. This study provides evidence that this transcriptional dysregulation results in a variety of mRNA processing events from the PRTN3 gene locus. In addition to elevated levels of PR3 message, leukocyte RNA from patients contained PR3 transcripts with an alternative 3' untranslated region. Furthermore, we detected usage of an alternative transcription start site within intron 1 of the PRTN3 gene locus that coincided with active disease (odds ratio, 3.3; 95% confidence interval, 1.3 to 8.4; P=0.01). This promoter may be developmentally regulated, because it was active in normal human bone marrow, multiple leukemia cell lines, MCF-7 cells, and subjects after GM-CSF treatment but not subjects with a neutrophil left shift. This transcript, which lacks exon 1 of PRTN3, encodes a 24-kD protein (p24(PR3/MBN)) with a sequence similar to that previously described for myeloblastin. Notably, PR3, p24(PR3/MBN), and MPO were synthesized in cultured neutrophils from patients with active ANCA-associated vasculitis, indicating that increased transcription results in newly synthesized autoantigens in peripheral neutrophils of patients. The synthesis of p24(PR3/MBN) seems to expand the autoantigen repertoire, because immunoblots showed that sera from patients recognized p24(PR3/MBN). These findings emphasize the importance of transcriptional dysregulation of the autoantigen in autoimmune disease. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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