Genetic control of myasthenia gravis : a study on cytokine and co-stimulator genes and their related functions

Abstract: Myasthenia gravis (MG) is a classical autoimmune disease characterised by muscle weakness due to an immune attack against the nicotinic acetylcholine receptor (AchR) on the postsynaptic membrane of the neuromuscular junction. The aim of the study was to identify the role of the genes encoding potential immune components, such as TNF, IL- 1, IL- I receptor antagonist, IL-4, IL- 10, and cytotoxic T lymphocyte antigen 4 (CTLA-4) in the pathogenesis of MG. The revealed positive association of IL- I [beta] TaqI restriction fragment length polymorphism allele 2 carriage in MG was more pronounced in patients without HLA-B8 and of noncarriers of IL-Ra allele 2, demonstrating a new genetic marker in MG, which exerts its maximum effect in patients with the lowest MHC associated susceptibility. A possible pathogenetic role of IL-1[beta] and intrinsic dysregulation of IL-1 in MG was also suggested. IL- I[beta]-/- mice were found to be resistant to the genesis of clinical experimental autoimmune MG. Compared with wild type mice, the T cell proliferation and the secretions of both Th 1 (IFN-[gamma] and IL-2) and Th2 (IL-4) from draining lymphnode cells upon torpedo AchR rechallenge in vitro were significantly lower in IL-1[beta]-/- mice, which had lower levels of antibodies to AchR in the circulations. This indicates a key role for IL- I in the pathogenesis of both human MG and experimental autoimmune MG. The TNF-[alpha] -308 allele 2, which is in strong association with HLA-B8 due to linkage disequilibrium, was associated with female patients having disease onset before the age 40 and with thymic hyperplasia. PBMC from patients positive for this allele had higher secretion of TNF-[alpha] when stimulated by anti-CD3 antibodies in vitro, indicating a subgroup of MG patients may have high inducible secretion of TNF-[alpha] in vivo, thus resulting the pathological changes in the thymus and the early onset of MG. There were no associations between the polymorphisms in the IL-4 gene and MG. This lack of association between a prototype Th2 cytokine (IL-4) gene and the autoantibodymediated disease contrasts to the results above. The prevalence of a "high secretor" phenotype of IL-10 (IL-10 I G/G) was higher in individuals with "high secretor" phenotype for IL- I[beta] in healthy controls. No such balance was found in MG patients. Microsatellite IL10.R allele 112 was associated with patients having normal thymus, while microsatellite ILIO.G allele 134 with patients having high levels of serum antibodies to AchR, indicating different mechanisms for IL- 10. IL10 may thus act as the ancient Roman god Janus in the disease. CTLA-4 plays a pivotal role in downregulating both cellular and humoral response by suppressing ongoing responses of activated T cells. Alleles with longer PCR products in an (AT)n polymorphism in Ctla-4 are positively associated to the disease with thymoma. Data in the functional studies point to the (AT)n in Ctla-4 as a disease facilitating mutation under certain permissive environments by enhancing the T cell reactivity via CD28 pathway.