title: Identification of CTLA-4 isoforms produced by alternative splicing and their association with myasthenia gravis.
abstract: Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness induced by autoantibodies against the acetylcholine receptor. CTLA-4 (CD152) plays an inhibitory role in the immune response and has been suggested to be involved in the pathophysiology of MG. In this study, we focused on alternative CTLA-4 mRNA expression in PBMCs from MG patients. We defined two new isoforms of CTLA-4 mRNA that arise due to alternative splicing. By semi-quantitative RT-PCR analysis, we observed a lower expression of sCTLA-4 mRNA relative to the membrane form in MG patients. In addition, the MG patients had lower levels of sCTLA-4 mRNA in PBMCs compared to healthy controls, as assessed by real-time PCR. One of the spliced isoforms (LCTLA-4) was more prevalent in MG patients compared to healthy controls. The alternative splicing was not associated with sex, thymectomy, serum levels of anti-AChR, immunosuppressive treatment or the four CTLA-4 gene polymorphisms analyzed. This study reveals an abnormal spectrum of mRNA expression of CTLA-4 in MG patients, which marks the importance of studying gene expression of alternative splicing.
authors.affiliation: Department of Medicine, Rheumatological Research Unit, CMM, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ming
authors.initials: M
authors.lastname: Gu
authors.forename: Maria
authors.initials: M
authors.lastname: Kakoulidou
authors.forename: Ricardo
authors.initials: R
authors.lastname: Giscombe
authors.forename: Ritva
authors.initials: R
authors.lastname: Pirskanen
authors.forename: Ann Kari
authors.initials: AK
authors.lastname: Lefvert
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: XiongBiao
authors.initials: X
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D015703:Antigens, CD / Q000097:blood / Q000235:genetics*; D060908:CTLA-4 Antigen; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D020033:Protein Isoforms; D012333:RNA, Messenger