title: Genetic control of autoantibody expression in autoimmune myasthenia gravis: role of the self-antigen and of HLA-linked loci.
abstract: Autoantibodies against the muscle acetylcholine receptor (AChR) play an essential role in the pathophysiology of autoimmune myasthenia gravis (MG). Their serum titers, however, vary considerably among patients. Our aim was to investigate whether their variation might be explained by genetic factors. Using different methods, we have obtained strong evidence for a three-locus association influencing autoantibody titers in MG patients with thymus hyperplasia or with a normal thymus. Two of the loci, one encoding the AChR alpha-subunit, the other encoding the alpha-chain of the class II antigen-presentation molecule, HLA-DQ, demonstrated interaction to determine high autoantibody titers. The third locus was associated with the 8.1 ancestral HLA haplotype. It exerted an additive effect and it is postulated to have a nonantigen specific immunoregulatory function. Our study demonstrates for the first time that polymorphism of an autoantigen gene may quantitatively modify the immune response against it. Altogether, the data lend support to a three-gene model to explain autoantibody expression in a subset of MG patients.
authors.affiliation: INSERM U580, Hôpital Necker, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Giraud
authors.forename: G
authors.initials: G
authors.lastname: Beaurain
authors.forename: B
authors.initials: B
authors.lastname: Eymard
authors.forename: C
authors.initials: C
authors.lastname: Tranchant
authors.forename: P
authors.initials: P
authors.lastname: Gajdos
authors.forename: H-J
authors.initials: HJ
authors.lastname: Garchon
mesh_terms: D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D001324:Autoantigens / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D006683:HLA-DQ Antigens / Q000235:genetics* / Q000276:immunology; D059848:HLA-DQ alpha-Chains; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D009157:Myasthenia Gravis / Q000208:ethnology / Q000235:genetics* / Q000276:immunology; D011110:Polymorphism, Genetic / Q000235:genetics; D011950:Receptors, Cholinergic / Q000235:genetics* / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology; D044465:White People / Q000235:genetics
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D011950:Receptors, Cholinergic