title: Proinsulin is encoded by an RNA splice variant in human blood myeloid cells.
abstract: Genes for peripheral tissue-restricted self-antigens are expressed in thymic and hematopoietic cells. In thymic medullary epithelial cells, self-antigen expression imposes selection on developing autoreactive T cells and regulates susceptibility to autoimmune disease in mouse models. Less is known about the role of self-antigen expression by hematopoietic cells. Here we demonstrate that one of the endocrine self-antigens expressed by human blood myeloid cells, proinsulin, is encoded by an RNA splice variant. The surface expression of immunoreactive proinsulin was significantly decreased after transfection of monocytes with small interfering RNA to proinsulin. Furthermore, analogous to proinsulin transcripts in the thymus, the abundance of the proinsulin RNA splice variant in blood cells corresponded with the length of the variable number of tandem repeats 5' of the proinsulin gene, known to be associated with type 1 diabetes susceptibility. Self-antigen expression by peripheral myeloid cells extends the umbrella of "immunological self" and, by analogy with the thymus, may be implicated in peripheral immune tolerance.
authors.affiliation: Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
authors.forename: Parth
authors.initials: P
authors.lastname: Narendran
authors.forename: Alana M
authors.initials: AM
authors.lastname: Neale
authors.forename: Bo Han
authors.initials: BH
authors.lastname: Lee
authors.forename: Katrina
authors.initials: K
authors.lastname: Ngui
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Steptoe
authors.forename: Grant
authors.initials: G
authors.lastname: Morahan
authors.forename: Ole
authors.initials: O
authors.lastname: Madsen
authors.forename: James A
authors.initials: JA
authors.lastname: Dromey
authors.forename: Kent P
authors.initials: KP
authors.lastname: Jensen
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Harrison
mesh_terms: D001324:Autoantigens / Q000378:metabolism; D001773:Blood Cells / Q000378:metabolism*; D019070:Cell Lineage; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D011384:Proinsulin / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D001324:Autoantigens; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011384:Proinsulin