Association of the AChRα-subunit Gene (CHRNA), DQA1*0101, and the DR3 Haplotype in Myasthenia Gravis. Evidence for a Three-gene Disease Model in a Subgroup of Patients

Pleiotropic effects of the 8.1 HLA haplotype in patients with autoimmune myasthenia gravis and thymus hyperplasia

“…Although the class II loci on the 8.1 haplotype showed no proper association, we have previously shown that a different class II gene allele, DQA1*0101, not associated with the 8.1 haplotype, is associated with MG and interacts with a polymorphism of CHRNA1, one of the AChR-encoding genes (39,40). Therefore, class II loci do contribute to MG predisposition as they do in many autoimmune diseases (41).…”

Epistasis between DSG1 and HLA class II genes in pemphigus foliaceus

“…This observation of epistatic interaction is reminiscent of results obtained in two other organ-specific autoimmune diseases, in which the interactive effect of two different loci was demonstrated: IDDM with the insulin gene and the HLA region, 24 and myasthenia gravis with CHRNA and two different HLA loci. 3,4 How HLA class II genes and the C/C(809) genotype interact to mediate PF susceptibility might be explained by the fact that MHC class II molecules and autoantigens intervene in the biological pathway leading to the autoimmune processes and tolerance breakage of autoreactive lymphocytes, since MHC gene products present antigens to immune T cells. 25 The C/T polymorphism at position 809 is a silent mutation and therefore, does not directly modify a putative T-cell epitope on the corresponding region of DSG1.…”

“…3 Furthermore, in this organ-specific autoimmune disease, a three-gene model involving HLA class II DQA*0101, DRB*03 genes and CHRNA has been proposed that supports the concept of epistasis. 4 Pemphigus is a group of rare and severe cutaneous organ-specific autoimmune diseases, characterized by the production of autoantibodies directed against desmosomal adhesion molecules expressed by keratinocytes 5 and responsible for the formation of intraepidermal blisters. In the sporadic form of pemphigus foliaceus (PF) and fogo selvagem, its endemic form observed in certain areas of Brazil, pathogenic autoantibodies bind to desmoglein 1 (DSG1), [6][7][8][9][10][11][12] a glycoprotein that mediates cell adhesion in the superficial layers of the epidermis.…”

Genetic control of autoantibody expression in autoimmune myasthenia gravis: role of the self-antigen and of HLA-linked loci

“…19 Remarkably, a synergistic association was also characterized between HB*14 and two HLA-linked gene alleles. 20 One was the class II DQA1*0101 allele while the other was in linkage disequilibrium with the 8.1 ancestral haplotype. To explain this pattern of association, we had proposed a three-locus working model.…”

“…To explain this pattern of association, we had proposed a three-locus working model. 20 In this model, an epitope of the AChR a-subunit would be presented to T lymphocytes or to their thymic precursors by an HLA-DQ molecule, whose a-chain is encoded by DQA1*0101. This presentation would perturb T-cell tolerization, leading to the emergence of auto-reactive lymphocytes.…”