Effects of Cytokines on Acetylcholine Receptor Expression: Implications for Myasthenia Gravis

Abstract

Myasthenia gravis is an autoimmune disease associated with thymic pathologies, including hyperplasia. In this study, we investigated the processes that may lead to thymic overexpression of the triggering Ag, the acetylcholine receptor (AChR). Using microarray technology, we found that IFN-regulated genes are more highly expressed in these pathological thymic tissues compared with age- and sex-matched normal thymus controls. Therefore, we investigated whether proinflammatory cytokines could locally modify AChR expression in myoid and thymic epithelial cells. We found that AChR transcripts are up-regulated by IFN-γ, and even more so by IFN-γ and TNF-α, as assessed by real-time RT-PCR, with the α-AChR subunit being the most sensitive to this regulation. The expression of AChR protein was increased at the cytoplasmic level in thymic epithelial cells and at the membrane in myoid cells. To examine whether IFN-γ could influence AChR expression in vivo, we analyzed AChR transcripts in IFN-γ gene knock-out mice, and found a significant decrease in AChR transcript levels in the thymus but not in the muscle, compared with wild-type mice. However, up-regulation of AChR protein expression was found in the muscles of animals with myasthenic symptoms treated with TNF-α. Altogether, these results indicate that proinflammatory cytokines influence the expression of AChR in vitro and in vivo. Because proinflammatory cytokine activity is evidenced in the thymus of myasthenia gravis patients, it could influence AChR expression and thereby contribute to the initiation of the autoimmune anti-AChR response.

Microarrays Reveal Distinct Gene Signatures in the Thymus of Seropositive and Seronegative Myasthenia Gravis Patients and the Role of CC Chemokine Ligand 21 in Thymic Hyperplasia

“…Consequently, the specific up-regulation of CCL21 in the thymus of MH patients could be involved in ectopic GC formation. It is noteworthy that we previously demonstrated the significantly increased expression of IFN-inducible genes in the thymus of MH patients (16). The increased expression of inflammatory cytokines, such as IFN-␥, could contribute to the initiation of the autoimmune anti-AChR response.…”

“…Total mRNA was reverse transcribed using the SuperScript II RT (Invitrogen Life Technologies) according to the manufacturer's instructions. PCRs were performed on the LightCycler apparatus as previously described (16). For each PCR, a standard curve was calculated using the thymic reference and for each sample, the mean of duplicates was given.…”

Effect of complement and its regulation on myasthenia gravis pathogenesis

“…Cytokines released by T-helper-cell subsets regulate humoral responses and are critical for the activation of AChR-specific T and B cells [81]. Studies of cytokine-deficient mice or treatments with peptides, antibodies and receptor antagonists provide considerable evidence for their role in EAMG pathogenesis.…”

Ectopic GC in the thymus of myasthenia gravis patients show characteristics of normal GC

“…Studies so far have focused on pro-inflammatory cytokines, which were shown to induce increased thymic expression of the auto-Ag AChR and presentation to autoreactive T cells [2]. However, emerging data have renewed interest in the importance of B cells in the pathophysiology of neurological autoimmune disorders, such as MG.…”