Myasthenia Gravis: An Acquired Interferonopathy?

Abstract

Myasthenia gravis (MG) is a rare autoimmune disease mediated by antibodies against components of the neuromuscular junction, particularly the acetylcholine receptor (AChR). The thymus plays a primary role in AChR-MG patients. In early-onset AChR-MG and thymoma-associated MG, an interferon type I (IFN-I) signature is clearly detected in the thymus. The origin of this chronic IFN-I expression in the thymus is not yet defined. IFN-I subtypes are normally produced in response to viral infection. However, genetic diseases called interferonopathies are associated with an aberrant chronic production of IFN-I defined as sterile inflammation. Some systemic autoimmune diseases also share common features with interferonopathies. This review aims to analyze the pathogenic role of IFN-I in these diseases as compared to AChR-MG in order to determine if AChR-MG could be an acquired interferonopathy.

Keywords: adaptive immunity; autoimmunity; germinal center; innate immunity; interferon type I; myasthenia gravis; pathogen infection; sterile inflammation; thymoma; thymus.

Figure 1

Mechanisms of IFN-I induction. IFN-I expression can be induced by diverse molecules from pathogens (bacteria or virus) or apoptotic host cells, PAMP and DAMP, respectively. These PAMP/DAMP are mostly nucleic acids (DNA and RNA) and are recognized by different cytosolic or membrane surface sensors. Their stimulation activates intracellular signaling cascades leading to the transcription of IFN-I subtypes. Once released, IFN-I subtypes interact with their receptor IFNAR1/2 that is ubiquitously expressed. Its stimulation induces the activation of TYK2 and JAK1, leading to the phosphorylation and heterodimerization of STAT1 and STAT2 that interact with interferon regulatory factor (IRF) 9. This complex, also known as IFN-stimulated gene factor 3 (ISGF3), then translocates into the nucleus and binds the IFN-I stimulated response element (ISRE) to regulate transcription of over 300 ISG. In interferonopathies such as AGS, genes involved in the metabolism of nucleic acids are mutated. This leads to the accumulation of endogenous nucleic acids and the abnormal stimulation of sensors triggering IFN-I expression and leading to the initiation and perpetuation of chronic inflammation.

Figure 2

Implication of IFN-β in thymic changes associated with EOMG. IFN-β induces the expression of ⍺-AChR by TEC but tends also to induce TEC death. This could lead to the capture of TEC proteins, including the ⍺-AChR, by DC favoring an initial cross-presentation and autoreactivity toward ⍺-AChR. In parallel, IFN-β induces the expression of CXCL13 and CCL21, chemokines leading to the recruitment of peripheral B cells, and ectopic germinal center development. Germinal centers allow the maturation of autoreactive AChR B cells and their survival might be favored by BAFF that is overexpressed by TEC in response to IFN-β. Next, thymic myoid cells presenting AChR at their surface could be the first target of anti-AChR antibodies exacerbating the autoimmune reaction. IFN-β also induces pro-inflammatory cytokines such as IL-23 favoring the differentiation of naive T cells into pro-inflammatory Th17 cells that produce IL-17. Altogether, this demonstrates that IFN-β is a key orchestrator of thymic changes in EOMG.