Autoimmune diseases involving the nervous system include conditions affecting both the
central nervous system (CNS)-such as neuromyelitis optica spectrum disorder (NMOSD) and
autoimmune encephalitis-and the peripheral nervous system, as exemplified by myasthenia
gravis (MG), which targets the neuromuscular junction. Although these disorders present
with distinct clinical features, they share a common immunopathogenic hallmark: the
presence of pathogenic autoantibodies directed against neural or neuromuscular antigens.
While the mechanisms underlying the production of these autoantibodies remain only
partially understood, increasing evidence points to defects in immune tolerance as key
contributors to disease onset. In MG, in particular, the thymus is directly implicated in
the disease process, with thymic follicular hyperplasia observed in early-onset forms and
thymoma present in a significant subset of patients. Notably, reduced expression of the
autoimmune regulator gene (AIRE) has been demonstrated in thymomas associated with MG,
suggesting a failure of central immune tolerance in the pathogenesis of this condition.
Additionally, other autoimmune diseases of the CNS, such as neuromyelitis optica (NMOSD)
and autoimmune encephalitis, have been associated with the contribution of peripheral
tolerance in promoting the onset and maintenance of autoimmunity.
However, several studies suggest that the thymic escape of autoreactive T cells is an
important pathophysiological mechanism in CNS autoimmune diseases mediated by
autoantibodies. In animal models, thymic negative selection is a critical factor in
determining susceptibility and severity of CNS inflammation. There is also indirect
clinical data suggesting that thymic function is important in human CNS autoimmune
diseases. In particular, the association between thymoma and paraneoplastic
encephalitis-such as in the case of encephalitis associated with voltage-gated potassium
channel (VGKC) complex antibodies (CASPR2 and LGI1)-highlights the involvement of thymic
tolerance in these diseases.
Thymic central tolerance is orchestrated by thymic epithelial cells (TECs), the most
abundant stromal cells, located in the cortical (cTEC) and medullary (mTEC) regions.
As known, HLA plays a crucial role in the selection of T-cells within the thymus. In the
initial phase, only those T-cells whose TCRs bind to HLA molecules expressed by
epithelial cells in the thymic cortex are positively selected, while the others undergo
apoptosis. Immature thymocytes co-express both CD4 and CD8, but if their TCR
preferentially recognizes class I HLA, they downregulate CD4 and upregulate CD8;
conversely, if they recognize class II HLA, the opposite occurs.
The T-cells then migrate to the thymic medulla, where a broad array of self-peptides
bound to HLA I and II are presented. At this stage, thymocytes that form high-affinity
interactions with these self-peptides are eliminated, a process that helps suppress
autoimmunity and foster self-tolerance. Several mechanisms have been proposed that link
HLA to disease, often involving the failure of thymic negative selection due to
disturbances in the TCR-peptide-HLA interaction.
The ectopic expression of thousands of genes, including tissue-specific antigens (TRA) by
mTECs, is crucial for eliminating T cells that bind to these antigens. The recognition of
autoantigens in the thymus is facilitated by multigenic transcription factors, such as
AIRE (autoimmune regulator), expressed in the thymic medulla. AIRE plays a crucial role
in inducing the expression of peripheral antigens in the thymus, enabling the elimination
of autoreactive T cells through negative selection.
The congenital loss of AIRE function leads to autoimmune polyglandular syndrome type 1
(APS1). This condition is characterized by a combination of Addison's disease,
hypoparathyroidism, chronic mucocutaneous candidiasis, and several other autoimmune
diseases caused by the presentation of a limited repertoire of autoantigens by mTECs,
compromising the removal of autoreactive T cells. The manifestations of APS1 underscore
the crucial role of AIRE in the presentation of autoantigens in the thymus and in
building thymic tolerance.
Despite the central role of the AIRE gene in mediating thymic tolerance, its contribution
to the pathogenesis of autoimmune neurological diseases remains largely unexplored. While
previous research has focused on peripheral tolerance mechanisms, few studies have
investigated how AIRE dysfunction might affect the presentation of key neural
autoantigens-such as AQP4, AChR, LGI1, and CASPR2-within medullary thymic epithelial
cells (mTECs).
Notably, no systematic screening for pathogenic antibodies has been conducted in patients
with AIRE mutations, and the role of AIRE gene variants in patients with NMOSD,
myasthenia gravis, or autoimmune encephalitis remains undefined.
Another important factor contributing to susceptibility to autoimmune diseases is HLA
typing. Several studies have demonstrated that specific HLA haplotypes are associated
with an increased risk of developing autoimmune neurological diseases. In particular,
NMOSD has been associated with the HLA-DRB1*03:01 haplotype, which seems to be a
significant risk factor in anti-AQP4 positive patients (Zéphir et al., 2009). Similarly,
myasthenia gravis is strongly correlated with HLA-DR3, especially in patients with
early-onset disease (Berrih-Aknin, 2017). Moreover, autoimmune encephalitis associated
with autoantibodies against LGI1 and CASPR2 shows a significant association with
HLA-DRB1*07:01, suggesting a crucial role for HLA in antigen presentation and the
development of neurological autoimmunity (Kim et al., 2017; van Sonderen et al., 2017).
The aim of this study is to explore the role of the AIRE gene in the pathogenesis of
autoimmune neurological diseases and investigate how specific HLA haplotypes may
predispose individuals to develop these conditions.
Our hypothesis is that alterations in AIRE expression and dysfunctions in central
tolerance may contribute to the development of neurological autoimmunity, especially in
individuals with certain high-risk HLA haplotypes.
