Trans-encoded DQ alpha beta heterodimers confer susceptibility to myasthenia gravis disease

Myasthenia gravis (MG) is an autoimmune disease associated with thymic abnormalities (hyperplasia and thymoma). With classical typing method, no clear association was observed between HLA class II and MG disease except in a subgroup of patients with hyperplasia. The aim of our work was to investigate a possible correlation between HLA class II alleles and MG disease using molecular typing which was proved to be much more informative in many diseases. Using polymerase chain reaction and 75 sequence-specific oligonucleotide probes, frequencies of HLA-DRB1, B3, B4, DQA1, DQB1 and DPB1 alleles were identified in 47 Caucasian MG patients and 105 healthy controls. None of the HLA class II alleles identified, was significantly increased in the group of patients compared to controls. However, further analysis of DQA1-DQB1 genotype demonstrated that susceptibility to the disease is associated with two trans DQ alpha beta heterodimers encoded by DQA1*01-DQB1*0201 or DQA1*01-DQB1*0301 combinations (72% in patients vs 29% in controls, RR = 6.2, Pc < 0.001). DQA1*01 group of alleles (DQA1*0101, 0102 or 0103 allele) encode DQ alpha chains sharing long polymorphic sequence including non-charged glycine and positively charged arginine residues at positions 55 and 64, respectively. DQB1*0301 and DQB1*0201 encode a DQ beta chain bearing a negatively charged glutamic acid at position 45 and 46, respectively. A combination of such DQ alpha and DQ beta chains may form susceptibility peptide-binding groove. In MG patients with thymic hyperplasia an additional association with DQA1*0501 in linkage disequilibrium with DQB1*0201 and DQB1*0301 alleles was observed (RR = 17.2, Pc < 0.001). Our data indicate that MG, like other autoimmune diseases, is associated with particular HLA-DQ alpha beta heterodimers, independently of clinical parameters. A role for DQA1*0501 allele in the manifestation of thymic hyperplasia disorders is suggested.