Myasthenia gravis is a chronic, organ-specific autoimmune disease caused by autoantibodies directed against proteins of the neuromuscular junction, most often the acetylcholine receptor. In these patients, the thymus acts as an effector tissue of the disease: it frequently displays abnormalities, such as follicular hyperplasia, and harbors ectopic germinal centers that sustain the local production of autoantibodies. Understanding the mechanisms that maintain this thymic inflammation therefore represents a major therapeutic challenge. The IL-23/Th17 pathway, already identified as a driver of inflammation in several autoimmune diseases and targeted in various therapeutic approaches, was investigated in this study with respect to the inflammatory and pathogenic events of the myasthenic thymus.
To explore this pathway, the researchers combined several approaches on thymuses from patients with anti-acetylcholine receptor antibody myasthenia gravis and on control thymuses: messenger RNA expression analysis by quantitative PCR, protein quantification by ELISA, immunohistochemistry to localize the relevant actors within thymic sections, flow cytometry, and primary cultures of thymic epithelial cells. Co-cultures of these epithelial cells with peripheral blood mononuclear cells were also used to study the cellular interactions involved.
The patients' thymuses showed overexpression of interleukin-17, a cytokine characteristic of activated Th17 lymphocytes. This activation was supported by increased secretion of interleukin-23 by thymic epithelial cells, together with enhanced expression of the cytokines involved in the development of Th17 cells. The authors establish that this interleukin-23 overexpression resulted from a dysregulation of the type I interferon pathway. The secreted interleukin-17 and the Th17 cells were localized around the ectopic germinal centers, these cells expressing podoplanin, a protein involved in B lymphocyte maturation and antibody secretion. The co-culture experiments showed that patient thymic epithelial cells stimulated interleukin-17 production by blood cells, while interleukin-17 in turn promoted interleukin-23 production.
These observations highlight a chronic inflammatory loop maintained by interactions between thymic cells, in which interleukin-23 and interleukin-17 mutually stimulate each other. This activation of the IL-23/Th17 pathway in the thymus could contribute to the maintenance of ectopic germinal centers and, consequently, to the local production of autoantibodies. The authors therefore propose that this pathway be considered a new therapeutic target to attenuate the pathophysiological events in patients with myasthenia gravis.