Immunogenetic analysis of the pathogenesis of the seronegative autoimmune disease

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Myasthenia gravis (MG) is a disease characterized by an autoimmune reaction against the acetylcholine receptor (AChR) at the neuromuscular junction. As the childhood-onset MG patients had negative or low titer of the serum AChR antibody, it was useful for the elucidation in the pathogenesis of the seronegative autoimmune diseases to analysis the cause of the childhood-onset myasthenia gravis. We have examined the frequencies of HLA-DRB, DQA and DQB alleles by PCR/SSO method and TCR Vα/β repertories from autologous AChR sensitized T cell line using RT-PCR in the childhood-onset MG patients with the general (G) type. The childhood-onset MG patients with G type were strongly associated with DRB1^*1302 / DQA1^*0102 / DQB1^*0604 allelic haplotype (pc<10^<-20>, R.R.=53.4). In the clinical course of these patients, the cellular immune responses have played the important role for the recurrence or the exacerbation. DQB1^*0604, which was found to be strongly associated with G type MG with childhood-onset, has a hydrophobic residue (valine, V) at position 57 of the DQB1 chain. This amino acid polymorphism of the DQB chain may be associated with insulin dependent diabetes mellitus, which is thought T cell-mediated immunity as the pathogenesis of the development. This data suggest that T cell-mediated immunity may be associated with development of G type MG with the childhood-onset. Therefore, the polymorphic residues in the HLA-DQB chain may contribute to susceptibility to clinically unique latent general (LG) type or G type MG.Furthermore, AChR sensitized CD4+ T cell line from G type MG patient expressed strongly TCRVα1, 2 or 3, and TCRVβ 6.1 or 8 clone. These T cell lines had activated TH1-like phenotype by IL-2 and IFN-γ production. In conclusion, childhood-onset MG patients with LG+G type may differ in the pathogenic mechanisms from those with other types of MG with adult-onset in which the autoantibodies are thought to be pathogenic.