T-Cell Imbalance and Inflammatory Cytokines as Potential Drug Targets for the Treatment of Myasthenia Gravis
Alec J Monhollen
Background: Myasthenia gravis is an autoimmune disorder against post-synaptic proteins in the neuromuscular junction, including the acetylcholine receptor and muscle-specific kinase.1,2 Symptoms can include general muscle weakness, ptosis, diplopia, and dysarthria.1,3 The current standard treatments are acetylcholinesterase inhibitors which function to increase the amount of acetylcholine in the neuromuscular junction.1 IL-17 and Th17 T-cells have been implicated in the pathogenesis of many autoimmune diseases, including myasthenia gravis. Regulatory T-cells inhibit the proliferation of CD4+ T-cells; therefore, they act as immunoregulators and act to prevent development of autoimmune diseases. Recent studies have shown an increase in Th17 and decrease in Treg T-cells, as well as their respective transcription factors, in patients with myasthenia gravis.4 The mechanisms that cause this T-cell imbalance could reveal new paths for treatment or prevention of myasthenia gravis.
Objective: My goal in this investigation was to review the mechanisms that alter T-cell balance in the pathogenesis of myasthenia gravis, as well as treatments that restore it.
Search Method: An online PubMed search was conducted using the MeSH search terms “myasthenia gravis,” “immunology,” and “physiopathology.” Results were restricted to the years 2018-2023.
Results: Thymic biopsies and peripheral blood samples demonstrated a significant decrease in Treg and increase in Th17 in patients with both ocular and general myasthenia gravis. The levels of the transcription factors responsible for maturation into Treg and Th17 T-cells (FOXP3 and RORγt, respectively) were also altered in myasthenia gravis patients.4 XLOC_003810 is a long non-coding RNA (lncRNA) that is able to influence the balance of Th17 and Treg T-cells. It was shown that patients with myasthenia gravis had an increased level of XLOC_003810 in their thymus. Additionally, when XLOC_003810 was introduced into cultures of CD4+ T-cells derived from myasthenia gravis patients, it aggravated the T-cell imbalance.5 Furthermore, effector memory (CD95) T-cells can lead to the upregulation of Th17 T-cells. The study found that the expression level of CD95 correlates with the symptom severity and IL17 production level in these patients. The link between CD95 stimulation level and IL17 production is found in Th17 T-cells.6 Tacrolimus inhibits calcineurin in the IL-2 transcription pathway and decreases serum levels of Il-2. Tacrolimus has been shown to be effective in myasthenia gravis that is refractory to other treatments by modulating cytokine release. Tacrolimus was able to improve clinical scores and quality of life in the patients in the experimental group. Additionally, helper t cells were decreased and regulatory t cells increased over the 12 month treatment phase.7
Conclusion: There is significant evidence that shows T-cell imbalance plays a role in the pathogenesis of myasthenia gravis.4 The common component in the pathways that influence T-cell balance are inflammatory cytokines that influence the balance of T-cells. By modulating the cytokine response in the myasthenia gravis disease state, it may be possible to halt or reverse the progression of the disease. Therapies that can restore T-cell balance without broadly suppressing the immune system should further be investigated.
- Gilhus NE, Tzartos S, Evoli A, Palace J, Burns TM, Verschuuren JJGM. Myasthenia gravis. Nat Rev Dis Primers. 2019;5(1):30. Published 2019 May 2. doi:10.1038/s41572-019-0079-y
- Uzawa A, Kuwabara S, Suzuki S, et al. Roles of cytokines and T cells in the pathogenesis of myasthenia gravis. Clin Exp Immunol. 2021;203(3):366-374. doi:10.1111/cei.13546
- Dresser L, Wlodarski R, Rezania K, Soliven B. Myasthenia Gravis: Epidemiology, Pathophysiology and Clinical Manifestations. J Clin Med. 2021;10(11):2235. Published 2021 May 21. doi:10.3390/jcm10112235
- Chen Y, Zhang XS, Wang YG, Lu C, Li J, Zhang P. Imbalance of Th17 and Tregs in thymoma may be a pathological mechanism of myasthenia gravis. Mol Immunol. 2021;133:67-76. doi:10.1016/j.molimm.2021.02.011
- Niu L, Jiang J, Yin Y, Hu B. LncRNA XLOC_003810 modulates thymic Th17/Treg balance in myasthenia gravis with thymoma. Clin Exp Pharmacol Physiol. 2020;47(6):989-996. doi:10.1111/1440-1681.13280
- Huang X, Zhu J, Liu T, et al. Increased Expression of CD95 in CD4+ Effector Memory T Cells Promotes Th17 Response in Patients with Myasthenia Gravis. J Neuroimmune Pharmacol. 2022;17(3-4):437-452. doi:10.1007/s11481-021-10030-7
- Wu H, Wang Z, Xi J, et al. Therapeutic and Immunoregulatory Effects of Tacrolimus in Patients with Refractory Generalized Myasthenia Gravis. Eur Neurol. 2020;83(5):500-507. doi:10.1159/000510396