Increased expression of Toll-like receptors 7 and 9 in myasthenia gravis thymus characterized by active Epstein–Barr virus infection

Acute Thymic Involution and Mechanisms for Recovery

“…Immunological changes are usually linked to TLRmediated immune activation. For example, TLR4 signaling plays a key role in immune cell recruitment in the MG thymus (Cordiglieri et al 2014), and TLR7 and TLR9 are also involved in the pathogenesis of the MG thymus (Cavalcante et al 2016). TLR4 is constitutively expressed on TECs (Huang et al 2014), and the expression of TLR4 was enhanced on the TECs of the involuted thymuses of myasthenic patients (Bernasconi et al 2005).…”

“…However, during certain pathological situations, such as myasthenia gravis (MG), the thymus undergoes histological alterations such as thymic follicular hyperplasia (Andersen et al 2016;Jordan et al 2016), whereas the immunological changes are usually linked to Toll-like receptor (TLR)-mediated immune activation. For example, TLR4 signaling plays a key role in immune cell recruitment in the MG thymus (Cordiglieri et al 2014), and TLR7 and TLR9 are also involved in the pathological effects on the thymus in MG (Cavalcante et al 2016). During age-related atrophy, thymic function is mainly affected by changes in the histological structure of the organ including expansion of the perivascular spaces and an increase in the adipose tissue.…”

Autoimmune Thyroiditis and Myasthenia Gravis

“…In myasthenic patients, the existence of a chronic inflammatory state in the thymus could alter innate immune responses leading to self-tolerance failure (36–39). The inflammatory state could be due to persistent viral replications, in fact, Epstein Barr virus (EBV), cytomegalovirus, human foamy virus, and Nile virus were found to be associated to MG (40, 41). Pathogen infections could play a role in AIDs through dysregulation of toll-like receptor-mediated innate immune responses, which can result in altered innate immune responses and long-term inflammation, rendering the thymus vulnerable to auto-sensitization (40, 41).…”

“…The inflammatory state could be due to persistent viral replications, in fact, Epstein Barr virus (EBV), cytomegalovirus, human foamy virus, and Nile virus were found to be associated to MG (40, 41). Pathogen infections could play a role in AIDs through dysregulation of toll-like receptor-mediated innate immune responses, which can result in altered innate immune responses and long-term inflammation, rendering the thymus vulnerable to auto-sensitization (40, 41). EBV is one of the main candidates suspected to play a role in MG initiation, since it is able to promote B-cell abnormal activation and survival, and to disrupt critical B-cell tolerance checkpoints (40, 42–44).…”

Toll‐like receptors 7 and 9 in myasthenia gravis thymus: amplifiers of autoimmunity?

“…They are key elements contributing to “autoimmune tautology”, implicated in a number of processes commonly observed in target organs of autoimmunity, including inflammation, type‐I interferon (IFN‐I)–mediated antiviral response, abnormal immune system activation, B cell dysfunction, lymphoid neogenesis, and germinal center (GC) response . Indeed, a wealth of data from patients and animal models indicate the involvement of TLRs, mainly TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9, in different autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), and myasthenia gravis (MG), as summarized in Table . Considering the role of TLRs as a critical link between innate and adaptive immunity, we posit that the most plausible hypothesis to explain the TLR contribution to autoimmune conditions is that aberrant expression or persistent triggering of these receptors by exogenous or endogenous ligands may lead to self‐sustained inflammation; uncontrolled cytokine, chemokine, and IFN‐I production; and abnormal maturation of antigen‐presenting cells, which in turn cause priming of adaptive immune/autoimmune cells, ultimately leading to autosensitization and chronic autoimmunity in a genetic predisposing background …”